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Trastuzumab Deruxtecan in HER2-Positive Breast Cancer

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Trastuzumab Deruxtecan in HER2-Positive Breast Cancer

Study 1 Overview (Cortés et al)

Objective: To compare the efficacy and safety of trastuzumab deruxtecan with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxane.

Design: Phase 3, multicenter, open-label randomized trial conducted at 169 centers and 15 countries.

Setting and participants: Eligible patients had to have unresectable or metastatic HER2-positive breast cancer that had progressed during or after treatment with trastuzumab and a taxane or had disease that progressed within 6 months after neoadjuvant or adjuvant treatment involving trastuzumab or taxane. Patients with stable or previously treated brain metastases were eligible. Patients were not eligible for the study if they had symptomatic brain metastases, prior exposure to trastuzumab emtansine, or a history of interstitial lung disease.

Intervention: Patients were randomized in a 1-to-1 fashion to receive either trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or trastuzumab emtansine 3.6 mg/kg every 3 weeks. Patients were stratified according to hormone-receptor status, prior treatment with epratuzumab, and the presence or absence of visceral disease.

Main outcome measures: The primary endpoint of the study was progression-free survival as determined by an independent central review. Secondary endpoints included overall survival, overall response, and safety.

Main results: A total of 524 patients were enrolled in the study, with 261 patients randomized to trastuzumab deruxtecan and 263 patients randomized to trastuzumab emtansine. The demographic and baseline characteristics were similar between the 2 cohorts, and 60% of patients in both groups received prior epratuzumab therapy. Stable brain metastases were present in around 20% of patients in each group, and 70% of patients in each group had visceral disease. The median duration of follow-up was 16.2 months with trastuzumab deruxtecan and 15.3 months with trastuzumab emtansine.

The median progression-free survival was not reached in the trastuzumab deruxtecan group and was 6.8 months in the trastuzumab emtansine group (95% CI, 5.6-8.2). At 12 months the percentage of patients alive without disease progression was significantly larger in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group. The hazard ratio for disease progression or death from any cause was 0.28 (95% CI, 0.22-0.37; P < .001). Subgroup analyses showed a benefit in progression-free survival with trastuzumab deruxtecan across all subgroups.

At the time of this analysis, the percentage of patients who were alive at 12 months was 94% with trastuzumab deruxtecan and 85.9% with trastuzumab emtansine. The response rates were significantly higher with trastuzumab deruxtecan compared with trastuzumab emtansine (79.7% vs 34.2%). A complete response was seen in 16% of patients in the trastuzumab deruxtecan arm, compared with 8.7% of patients in the trastuzumab emtansine group. The disease control rate (complete response, partial response, or stable disease) was higher in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group (96.6% vs 76.8%).

Serious adverse events were reported in 19% of patients in the trastuzumab deruxtecan group and 18% of patients in the trastuzumab emtansine group. Discontinuation due to adverse events was higher in the trastuzumab deruxtecan group, with 13.6% of patients discontinuing trastuzumab deruxtecan. Grade 3 or higher adverse events were seen in 52% of patients treated with trastuzumab deruxtecan and 48% of patients treated with trastuzumab emtansine. The most commonly reported adverse event with trastuzumab deruxtecan was nausea/vomiting and fatigue. These adverse events were seen more in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group. No drug-related grade 5 adverse events were reported.

In the trastuzumab deruxtecan group, 10.5% of patients receiving trastuzumab deruxtecan developed interstitial lung disease or pneumonitis. Seven patients had grade 1 events, 18 patients had grade 2 events, and 2 patients had grade 3 events. No grade 4 or 5 events were noted in either treatment group. The median time to onset of interstitial lung disease or pneumonitis in those receiving trastuzumab deruxtecan was 168 days (range, 33-507). Discontinuation of therapy due to interstitial lung disease or pneumonitis occurred in 8% of patients receiving trastuzumab deruxtecan and 1% of patients receiving trastuzumab emtansine.

Conclusion: Trastuzumab deruxtecan significantly decreases the risk of disease progression or death compared to trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on prior trastuzumab and taxane-based therapy.

 

 

Study 2 Overview (Modi et al)

Objective: To assess the efficacy of trastuzumab deruxtecan in patients with unresectable or metastatic breast cancer with low levels of HER2 expression.

Design: This was a randomized, 2-group, open-label, phase 3 trial.

Setting and participants: The trial was designed with a planned enrollment of 480 patients with hormone receptor–positive disease and 60 patients with hormone receptor–negative disease. Patients were randomized in a 2:1 ratio. Randomization was stratified according to HER2 status (immunohistochemical [IHC] 1+ vs IHC 2+/in situ hybridization [ISH] negative), number of prior lines of therapy, and hormone-receptor status. IHC scores for HER2 expression were determined through central testing. Specimens that had HER2 IHC scores of 2+ were reflexed to ISH. Specimens were considered HER2-low-expressing if they had an IHC score of 1+ or if they had an IHC score of 2+ and were ISH negative.

Eligible patients had to have received chemotherapy for metastatic disease or had disease recurrence during or within 6 months after completing adjuvant chemotherapy. Patients with hormone receptor–positive disease must have had at least 1 line of endocrine therapy. Patients were eligible if they had stable brain metastases. Patients with interstitial lung disease were excluded.

Intervention: Patients were randomized to receive trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel).

Main outcome measures: The primary endpoint was progression-free survival in patients with hormone receptor–positive disease. Secondary endpoints were progression-free survival among all patients, overall survival in hormone receptor–positive patients, and overall survival in all patients. Additional secondary endpoints included objective response rates, duration of response, and efficacy in hormone receptor–negative patients.

Main results: A total of 373 patients were assigned to the trastuzumab deruxtecan group and 184 patients were assigned to the physician’s choice chemotherapy group; 88% of patients in each cohort were hormone receptor–positive. In the physician’s choice chemotherapy group, 51% received eribulin, 20% received capecitabine, 10% received nab-paclitaxel, 10% received gemcitabine, and 8% received paclitaxel. The demographic and baseline characteristics were similar between both cohorts. The median duration of follow-up was 18.4 months.

The median progression-free survival in the hormone receptor–positive cohort was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice chemotherapy group (HR, 0.51; 95% CI, 0.4-0.64). Subgroup analyses revealed a benefit across all subgroups. The median progression-free survival among patients with a HER2 IHC score of 1+ and those with a HER2 IHC score of 2+/negative ISH were identical. In patients who received a prior CDK 4/6 inhibitor, the median progression-free survival was also 10 months in the trastuzumab deruxtecan group. In those who were CDK 4/6- naïve, the progression-free survival was 11.7 months. The progression-free survival in all patients was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice chemotherapy group (HR, 0.46; 95% CI, 0.24-0.89).

The median overall survival in the hormone receptor–positive cohort was 23.9 months in the trastuzumab deruxtecan group compared with 17.5 months in the physician’s choice chemotherapy group (HR, 0.64; 95% CI, 0.48-0.86; P = .003). The median overall survival in the entire population was 23.4 months in the trastuzumab deruxtecan group vs 16.8 months in the physician’s choice chemotherapy group. In the hormone receptor–negative cohort, the median overall survival was 18.2 months in the trastuzumab deruxtecan group and 8.3 months in the physician’s choice chemotherapy group. Complete responses were seen in 3.6% in the trastuzumab deruxtecan group and 0.6% and the physician’s choice chemotherapy group. The median duration of response was 10.7 months in the trastuzumab deruxtecan group and 6.8 months in the physician’s choice chemotherapy group.

Incidence of serious adverse events was 27% in the trastuzumab deruxtecan group and 25% in the physician’s choice chemotherapy group. Grade 3 or higher events occurred in 52% of the trastuzumab deruxtecan group and 67% of the physician’s choice chemotherapy group. Discontinuation due to adverse events occurred in 16% in the trastuzumab deruxtecan group and 18% in the physician’s choice chemotherapy group; 14 patients in the trastuzumab deruxtecan group and 5 patients in the physician’s choice chemotherapy group had an adverse event that was associated with death. Death due to pneumonitis in the trastuzumab deruxtecan group occurred in 2 patients. Drug-related interstitial lung disease or pneumonitis occurred in 45 patients who received trastuzumab deruxtecan. The majority of these events were grade 1 and grade 2. However, 3 patients had grade 5 interstitial lung disease or pneumonitis.

Conclusion: Treatment with trastuzumab deruxtecan led to a significant improvement in progression-free survival compared to physician’s choice chemotherapy in patients with HER2-low metastatic breast cancer.

 

 

Commentary

Trastuzumab deruxtecan is an antibody drug conjugate that consists of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase 1 inhibitor. This antibody drug conjugate is unique compared with prior antibody drug conjugates such as trastuzumab emtansine in that it has a high drug-to-antibody ratio (~8). Furthermore, there appears to be a unique bystander effect resulting in off-target cytotoxicity to neighboring tumor cells, enhancing the efficacy of this novel therapy. Prior studies of trastuzumab deruxtecan have shown durable activity in heavily pretreated patients with metastatic HER2-positive breast cancer.1

HER2-positive breast cancer represents approximately 20% of breast cancer cases in women.2 Historically, HER2 positivity has been defined by strong HER2 expression with IHC staining (ie, score 3+) or HER2 amplification through ISH. Conversely, HER2-negative disease has historically been defined as those with IHC scores of 0 or 1+. This group represents approximately 60% of HER2-negative metastatic breast cancer patients.3 These patients have limited targeted treatment options after progressing on primary therapy. Prior data has shown that patients with low HER2 expression represent a heterogeneous population and thus, the historic categorization of HER2 status as positive or negative may in fact not adequately characterize the proportion of patients who may derive clinical benefit from HER2-directed therapies. Nevertheless, there have been no data to date that have shown improved outcomes in low HER2 expressers with anti-HER2 therapies.

The current studies add to the rapidly growing body of literature outlining the efficacy of the novel antibody drug conjugate trastuzumab deruxtecan. The implications of the data presented in these 2 studies are immediately practice changing.

In the DESTINY-Breast03 trial, Cortéz and colleagues show that trastuzumab deruxtecan therapy significantly prolongs progression-free survival compared with trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on first-line trastuzumab and taxane-based therapy. With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in this trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer. The overall survival in this trial was immature at the time of this analysis, and thus continued follow-up to validate the results noted here are warranted.

The DESTINY-Breast04 trial by Modi et al expands the cohort of patients who benefit from trastuzumab deruxtecan profoundly. This study defines a population of patients with HER2-low metastatic breast cancer who will now be eligible for HER2-directed therapies. These data show that therapy with trastuzumab deruxtecan leads to a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy in patients with metastatic breast cancer with low expression of HER2. This benefit was seen in both the estrogen receptor–positive cohort as well as the entire population, including pre-treated triple-negative disease. Furthermore, this study does not define a threshold of HER2 expression by IHC that predicts benefit with trastuzumab deruxtecan. Patients with an IHC score of 1+ as well as those with a score of 2+/ISH negative both benefit to a similar extent from trastuzumab deruxtecan. Interestingly, in the DAISY trial, antitumor activity was noted with trastuzumab deruxtecan even in those without any detectable HER2 expression on IHC.4 Given the inconsistency and potential false negatives of IHC along with heterogeneous HER2 expression, further work is needed to better identify patients with low levels of HER2 expression who may benefit from this novel antibody drug conjugate. Thus, a reliable test to quantitatively assess the level of HER2 expression is needed in order to determine more accurately which patients will benefit from trastuzumab deruxtecan.

Last, trastuzumab deruxtecan has been associated with interstitial lung disease and pneumonitis. Interstitial lung disease and pneumonitis occurred in approximately 10% of patients who received trastuzumab deruxtecan in the DESTINY-Breast03 trial and about 12% of patients in the DESTINY-Breast04 trial. Most of these events were grade 1 and grade 2. Nevertheless, clinicians must be aware of this risk and monitor patients frequently for the development of pneumonitis or interstitial lung disease.

 

 

Application for Clinical Practice and System Implementation

The results of the current studies show a longer progression-free survival with trastuzumab deruxtecan in both HER2-low expressing metastatic breast cancer and HER2-positive metastatic breast cancer following taxane and trastuzumab-based therapy. These results are clearly practice changing and represent a new standard of care in these patient populations. It is incumbent upon treating oncologists to work with our pathology colleagues to assess HER2 IHC thoroughly in order to identify all potential patients who may benefit from trastuzumab deruxtecan in the metastatic setting. The continued advancement of anti-HER2 therapy will undoubtedly have a significant impact on patient outcomes going forward.

Practice Points

  • With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in the DESTINY-Breast03 trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer.
  • In the DESTINY-Breast04 trial, a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy was seen in patients with metastatic breast cancer with low expression of HER2, including both the estrogen receptor–positive cohort as well as the entire population, including those with pre-treated triple-negative disease.

­—Daniel Isaac, DO, MS

References

1. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510

2. National Cancer Institute. Cancer stat facts. female breast cancer. Accessed July 25, 2022. https://seer.cancer.gov/statfacts/html/breast.html

3. Schettini F, Chic N, Braso-Maristany F, et al. Clinical, pathological and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer. 2021;7(`1):1. doi:10.1038/s41523-020-00208-2

4. Dieras VDE, Deluche E, Lusque A, et al. Trastuzumab deruxtecan for advanced breast cancer patients, regardless of HER2 status: a phase II study with biomarkers analysis. In: Proceedings of Abstracts of the 2021 San Antonio Breast Cancer Symposium, December 7-10, 2021. San Antonio: American Association for Cancer Research, 2021. Abstract.

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Study 1 Overview (Cortés et al)

Objective: To compare the efficacy and safety of trastuzumab deruxtecan with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxane.

Design: Phase 3, multicenter, open-label randomized trial conducted at 169 centers and 15 countries.

Setting and participants: Eligible patients had to have unresectable or metastatic HER2-positive breast cancer that had progressed during or after treatment with trastuzumab and a taxane or had disease that progressed within 6 months after neoadjuvant or adjuvant treatment involving trastuzumab or taxane. Patients with stable or previously treated brain metastases were eligible. Patients were not eligible for the study if they had symptomatic brain metastases, prior exposure to trastuzumab emtansine, or a history of interstitial lung disease.

Intervention: Patients were randomized in a 1-to-1 fashion to receive either trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or trastuzumab emtansine 3.6 mg/kg every 3 weeks. Patients were stratified according to hormone-receptor status, prior treatment with epratuzumab, and the presence or absence of visceral disease.

Main outcome measures: The primary endpoint of the study was progression-free survival as determined by an independent central review. Secondary endpoints included overall survival, overall response, and safety.

Main results: A total of 524 patients were enrolled in the study, with 261 patients randomized to trastuzumab deruxtecan and 263 patients randomized to trastuzumab emtansine. The demographic and baseline characteristics were similar between the 2 cohorts, and 60% of patients in both groups received prior epratuzumab therapy. Stable brain metastases were present in around 20% of patients in each group, and 70% of patients in each group had visceral disease. The median duration of follow-up was 16.2 months with trastuzumab deruxtecan and 15.3 months with trastuzumab emtansine.

The median progression-free survival was not reached in the trastuzumab deruxtecan group and was 6.8 months in the trastuzumab emtansine group (95% CI, 5.6-8.2). At 12 months the percentage of patients alive without disease progression was significantly larger in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group. The hazard ratio for disease progression or death from any cause was 0.28 (95% CI, 0.22-0.37; P < .001). Subgroup analyses showed a benefit in progression-free survival with trastuzumab deruxtecan across all subgroups.

At the time of this analysis, the percentage of patients who were alive at 12 months was 94% with trastuzumab deruxtecan and 85.9% with trastuzumab emtansine. The response rates were significantly higher with trastuzumab deruxtecan compared with trastuzumab emtansine (79.7% vs 34.2%). A complete response was seen in 16% of patients in the trastuzumab deruxtecan arm, compared with 8.7% of patients in the trastuzumab emtansine group. The disease control rate (complete response, partial response, or stable disease) was higher in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group (96.6% vs 76.8%).

Serious adverse events were reported in 19% of patients in the trastuzumab deruxtecan group and 18% of patients in the trastuzumab emtansine group. Discontinuation due to adverse events was higher in the trastuzumab deruxtecan group, with 13.6% of patients discontinuing trastuzumab deruxtecan. Grade 3 or higher adverse events were seen in 52% of patients treated with trastuzumab deruxtecan and 48% of patients treated with trastuzumab emtansine. The most commonly reported adverse event with trastuzumab deruxtecan was nausea/vomiting and fatigue. These adverse events were seen more in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group. No drug-related grade 5 adverse events were reported.

In the trastuzumab deruxtecan group, 10.5% of patients receiving trastuzumab deruxtecan developed interstitial lung disease or pneumonitis. Seven patients had grade 1 events, 18 patients had grade 2 events, and 2 patients had grade 3 events. No grade 4 or 5 events were noted in either treatment group. The median time to onset of interstitial lung disease or pneumonitis in those receiving trastuzumab deruxtecan was 168 days (range, 33-507). Discontinuation of therapy due to interstitial lung disease or pneumonitis occurred in 8% of patients receiving trastuzumab deruxtecan and 1% of patients receiving trastuzumab emtansine.

Conclusion: Trastuzumab deruxtecan significantly decreases the risk of disease progression or death compared to trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on prior trastuzumab and taxane-based therapy.

 

 

Study 2 Overview (Modi et al)

Objective: To assess the efficacy of trastuzumab deruxtecan in patients with unresectable or metastatic breast cancer with low levels of HER2 expression.

Design: This was a randomized, 2-group, open-label, phase 3 trial.

Setting and participants: The trial was designed with a planned enrollment of 480 patients with hormone receptor–positive disease and 60 patients with hormone receptor–negative disease. Patients were randomized in a 2:1 ratio. Randomization was stratified according to HER2 status (immunohistochemical [IHC] 1+ vs IHC 2+/in situ hybridization [ISH] negative), number of prior lines of therapy, and hormone-receptor status. IHC scores for HER2 expression were determined through central testing. Specimens that had HER2 IHC scores of 2+ were reflexed to ISH. Specimens were considered HER2-low-expressing if they had an IHC score of 1+ or if they had an IHC score of 2+ and were ISH negative.

Eligible patients had to have received chemotherapy for metastatic disease or had disease recurrence during or within 6 months after completing adjuvant chemotherapy. Patients with hormone receptor–positive disease must have had at least 1 line of endocrine therapy. Patients were eligible if they had stable brain metastases. Patients with interstitial lung disease were excluded.

Intervention: Patients were randomized to receive trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel).

Main outcome measures: The primary endpoint was progression-free survival in patients with hormone receptor–positive disease. Secondary endpoints were progression-free survival among all patients, overall survival in hormone receptor–positive patients, and overall survival in all patients. Additional secondary endpoints included objective response rates, duration of response, and efficacy in hormone receptor–negative patients.

Main results: A total of 373 patients were assigned to the trastuzumab deruxtecan group and 184 patients were assigned to the physician’s choice chemotherapy group; 88% of patients in each cohort were hormone receptor–positive. In the physician’s choice chemotherapy group, 51% received eribulin, 20% received capecitabine, 10% received nab-paclitaxel, 10% received gemcitabine, and 8% received paclitaxel. The demographic and baseline characteristics were similar between both cohorts. The median duration of follow-up was 18.4 months.

The median progression-free survival in the hormone receptor–positive cohort was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice chemotherapy group (HR, 0.51; 95% CI, 0.4-0.64). Subgroup analyses revealed a benefit across all subgroups. The median progression-free survival among patients with a HER2 IHC score of 1+ and those with a HER2 IHC score of 2+/negative ISH were identical. In patients who received a prior CDK 4/6 inhibitor, the median progression-free survival was also 10 months in the trastuzumab deruxtecan group. In those who were CDK 4/6- naïve, the progression-free survival was 11.7 months. The progression-free survival in all patients was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice chemotherapy group (HR, 0.46; 95% CI, 0.24-0.89).

The median overall survival in the hormone receptor–positive cohort was 23.9 months in the trastuzumab deruxtecan group compared with 17.5 months in the physician’s choice chemotherapy group (HR, 0.64; 95% CI, 0.48-0.86; P = .003). The median overall survival in the entire population was 23.4 months in the trastuzumab deruxtecan group vs 16.8 months in the physician’s choice chemotherapy group. In the hormone receptor–negative cohort, the median overall survival was 18.2 months in the trastuzumab deruxtecan group and 8.3 months in the physician’s choice chemotherapy group. Complete responses were seen in 3.6% in the trastuzumab deruxtecan group and 0.6% and the physician’s choice chemotherapy group. The median duration of response was 10.7 months in the trastuzumab deruxtecan group and 6.8 months in the physician’s choice chemotherapy group.

Incidence of serious adverse events was 27% in the trastuzumab deruxtecan group and 25% in the physician’s choice chemotherapy group. Grade 3 or higher events occurred in 52% of the trastuzumab deruxtecan group and 67% of the physician’s choice chemotherapy group. Discontinuation due to adverse events occurred in 16% in the trastuzumab deruxtecan group and 18% in the physician’s choice chemotherapy group; 14 patients in the trastuzumab deruxtecan group and 5 patients in the physician’s choice chemotherapy group had an adverse event that was associated with death. Death due to pneumonitis in the trastuzumab deruxtecan group occurred in 2 patients. Drug-related interstitial lung disease or pneumonitis occurred in 45 patients who received trastuzumab deruxtecan. The majority of these events were grade 1 and grade 2. However, 3 patients had grade 5 interstitial lung disease or pneumonitis.

Conclusion: Treatment with trastuzumab deruxtecan led to a significant improvement in progression-free survival compared to physician’s choice chemotherapy in patients with HER2-low metastatic breast cancer.

 

 

Commentary

Trastuzumab deruxtecan is an antibody drug conjugate that consists of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase 1 inhibitor. This antibody drug conjugate is unique compared with prior antibody drug conjugates such as trastuzumab emtansine in that it has a high drug-to-antibody ratio (~8). Furthermore, there appears to be a unique bystander effect resulting in off-target cytotoxicity to neighboring tumor cells, enhancing the efficacy of this novel therapy. Prior studies of trastuzumab deruxtecan have shown durable activity in heavily pretreated patients with metastatic HER2-positive breast cancer.1

HER2-positive breast cancer represents approximately 20% of breast cancer cases in women.2 Historically, HER2 positivity has been defined by strong HER2 expression with IHC staining (ie, score 3+) or HER2 amplification through ISH. Conversely, HER2-negative disease has historically been defined as those with IHC scores of 0 or 1+. This group represents approximately 60% of HER2-negative metastatic breast cancer patients.3 These patients have limited targeted treatment options after progressing on primary therapy. Prior data has shown that patients with low HER2 expression represent a heterogeneous population and thus, the historic categorization of HER2 status as positive or negative may in fact not adequately characterize the proportion of patients who may derive clinical benefit from HER2-directed therapies. Nevertheless, there have been no data to date that have shown improved outcomes in low HER2 expressers with anti-HER2 therapies.

The current studies add to the rapidly growing body of literature outlining the efficacy of the novel antibody drug conjugate trastuzumab deruxtecan. The implications of the data presented in these 2 studies are immediately practice changing.

In the DESTINY-Breast03 trial, Cortéz and colleagues show that trastuzumab deruxtecan therapy significantly prolongs progression-free survival compared with trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on first-line trastuzumab and taxane-based therapy. With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in this trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer. The overall survival in this trial was immature at the time of this analysis, and thus continued follow-up to validate the results noted here are warranted.

The DESTINY-Breast04 trial by Modi et al expands the cohort of patients who benefit from trastuzumab deruxtecan profoundly. This study defines a population of patients with HER2-low metastatic breast cancer who will now be eligible for HER2-directed therapies. These data show that therapy with trastuzumab deruxtecan leads to a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy in patients with metastatic breast cancer with low expression of HER2. This benefit was seen in both the estrogen receptor–positive cohort as well as the entire population, including pre-treated triple-negative disease. Furthermore, this study does not define a threshold of HER2 expression by IHC that predicts benefit with trastuzumab deruxtecan. Patients with an IHC score of 1+ as well as those with a score of 2+/ISH negative both benefit to a similar extent from trastuzumab deruxtecan. Interestingly, in the DAISY trial, antitumor activity was noted with trastuzumab deruxtecan even in those without any detectable HER2 expression on IHC.4 Given the inconsistency and potential false negatives of IHC along with heterogeneous HER2 expression, further work is needed to better identify patients with low levels of HER2 expression who may benefit from this novel antibody drug conjugate. Thus, a reliable test to quantitatively assess the level of HER2 expression is needed in order to determine more accurately which patients will benefit from trastuzumab deruxtecan.

Last, trastuzumab deruxtecan has been associated with interstitial lung disease and pneumonitis. Interstitial lung disease and pneumonitis occurred in approximately 10% of patients who received trastuzumab deruxtecan in the DESTINY-Breast03 trial and about 12% of patients in the DESTINY-Breast04 trial. Most of these events were grade 1 and grade 2. Nevertheless, clinicians must be aware of this risk and monitor patients frequently for the development of pneumonitis or interstitial lung disease.

 

 

Application for Clinical Practice and System Implementation

The results of the current studies show a longer progression-free survival with trastuzumab deruxtecan in both HER2-low expressing metastatic breast cancer and HER2-positive metastatic breast cancer following taxane and trastuzumab-based therapy. These results are clearly practice changing and represent a new standard of care in these patient populations. It is incumbent upon treating oncologists to work with our pathology colleagues to assess HER2 IHC thoroughly in order to identify all potential patients who may benefit from trastuzumab deruxtecan in the metastatic setting. The continued advancement of anti-HER2 therapy will undoubtedly have a significant impact on patient outcomes going forward.

Practice Points

  • With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in the DESTINY-Breast03 trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer.
  • In the DESTINY-Breast04 trial, a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy was seen in patients with metastatic breast cancer with low expression of HER2, including both the estrogen receptor–positive cohort as well as the entire population, including those with pre-treated triple-negative disease.

­—Daniel Isaac, DO, MS

Study 1 Overview (Cortés et al)

Objective: To compare the efficacy and safety of trastuzumab deruxtecan with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxane.

Design: Phase 3, multicenter, open-label randomized trial conducted at 169 centers and 15 countries.

Setting and participants: Eligible patients had to have unresectable or metastatic HER2-positive breast cancer that had progressed during or after treatment with trastuzumab and a taxane or had disease that progressed within 6 months after neoadjuvant or adjuvant treatment involving trastuzumab or taxane. Patients with stable or previously treated brain metastases were eligible. Patients were not eligible for the study if they had symptomatic brain metastases, prior exposure to trastuzumab emtansine, or a history of interstitial lung disease.

Intervention: Patients were randomized in a 1-to-1 fashion to receive either trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or trastuzumab emtansine 3.6 mg/kg every 3 weeks. Patients were stratified according to hormone-receptor status, prior treatment with epratuzumab, and the presence or absence of visceral disease.

Main outcome measures: The primary endpoint of the study was progression-free survival as determined by an independent central review. Secondary endpoints included overall survival, overall response, and safety.

Main results: A total of 524 patients were enrolled in the study, with 261 patients randomized to trastuzumab deruxtecan and 263 patients randomized to trastuzumab emtansine. The demographic and baseline characteristics were similar between the 2 cohorts, and 60% of patients in both groups received prior epratuzumab therapy. Stable brain metastases were present in around 20% of patients in each group, and 70% of patients in each group had visceral disease. The median duration of follow-up was 16.2 months with trastuzumab deruxtecan and 15.3 months with trastuzumab emtansine.

The median progression-free survival was not reached in the trastuzumab deruxtecan group and was 6.8 months in the trastuzumab emtansine group (95% CI, 5.6-8.2). At 12 months the percentage of patients alive without disease progression was significantly larger in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group. The hazard ratio for disease progression or death from any cause was 0.28 (95% CI, 0.22-0.37; P < .001). Subgroup analyses showed a benefit in progression-free survival with trastuzumab deruxtecan across all subgroups.

At the time of this analysis, the percentage of patients who were alive at 12 months was 94% with trastuzumab deruxtecan and 85.9% with trastuzumab emtansine. The response rates were significantly higher with trastuzumab deruxtecan compared with trastuzumab emtansine (79.7% vs 34.2%). A complete response was seen in 16% of patients in the trastuzumab deruxtecan arm, compared with 8.7% of patients in the trastuzumab emtansine group. The disease control rate (complete response, partial response, or stable disease) was higher in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group (96.6% vs 76.8%).

Serious adverse events were reported in 19% of patients in the trastuzumab deruxtecan group and 18% of patients in the trastuzumab emtansine group. Discontinuation due to adverse events was higher in the trastuzumab deruxtecan group, with 13.6% of patients discontinuing trastuzumab deruxtecan. Grade 3 or higher adverse events were seen in 52% of patients treated with trastuzumab deruxtecan and 48% of patients treated with trastuzumab emtansine. The most commonly reported adverse event with trastuzumab deruxtecan was nausea/vomiting and fatigue. These adverse events were seen more in the trastuzumab deruxtecan group compared with the trastuzumab emtansine group. No drug-related grade 5 adverse events were reported.

In the trastuzumab deruxtecan group, 10.5% of patients receiving trastuzumab deruxtecan developed interstitial lung disease or pneumonitis. Seven patients had grade 1 events, 18 patients had grade 2 events, and 2 patients had grade 3 events. No grade 4 or 5 events were noted in either treatment group. The median time to onset of interstitial lung disease or pneumonitis in those receiving trastuzumab deruxtecan was 168 days (range, 33-507). Discontinuation of therapy due to interstitial lung disease or pneumonitis occurred in 8% of patients receiving trastuzumab deruxtecan and 1% of patients receiving trastuzumab emtansine.

Conclusion: Trastuzumab deruxtecan significantly decreases the risk of disease progression or death compared to trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on prior trastuzumab and taxane-based therapy.

 

 

Study 2 Overview (Modi et al)

Objective: To assess the efficacy of trastuzumab deruxtecan in patients with unresectable or metastatic breast cancer with low levels of HER2 expression.

Design: This was a randomized, 2-group, open-label, phase 3 trial.

Setting and participants: The trial was designed with a planned enrollment of 480 patients with hormone receptor–positive disease and 60 patients with hormone receptor–negative disease. Patients were randomized in a 2:1 ratio. Randomization was stratified according to HER2 status (immunohistochemical [IHC] 1+ vs IHC 2+/in situ hybridization [ISH] negative), number of prior lines of therapy, and hormone-receptor status. IHC scores for HER2 expression were determined through central testing. Specimens that had HER2 IHC scores of 2+ were reflexed to ISH. Specimens were considered HER2-low-expressing if they had an IHC score of 1+ or if they had an IHC score of 2+ and were ISH negative.

Eligible patients had to have received chemotherapy for metastatic disease or had disease recurrence during or within 6 months after completing adjuvant chemotherapy. Patients with hormone receptor–positive disease must have had at least 1 line of endocrine therapy. Patients were eligible if they had stable brain metastases. Patients with interstitial lung disease were excluded.

Intervention: Patients were randomized to receive trastuzumab deruxtecan 5.4 mg/kg every 3 weeks or physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel).

Main outcome measures: The primary endpoint was progression-free survival in patients with hormone receptor–positive disease. Secondary endpoints were progression-free survival among all patients, overall survival in hormone receptor–positive patients, and overall survival in all patients. Additional secondary endpoints included objective response rates, duration of response, and efficacy in hormone receptor–negative patients.

Main results: A total of 373 patients were assigned to the trastuzumab deruxtecan group and 184 patients were assigned to the physician’s choice chemotherapy group; 88% of patients in each cohort were hormone receptor–positive. In the physician’s choice chemotherapy group, 51% received eribulin, 20% received capecitabine, 10% received nab-paclitaxel, 10% received gemcitabine, and 8% received paclitaxel. The demographic and baseline characteristics were similar between both cohorts. The median duration of follow-up was 18.4 months.

The median progression-free survival in the hormone receptor–positive cohort was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice chemotherapy group (HR, 0.51; 95% CI, 0.4-0.64). Subgroup analyses revealed a benefit across all subgroups. The median progression-free survival among patients with a HER2 IHC score of 1+ and those with a HER2 IHC score of 2+/negative ISH were identical. In patients who received a prior CDK 4/6 inhibitor, the median progression-free survival was also 10 months in the trastuzumab deruxtecan group. In those who were CDK 4/6- naïve, the progression-free survival was 11.7 months. The progression-free survival in all patients was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice chemotherapy group (HR, 0.46; 95% CI, 0.24-0.89).

The median overall survival in the hormone receptor–positive cohort was 23.9 months in the trastuzumab deruxtecan group compared with 17.5 months in the physician’s choice chemotherapy group (HR, 0.64; 95% CI, 0.48-0.86; P = .003). The median overall survival in the entire population was 23.4 months in the trastuzumab deruxtecan group vs 16.8 months in the physician’s choice chemotherapy group. In the hormone receptor–negative cohort, the median overall survival was 18.2 months in the trastuzumab deruxtecan group and 8.3 months in the physician’s choice chemotherapy group. Complete responses were seen in 3.6% in the trastuzumab deruxtecan group and 0.6% and the physician’s choice chemotherapy group. The median duration of response was 10.7 months in the trastuzumab deruxtecan group and 6.8 months in the physician’s choice chemotherapy group.

Incidence of serious adverse events was 27% in the trastuzumab deruxtecan group and 25% in the physician’s choice chemotherapy group. Grade 3 or higher events occurred in 52% of the trastuzumab deruxtecan group and 67% of the physician’s choice chemotherapy group. Discontinuation due to adverse events occurred in 16% in the trastuzumab deruxtecan group and 18% in the physician’s choice chemotherapy group; 14 patients in the trastuzumab deruxtecan group and 5 patients in the physician’s choice chemotherapy group had an adverse event that was associated with death. Death due to pneumonitis in the trastuzumab deruxtecan group occurred in 2 patients. Drug-related interstitial lung disease or pneumonitis occurred in 45 patients who received trastuzumab deruxtecan. The majority of these events were grade 1 and grade 2. However, 3 patients had grade 5 interstitial lung disease or pneumonitis.

Conclusion: Treatment with trastuzumab deruxtecan led to a significant improvement in progression-free survival compared to physician’s choice chemotherapy in patients with HER2-low metastatic breast cancer.

 

 

Commentary

Trastuzumab deruxtecan is an antibody drug conjugate that consists of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase 1 inhibitor. This antibody drug conjugate is unique compared with prior antibody drug conjugates such as trastuzumab emtansine in that it has a high drug-to-antibody ratio (~8). Furthermore, there appears to be a unique bystander effect resulting in off-target cytotoxicity to neighboring tumor cells, enhancing the efficacy of this novel therapy. Prior studies of trastuzumab deruxtecan have shown durable activity in heavily pretreated patients with metastatic HER2-positive breast cancer.1

HER2-positive breast cancer represents approximately 20% of breast cancer cases in women.2 Historically, HER2 positivity has been defined by strong HER2 expression with IHC staining (ie, score 3+) or HER2 amplification through ISH. Conversely, HER2-negative disease has historically been defined as those with IHC scores of 0 or 1+. This group represents approximately 60% of HER2-negative metastatic breast cancer patients.3 These patients have limited targeted treatment options after progressing on primary therapy. Prior data has shown that patients with low HER2 expression represent a heterogeneous population and thus, the historic categorization of HER2 status as positive or negative may in fact not adequately characterize the proportion of patients who may derive clinical benefit from HER2-directed therapies. Nevertheless, there have been no data to date that have shown improved outcomes in low HER2 expressers with anti-HER2 therapies.

The current studies add to the rapidly growing body of literature outlining the efficacy of the novel antibody drug conjugate trastuzumab deruxtecan. The implications of the data presented in these 2 studies are immediately practice changing.

In the DESTINY-Breast03 trial, Cortéz and colleagues show that trastuzumab deruxtecan therapy significantly prolongs progression-free survival compared with trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on first-line trastuzumab and taxane-based therapy. With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in this trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer. The overall survival in this trial was immature at the time of this analysis, and thus continued follow-up to validate the results noted here are warranted.

The DESTINY-Breast04 trial by Modi et al expands the cohort of patients who benefit from trastuzumab deruxtecan profoundly. This study defines a population of patients with HER2-low metastatic breast cancer who will now be eligible for HER2-directed therapies. These data show that therapy with trastuzumab deruxtecan leads to a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy in patients with metastatic breast cancer with low expression of HER2. This benefit was seen in both the estrogen receptor–positive cohort as well as the entire population, including pre-treated triple-negative disease. Furthermore, this study does not define a threshold of HER2 expression by IHC that predicts benefit with trastuzumab deruxtecan. Patients with an IHC score of 1+ as well as those with a score of 2+/ISH negative both benefit to a similar extent from trastuzumab deruxtecan. Interestingly, in the DAISY trial, antitumor activity was noted with trastuzumab deruxtecan even in those without any detectable HER2 expression on IHC.4 Given the inconsistency and potential false negatives of IHC along with heterogeneous HER2 expression, further work is needed to better identify patients with low levels of HER2 expression who may benefit from this novel antibody drug conjugate. Thus, a reliable test to quantitatively assess the level of HER2 expression is needed in order to determine more accurately which patients will benefit from trastuzumab deruxtecan.

Last, trastuzumab deruxtecan has been associated with interstitial lung disease and pneumonitis. Interstitial lung disease and pneumonitis occurred in approximately 10% of patients who received trastuzumab deruxtecan in the DESTINY-Breast03 trial and about 12% of patients in the DESTINY-Breast04 trial. Most of these events were grade 1 and grade 2. Nevertheless, clinicians must be aware of this risk and monitor patients frequently for the development of pneumonitis or interstitial lung disease.

 

 

Application for Clinical Practice and System Implementation

The results of the current studies show a longer progression-free survival with trastuzumab deruxtecan in both HER2-low expressing metastatic breast cancer and HER2-positive metastatic breast cancer following taxane and trastuzumab-based therapy. These results are clearly practice changing and represent a new standard of care in these patient populations. It is incumbent upon treating oncologists to work with our pathology colleagues to assess HER2 IHC thoroughly in order to identify all potential patients who may benefit from trastuzumab deruxtecan in the metastatic setting. The continued advancement of anti-HER2 therapy will undoubtedly have a significant impact on patient outcomes going forward.

Practice Points

  • With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in the DESTINY-Breast03 trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer.
  • In the DESTINY-Breast04 trial, a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy was seen in patients with metastatic breast cancer with low expression of HER2, including both the estrogen receptor–positive cohort as well as the entire population, including those with pre-treated triple-negative disease.

­—Daniel Isaac, DO, MS

References

1. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510

2. National Cancer Institute. Cancer stat facts. female breast cancer. Accessed July 25, 2022. https://seer.cancer.gov/statfacts/html/breast.html

3. Schettini F, Chic N, Braso-Maristany F, et al. Clinical, pathological and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer. 2021;7(`1):1. doi:10.1038/s41523-020-00208-2

4. Dieras VDE, Deluche E, Lusque A, et al. Trastuzumab deruxtecan for advanced breast cancer patients, regardless of HER2 status: a phase II study with biomarkers analysis. In: Proceedings of Abstracts of the 2021 San Antonio Breast Cancer Symposium, December 7-10, 2021. San Antonio: American Association for Cancer Research, 2021. Abstract.

References

1. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510

2. National Cancer Institute. Cancer stat facts. female breast cancer. Accessed July 25, 2022. https://seer.cancer.gov/statfacts/html/breast.html

3. Schettini F, Chic N, Braso-Maristany F, et al. Clinical, pathological and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer. 2021;7(`1):1. doi:10.1038/s41523-020-00208-2

4. Dieras VDE, Deluche E, Lusque A, et al. Trastuzumab deruxtecan for advanced breast cancer patients, regardless of HER2 status: a phase II study with biomarkers analysis. In: Proceedings of Abstracts of the 2021 San Antonio Breast Cancer Symposium, December 7-10, 2021. San Antonio: American Association for Cancer Research, 2021. Abstract.

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How to better identify and manage women with elevated breast cancer risk

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How to better identify and manage women with elevated breast cancer risk

Breast cancer is the most common invasive cancer in women in the United States; it is estimated that there will be 287,850 new cases of breast cancer in the United States during 2022 with 43,250 deaths.1 Lives are extended and saved every day because of a robust arsenal of treatments and interventions available to those who have been given a diagnosis of breast cancer. And, of course, lives are also extended and saved when we identify women at risk and provide early interventions. But in busy offices where time is short and there are competing demands on our time, proper assessment of a woman’s risk of breast cancer does not always happen. As a result, women with a higher risk of breast cancer may not be getting appropriate management.2,3

Familiarizing yourself with several risk-assessment tools and knowing when genetic testing is needed can make a big difference. Knowing the timing of mammograms and magnetic resonance imaging (MRI) for women deemed to be at high risk is also key. The following review employs a case-based approach (with an accompanying ALGORITHM) to illustrate how best to identify women who are at heightened risk of breast cancer and maximize their care. We also discuss the chemoprophylaxis regimens that may be used for those at increased risk.

How to assess breast cancer risk

CASE

Rachel P, age 37, presents to establish care. She has an Ashkenazi Jewish background and wonders if she should start doing breast cancer screening before age 40. She has 2 children, ages 4 years and 2 years. Her maternal aunt had unilateral breast cancer at age 54, and her maternal grandmother died of ovarian cancer at age 65.

Risk assessment

The risk assessment process (see ALGORITHM) must start with either the clinician or the patient initiating the discussion about breast cancer risk. The clinician may initiate the discussion with a new patient or at an annual physical examination. The patient may start the discussion because they are experiencing new breast symptoms, have anxiety about developing breast cancer, or have a family member with a new cancer diagnosis.

Risk factors. There are single factors that convey enough risk to automatically designate the patient as high risk (see TABLE 14-9). These factors include having a history of chest radiation between the ages of 10 and 30, a history of breast biopsy with either lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH), past breast and/or ovarian cancer, and either a family or personal history of a high penetrant genetic variant for breast cancer.4-9

High-risk factors for breast cancer

In women with previous chest radiation, breast cancer risk correlates with the total dose of radiation.5 For women with a personal history of breast cancer, the younger the age at diagnosis, the higher the risk of contralateral breast cancer.5 Precancerous changes such as ADH, LCIS, and ductal carcinoma in situ (DCIS) also confer moderate increases in risk. Women with these diagnoses will commonly have follow-up with specialists.

Risk assessment tools. There are several models available to assess a woman’s breast cancer risk (see TABLE 210-12). The Gail model (https://bcrisktool.cancer.gov/) is the oldest, quickest, and most widely known. However, the Gail model only accounts for first-degree relatives diagnosed with breast cancer, may underpredict risk in women with a more extensive family history, and has not been studied in women younger than 35. The International Breast Cancer Intervention Study (IBIS) Risk Evaluation Tool (https://ibis-risk-calculator.magview.com/), commonly referred to as the Tyrer-Cuzick model, incorporates second-degree relatives into the prediction model—although women may not know their full family history. Both the IBIS and the Breast Cancer Surveillance Consortium (BCSC) model (https://tools.bcsc-scc.org/BC5yearRisk/intro.htm) include breast density in the prediction algorithm. The choice of tool depends on clinician comfort and individual patient risk factors. There is no evidence that one model is better than another.10-12

Commonly used breast cancer risk assessment tools

Continue to: CASE

 

 

CASE

Ms. P’s clinician starts with an assessment using the Gail model. However, when the result comes back with average risk, the clinician decides to follow up with the Tyrer-Cuzick model in order to incorporate Ms. P’s multiple ­second-degree relatives with breast and ovarian cancer. (The BCSC model was not used because it only includes first-degree relatives.)

Genetic testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing if a woman has a first- or ­second-degree relative with pancreatic cancer, metastatic prostate cancer, male breast cancer, breast cancer at age 45 or younger, 2 or more breast cancers in a single person, 2 or more people on the same side of the family with at least 1 diagnosed at age 50 or younger, or any relative with ovarian cancer (see TABLE 3).7 Before ordering genetic testing, it is useful to refer the patient to a genetic counselor for a thorough discussion of options.

Genetic testing criteria

Results of genetic testing may include high-risk variants, moderate-risk variants, and variants of unknown significance (VUS), or be negative for any variants. High-risk variants for breast cancer include BRCA1, BRCA2, PALB2, and cancer syndrome variants such as TP53, PTEN, STK11, and CDH1.5,6,9,13-15 These high-risk variants confer sufficient risk that women with these mutations are automatically categorized in the high-risk group. It is estimated that high-risk variants account for only 25% of the genetic risk for breast cancer.16

BRCA1/2 and PTEN mutations confer greater than 80% lifetime risk, while other high-risk variants such as TP53, CDH1, and STK11 confer risks between 25% and 40%. These variants are also associated with cancers of other organs, depending on the mutation.17

Moderate-risk variants—ATM and CHEK2—do not confer sufficient risk to elevate women into the high-risk group. However, they do qualify these intermediate-risk women to participate in a specialized management strategy.5,9,13,18

VUS are those for which the associated risk is unclear, but more research may be done to categorize the risk.9 The clinical management of women with VUS usually entails close monitoring.

In an effort to better characterize breast cancer risk using a combination of pathogenic variants found in broad multi-gene cancer predisposition panels, researchers have developed a method to combine risks in a “polygenic risk score” (PRS) that can be used to counsel women (see “What is a polygenic risk score for breast cancer?” on page 203).19-21PRS predicts an additional 18% of genetic risk in women of European descent.21

SIDEBAR
What is a polygenic risk score for breast cancer?

  • A polygenic risk score (PRS) is a mathematical method to combine results from a variety of different single nucleotide polymorphisms (SNPs; ie, single base pair variants) into a prediction tool that can estimate a woman’s lifetime risk of breast cancer.
  • A PRS may be most accurate in determining risk for women with intermediate pathogenic variants, such as ATM and CHEK2. 19,20
  • PRS has not been studied in non-White women.21

Continue to: CASE

 

 

CASE

Using the assessment results, the clinician talks to Ms. P about her lifetime risk for breast cancer. The Gail model indicates her lifetime risk is 13.3%, just slightly higher than the average (12.5%), and her 5-year risk is 0.5% (average, 0.4%). The IBIS or Tyrer-­Cuzick model, which takes into account her second-degree relatives with breast and ovarian cancer and her Ashkenazi ethnicity (which confers increased risk due to elevated risk of BRCA mutations), predicts her lifetime risk of breast cancer to be 20.4%. This categorizes Ms. P as high risk.

Enhanced screening recommendations for women at high risk

TABLE 48,13,22 summarizes screening recommendations for women deemed to be at high risk for breast cancer. The American Cancer Society (ACS), NCCN, and the American College of Radiology (ACR) recommend that women with at least a 20% lifetime risk have yearly magnetic resonance imaging (MRI) and mammography (staggered so that the patient has 1 test every 6 months) starting 10 years before the age of onset for the youngest affected relative but not before age 30.8 For carriers of high-risk (as well as intermediate-risk) genes, NCCN recommends annual MRI screening starting at age 40.13BRCA1/2 screening includes annual MRI starting at age 25 and annual mammography every 6 months starting at age 30.22 Clinicians should counsel women with moderate risk factors (elevated breast density; personal history of ADH, LCIS, or DCIS) about the potential risks and benefits of enhanced screening and chemoprophylaxis.

Screening recommendations for women at high risk

Risk-reduction strategies

Chemoprophylaxis

The US Preventive Services Task Force (USPSTF) recommends that all women at increased risk for breast cancer consider chemoprophylaxis (B recommendation)23 based on convincing evidence that 5 years of treatment with either a synthetic estrogen reuptake modulator (SERM) or an aromatase inhibitor (AI) decreases the incidence of estrogen receptor positive breast cancers. (See TABLE 57,23,24 for absolute risk reduction.) There is no benefit for chemoprophylaxis in women at average risk (D recommendation).23 It is unclear whether chemoprophylaxis is indicated in women with moderate increased risk (ie, who do not meet the 20% lifetime risk criteria). Chemoprophylaxis may not be effective in women with BRCA1 mutations, as they often develop triple-negative breast cancers.

Chemoprophylaxis regimens for prevention of breast cancer

Accurate risk assessment and shared decision-making enable the clinician and patient to discuss the potential risks and benefits of chemoprophylaxis.7,24 The USPSTF did not find that any 1 risk prediction tool was better than another to identify women who should be counseled about chemoprophylaxis. Clinicians should counsel all women taking AIs about optimizing bone health with adequate calcium and vitamin D intake and routine bone density tests.

Surgical risk reduction

The NCCN guidelines state that risk-reducing bilateral mastectomy is reserved for individuals with high-risk gene variants and individuals with prior chest radiation between ages 10 and 30.25 NCCN also recommends discussing risk-reducing mastectomy with all women with BRCA mutations.22

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer.

Bilateral mastectomy is the most effective method to reduce breast cancer risk and should be discussed after age 25 in women with BRCA mutations and at least 8 years after chest radiation is completed.26 There is a reduction in breast cancer incidence of 90%.25 Breast imaging for screening (mammography or MRI) is not indicated after risk-reducing mastectomy. However, clinical breast examinations of the surgical site are important, because there is a small risk of developing breast cancer in that area.26

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer. It can also reduce the risk of breast cancer in women with BRCA mutations.27

Continue to: CASE

 

 

CASE

Based on her risk assessment results, family history, and genetic heritage, Ms. P qualifies for referral to a genetic counselor for discussion of BRCA testing. The clinician discusses adding annual MRI to Ms. P’s breast cancer screening regimen, based on ACS, NCCN, and ACR recommendations, due to her 20.4% lifetime risk. Discussion of whether and when to start chemoprophylaxis is typically based on breast cancer risk, projected benefit, and the potential impact of medication adverse effects. A high-risk woman is eligible for 5 years of chemoprophylaxis (tamoxifen if premenopausal) based on her lifetime risk. The clinician discusses timing with Ms. P, and even though she is finished with childbearing, she would like to wait until she is age 45, which is before the age at which her aunt was given a diagnosis of breast cancer.

Conclusion

Primary care clinicians are well positioned to identify women with an elevated risk of breast cancer and refer them for enhanced screening and chemoprophylaxis (see ALGORITHM). Shared decision-making with the inclusion of patient decision aids (https://decisionaid.ohri.ca/AZsearch.php?criteria=breast+cancer) about genetic testing, chemoprophylaxis, and prophylactic mastectomy or oophorectomy may help women at intermediate or high risk of breast cancer feel empowered to make decisions about their breast—and overall—health.

CORRESPONDENCE
Sarina Schrager, MD, MS, Professor, Department of Family Medicine and Community Health, University of Wisconsin, 1100 Delaplaine Court, Madison, WI 53715; sbschrag@wisc.edu

References

1. National Cancer Institute. Cancer stat facts: female breast cancer. Accessed May 13, 2022. https://seer.cancer.gov/statfacts/html/breast.html

2. Guerra CE, Sherman M, Armstrong K. Diffusion of breast cancer risk assessment in primary care. J Am Board Fam Med. 2009;22:272-279. doi:10.3122/jabfm.2009.03.080153

3. Hamilton JG, Abdiwahab E, Edwards HM, et al. Primary care providers’ cancer genetic testing-related knowledge, attitudes, and communication behaviors: a systematic review and research agenda. J Gen Intern Med. 2017;32:315-324. doi:10.1007/s11606-016-3943-4

4. Eden KB, Ivlev I, Bensching KL, et al. Use of an online breast cancer risk assessment and patient decision aid in primary care practices. J Womens Health (Larchmt). 2020;29:763-769. doi: 10.1089/jwh.2019.8143

5. Kleibl Z, Kristensen VN. Women at high risk of breast cancer: molecular characteristics, clinical presentation and management. Breast. 2016;28:136-44. doi: 10.1016/j.breast.2016.05.006

6. Sciaraffa T, Guido B, Khan SA, et al. Breast cancer risk assessment and management programs: a practical guide. Breast J. 2020;26:1556-1564. doi: 10.1111/tbj.13967

7. Farkas A, Vanderberg R, Merriam S, et al. Breast cancer chemoprevention: a practical guide for the primary care provider. J Womens Health (Larchmt). 2020;29:46-56. doi: 10.1089/jwh.2018.7643

8. McClintock AH, Golob AL, Laya MB. Breast cancer risk assessment: a step-wise approach for primary care providers on the front lines of shared decision making. Mayo Clin Proc. 2020;95:1268-1275. doi: 10.1016/j.mayocp.2020.04.017

9. Catana A, Apostu AP, Antemie RG. Multi gene panel testing for hereditary breast cancer - is it ready to be used? Med Pharm Rep. 2019;92:220-225. doi: 10.15386/mpr-1083

10. Barke LD, Freivogel ME. Breast cancer risk assessment models and high-risk screening. Radiol Clin North Am. 2017;55:457-474. doi: 10.1016/j.rcl.2016.12.013

11. Amir E, Freedman OC, Seruga B, et al. Assessing women at high risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst. 2010;102:680-91. doi: 10.1093/jnci/djq088

12. Kim G, Bahl M. Assessing risk of breast cancer: a review of risk prediction models. J Breast Imaging. 2021;3:144-155. doi: 10.1093/jbi/wbab001

13. Narod SA. Which genes for hereditary breast cancer? N Engl J Med. 2021;384:471-473. doi: 10.1056/NEJMe2035083

14. Couch FJ, Shimelis H, Hu C, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 2017;3:1190-1196. doi: 10.1001/jamaoncol.2017.0424

15. Obeid EI, Hall MJ, Daly MB. Multigene panel testing and breast cancer risk: is it time to scale down? JAMA Oncol. 2017;3:1176-1177. doi: 10.1001/jamaoncol.2017.0342

16. Michailidou K, Lindström S, Dennis J, et al. Association analysis identifies 65 new breast cancer risk loci. Nature. 2017;551:92-94. doi: 10.1038/nature24284

17. Shiovitz S, Korde LA. Genetics of breast cancer: a topic in evolution. Ann Oncol. 2015;26:1291-1299. doi: 10.1093/annonc/mdv022

18. Hu C, Hart SN, Gnanaolivu R, et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med. 2021;384:440-451. doi: 10.1056/NEJMoa2005936

19. Gao C, Polley EC, Hart SN, et al. Risk of breast cancer among carriers of pathogenic variants in breast cancer predisposition genes varies by polygenic risk score. J Clin Oncol. 2021;39:2564-2573. doi: 10.1200/JCO.20.01992

20. Gallagher S, Hughes E, Wagner S, et al. Association of a polygenic risk score with breast cancer among women carriers of high- and moderate-risk breast cancer genes. JAMA Netw Open. 2020;3:e208501. doi: 10.1001/jamanetworkopen.2020.8501

21. Yanes T, Young MA, Meiser B, et al. Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field. Breast Cancer Res. 2020;22:21. doi: 10.1186/s13058-020-01260-3

22. Schrager S, Torell E, Ledford K, et al. Managing a woman with BRCA mutations? Shared decision-making is key. J Fam Pract. 2020;69:237-243

23. US Preventive Services Task Force; Owens DK, Davidson KW, Krist AH, et al. Medication use to reduce risk of breast cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322:857-867. doi: 10.1001/jama.2019.11885

24. Pruthi S, Heisey RE, Bevers TB. Chemoprevention for breast cancer. Ann Surg Oncol 2015;22:3230-3235. doi: 10.1245/s10434-015-4715-9

25. Britt KL, Cuzick J, Phillips KA. Key steps for effective breast cancer prevention. Nat Rev Cancer. 2020;20:417-436. doi: 10.1038/s41568-020-0266-x

26. Jatoi I, Kemp Z. Risk-reducing mastectomy. JAMA. 2021;325:1781-1782. doi: 10.1001/jama.2020.22414

27. Choi Y, Terry MB, Daly MB, et al. Association of risk-reducing salpingo-oophorectomy with breast cancer risk in women with BRCA1 and BRCA2 pathogenic variants. JAMA Oncol. 2021;7:585-592. doi:10.1001/jamaoncol.2020.7995

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The authors reported no potential conflict of interest relevant to this article.

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Breast cancer is the most common invasive cancer in women in the United States; it is estimated that there will be 287,850 new cases of breast cancer in the United States during 2022 with 43,250 deaths.1 Lives are extended and saved every day because of a robust arsenal of treatments and interventions available to those who have been given a diagnosis of breast cancer. And, of course, lives are also extended and saved when we identify women at risk and provide early interventions. But in busy offices where time is short and there are competing demands on our time, proper assessment of a woman’s risk of breast cancer does not always happen. As a result, women with a higher risk of breast cancer may not be getting appropriate management.2,3

Familiarizing yourself with several risk-assessment tools and knowing when genetic testing is needed can make a big difference. Knowing the timing of mammograms and magnetic resonance imaging (MRI) for women deemed to be at high risk is also key. The following review employs a case-based approach (with an accompanying ALGORITHM) to illustrate how best to identify women who are at heightened risk of breast cancer and maximize their care. We also discuss the chemoprophylaxis regimens that may be used for those at increased risk.

How to assess breast cancer risk

CASE

Rachel P, age 37, presents to establish care. She has an Ashkenazi Jewish background and wonders if she should start doing breast cancer screening before age 40. She has 2 children, ages 4 years and 2 years. Her maternal aunt had unilateral breast cancer at age 54, and her maternal grandmother died of ovarian cancer at age 65.

Risk assessment

The risk assessment process (see ALGORITHM) must start with either the clinician or the patient initiating the discussion about breast cancer risk. The clinician may initiate the discussion with a new patient or at an annual physical examination. The patient may start the discussion because they are experiencing new breast symptoms, have anxiety about developing breast cancer, or have a family member with a new cancer diagnosis.

Risk factors. There are single factors that convey enough risk to automatically designate the patient as high risk (see TABLE 14-9). These factors include having a history of chest radiation between the ages of 10 and 30, a history of breast biopsy with either lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH), past breast and/or ovarian cancer, and either a family or personal history of a high penetrant genetic variant for breast cancer.4-9

High-risk factors for breast cancer

In women with previous chest radiation, breast cancer risk correlates with the total dose of radiation.5 For women with a personal history of breast cancer, the younger the age at diagnosis, the higher the risk of contralateral breast cancer.5 Precancerous changes such as ADH, LCIS, and ductal carcinoma in situ (DCIS) also confer moderate increases in risk. Women with these diagnoses will commonly have follow-up with specialists.

Risk assessment tools. There are several models available to assess a woman’s breast cancer risk (see TABLE 210-12). The Gail model (https://bcrisktool.cancer.gov/) is the oldest, quickest, and most widely known. However, the Gail model only accounts for first-degree relatives diagnosed with breast cancer, may underpredict risk in women with a more extensive family history, and has not been studied in women younger than 35. The International Breast Cancer Intervention Study (IBIS) Risk Evaluation Tool (https://ibis-risk-calculator.magview.com/), commonly referred to as the Tyrer-Cuzick model, incorporates second-degree relatives into the prediction model—although women may not know their full family history. Both the IBIS and the Breast Cancer Surveillance Consortium (BCSC) model (https://tools.bcsc-scc.org/BC5yearRisk/intro.htm) include breast density in the prediction algorithm. The choice of tool depends on clinician comfort and individual patient risk factors. There is no evidence that one model is better than another.10-12

Commonly used breast cancer risk assessment tools

Continue to: CASE

 

 

CASE

Ms. P’s clinician starts with an assessment using the Gail model. However, when the result comes back with average risk, the clinician decides to follow up with the Tyrer-Cuzick model in order to incorporate Ms. P’s multiple ­second-degree relatives with breast and ovarian cancer. (The BCSC model was not used because it only includes first-degree relatives.)

Genetic testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing if a woman has a first- or ­second-degree relative with pancreatic cancer, metastatic prostate cancer, male breast cancer, breast cancer at age 45 or younger, 2 or more breast cancers in a single person, 2 or more people on the same side of the family with at least 1 diagnosed at age 50 or younger, or any relative with ovarian cancer (see TABLE 3).7 Before ordering genetic testing, it is useful to refer the patient to a genetic counselor for a thorough discussion of options.

Genetic testing criteria

Results of genetic testing may include high-risk variants, moderate-risk variants, and variants of unknown significance (VUS), or be negative for any variants. High-risk variants for breast cancer include BRCA1, BRCA2, PALB2, and cancer syndrome variants such as TP53, PTEN, STK11, and CDH1.5,6,9,13-15 These high-risk variants confer sufficient risk that women with these mutations are automatically categorized in the high-risk group. It is estimated that high-risk variants account for only 25% of the genetic risk for breast cancer.16

BRCA1/2 and PTEN mutations confer greater than 80% lifetime risk, while other high-risk variants such as TP53, CDH1, and STK11 confer risks between 25% and 40%. These variants are also associated with cancers of other organs, depending on the mutation.17

Moderate-risk variants—ATM and CHEK2—do not confer sufficient risk to elevate women into the high-risk group. However, they do qualify these intermediate-risk women to participate in a specialized management strategy.5,9,13,18

VUS are those for which the associated risk is unclear, but more research may be done to categorize the risk.9 The clinical management of women with VUS usually entails close monitoring.

In an effort to better characterize breast cancer risk using a combination of pathogenic variants found in broad multi-gene cancer predisposition panels, researchers have developed a method to combine risks in a “polygenic risk score” (PRS) that can be used to counsel women (see “What is a polygenic risk score for breast cancer?” on page 203).19-21PRS predicts an additional 18% of genetic risk in women of European descent.21

SIDEBAR
What is a polygenic risk score for breast cancer?

  • A polygenic risk score (PRS) is a mathematical method to combine results from a variety of different single nucleotide polymorphisms (SNPs; ie, single base pair variants) into a prediction tool that can estimate a woman’s lifetime risk of breast cancer.
  • A PRS may be most accurate in determining risk for women with intermediate pathogenic variants, such as ATM and CHEK2. 19,20
  • PRS has not been studied in non-White women.21

Continue to: CASE

 

 

CASE

Using the assessment results, the clinician talks to Ms. P about her lifetime risk for breast cancer. The Gail model indicates her lifetime risk is 13.3%, just slightly higher than the average (12.5%), and her 5-year risk is 0.5% (average, 0.4%). The IBIS or Tyrer-­Cuzick model, which takes into account her second-degree relatives with breast and ovarian cancer and her Ashkenazi ethnicity (which confers increased risk due to elevated risk of BRCA mutations), predicts her lifetime risk of breast cancer to be 20.4%. This categorizes Ms. P as high risk.

Enhanced screening recommendations for women at high risk

TABLE 48,13,22 summarizes screening recommendations for women deemed to be at high risk for breast cancer. The American Cancer Society (ACS), NCCN, and the American College of Radiology (ACR) recommend that women with at least a 20% lifetime risk have yearly magnetic resonance imaging (MRI) and mammography (staggered so that the patient has 1 test every 6 months) starting 10 years before the age of onset for the youngest affected relative but not before age 30.8 For carriers of high-risk (as well as intermediate-risk) genes, NCCN recommends annual MRI screening starting at age 40.13BRCA1/2 screening includes annual MRI starting at age 25 and annual mammography every 6 months starting at age 30.22 Clinicians should counsel women with moderate risk factors (elevated breast density; personal history of ADH, LCIS, or DCIS) about the potential risks and benefits of enhanced screening and chemoprophylaxis.

Screening recommendations for women at high risk

Risk-reduction strategies

Chemoprophylaxis

The US Preventive Services Task Force (USPSTF) recommends that all women at increased risk for breast cancer consider chemoprophylaxis (B recommendation)23 based on convincing evidence that 5 years of treatment with either a synthetic estrogen reuptake modulator (SERM) or an aromatase inhibitor (AI) decreases the incidence of estrogen receptor positive breast cancers. (See TABLE 57,23,24 for absolute risk reduction.) There is no benefit for chemoprophylaxis in women at average risk (D recommendation).23 It is unclear whether chemoprophylaxis is indicated in women with moderate increased risk (ie, who do not meet the 20% lifetime risk criteria). Chemoprophylaxis may not be effective in women with BRCA1 mutations, as they often develop triple-negative breast cancers.

Chemoprophylaxis regimens for prevention of breast cancer

Accurate risk assessment and shared decision-making enable the clinician and patient to discuss the potential risks and benefits of chemoprophylaxis.7,24 The USPSTF did not find that any 1 risk prediction tool was better than another to identify women who should be counseled about chemoprophylaxis. Clinicians should counsel all women taking AIs about optimizing bone health with adequate calcium and vitamin D intake and routine bone density tests.

Surgical risk reduction

The NCCN guidelines state that risk-reducing bilateral mastectomy is reserved for individuals with high-risk gene variants and individuals with prior chest radiation between ages 10 and 30.25 NCCN also recommends discussing risk-reducing mastectomy with all women with BRCA mutations.22

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer.

Bilateral mastectomy is the most effective method to reduce breast cancer risk and should be discussed after age 25 in women with BRCA mutations and at least 8 years after chest radiation is completed.26 There is a reduction in breast cancer incidence of 90%.25 Breast imaging for screening (mammography or MRI) is not indicated after risk-reducing mastectomy. However, clinical breast examinations of the surgical site are important, because there is a small risk of developing breast cancer in that area.26

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer. It can also reduce the risk of breast cancer in women with BRCA mutations.27

Continue to: CASE

 

 

CASE

Based on her risk assessment results, family history, and genetic heritage, Ms. P qualifies for referral to a genetic counselor for discussion of BRCA testing. The clinician discusses adding annual MRI to Ms. P’s breast cancer screening regimen, based on ACS, NCCN, and ACR recommendations, due to her 20.4% lifetime risk. Discussion of whether and when to start chemoprophylaxis is typically based on breast cancer risk, projected benefit, and the potential impact of medication adverse effects. A high-risk woman is eligible for 5 years of chemoprophylaxis (tamoxifen if premenopausal) based on her lifetime risk. The clinician discusses timing with Ms. P, and even though she is finished with childbearing, she would like to wait until she is age 45, which is before the age at which her aunt was given a diagnosis of breast cancer.

Conclusion

Primary care clinicians are well positioned to identify women with an elevated risk of breast cancer and refer them for enhanced screening and chemoprophylaxis (see ALGORITHM). Shared decision-making with the inclusion of patient decision aids (https://decisionaid.ohri.ca/AZsearch.php?criteria=breast+cancer) about genetic testing, chemoprophylaxis, and prophylactic mastectomy or oophorectomy may help women at intermediate or high risk of breast cancer feel empowered to make decisions about their breast—and overall—health.

CORRESPONDENCE
Sarina Schrager, MD, MS, Professor, Department of Family Medicine and Community Health, University of Wisconsin, 1100 Delaplaine Court, Madison, WI 53715; sbschrag@wisc.edu

Breast cancer is the most common invasive cancer in women in the United States; it is estimated that there will be 287,850 new cases of breast cancer in the United States during 2022 with 43,250 deaths.1 Lives are extended and saved every day because of a robust arsenal of treatments and interventions available to those who have been given a diagnosis of breast cancer. And, of course, lives are also extended and saved when we identify women at risk and provide early interventions. But in busy offices where time is short and there are competing demands on our time, proper assessment of a woman’s risk of breast cancer does not always happen. As a result, women with a higher risk of breast cancer may not be getting appropriate management.2,3

Familiarizing yourself with several risk-assessment tools and knowing when genetic testing is needed can make a big difference. Knowing the timing of mammograms and magnetic resonance imaging (MRI) for women deemed to be at high risk is also key. The following review employs a case-based approach (with an accompanying ALGORITHM) to illustrate how best to identify women who are at heightened risk of breast cancer and maximize their care. We also discuss the chemoprophylaxis regimens that may be used for those at increased risk.

How to assess breast cancer risk

CASE

Rachel P, age 37, presents to establish care. She has an Ashkenazi Jewish background and wonders if she should start doing breast cancer screening before age 40. She has 2 children, ages 4 years and 2 years. Her maternal aunt had unilateral breast cancer at age 54, and her maternal grandmother died of ovarian cancer at age 65.

Risk assessment

The risk assessment process (see ALGORITHM) must start with either the clinician or the patient initiating the discussion about breast cancer risk. The clinician may initiate the discussion with a new patient or at an annual physical examination. The patient may start the discussion because they are experiencing new breast symptoms, have anxiety about developing breast cancer, or have a family member with a new cancer diagnosis.

Risk factors. There are single factors that convey enough risk to automatically designate the patient as high risk (see TABLE 14-9). These factors include having a history of chest radiation between the ages of 10 and 30, a history of breast biopsy with either lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH), past breast and/or ovarian cancer, and either a family or personal history of a high penetrant genetic variant for breast cancer.4-9

High-risk factors for breast cancer

In women with previous chest radiation, breast cancer risk correlates with the total dose of radiation.5 For women with a personal history of breast cancer, the younger the age at diagnosis, the higher the risk of contralateral breast cancer.5 Precancerous changes such as ADH, LCIS, and ductal carcinoma in situ (DCIS) also confer moderate increases in risk. Women with these diagnoses will commonly have follow-up with specialists.

Risk assessment tools. There are several models available to assess a woman’s breast cancer risk (see TABLE 210-12). The Gail model (https://bcrisktool.cancer.gov/) is the oldest, quickest, and most widely known. However, the Gail model only accounts for first-degree relatives diagnosed with breast cancer, may underpredict risk in women with a more extensive family history, and has not been studied in women younger than 35. The International Breast Cancer Intervention Study (IBIS) Risk Evaluation Tool (https://ibis-risk-calculator.magview.com/), commonly referred to as the Tyrer-Cuzick model, incorporates second-degree relatives into the prediction model—although women may not know their full family history. Both the IBIS and the Breast Cancer Surveillance Consortium (BCSC) model (https://tools.bcsc-scc.org/BC5yearRisk/intro.htm) include breast density in the prediction algorithm. The choice of tool depends on clinician comfort and individual patient risk factors. There is no evidence that one model is better than another.10-12

Commonly used breast cancer risk assessment tools

Continue to: CASE

 

 

CASE

Ms. P’s clinician starts with an assessment using the Gail model. However, when the result comes back with average risk, the clinician decides to follow up with the Tyrer-Cuzick model in order to incorporate Ms. P’s multiple ­second-degree relatives with breast and ovarian cancer. (The BCSC model was not used because it only includes first-degree relatives.)

Genetic testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing if a woman has a first- or ­second-degree relative with pancreatic cancer, metastatic prostate cancer, male breast cancer, breast cancer at age 45 or younger, 2 or more breast cancers in a single person, 2 or more people on the same side of the family with at least 1 diagnosed at age 50 or younger, or any relative with ovarian cancer (see TABLE 3).7 Before ordering genetic testing, it is useful to refer the patient to a genetic counselor for a thorough discussion of options.

Genetic testing criteria

Results of genetic testing may include high-risk variants, moderate-risk variants, and variants of unknown significance (VUS), or be negative for any variants. High-risk variants for breast cancer include BRCA1, BRCA2, PALB2, and cancer syndrome variants such as TP53, PTEN, STK11, and CDH1.5,6,9,13-15 These high-risk variants confer sufficient risk that women with these mutations are automatically categorized in the high-risk group. It is estimated that high-risk variants account for only 25% of the genetic risk for breast cancer.16

BRCA1/2 and PTEN mutations confer greater than 80% lifetime risk, while other high-risk variants such as TP53, CDH1, and STK11 confer risks between 25% and 40%. These variants are also associated with cancers of other organs, depending on the mutation.17

Moderate-risk variants—ATM and CHEK2—do not confer sufficient risk to elevate women into the high-risk group. However, they do qualify these intermediate-risk women to participate in a specialized management strategy.5,9,13,18

VUS are those for which the associated risk is unclear, but more research may be done to categorize the risk.9 The clinical management of women with VUS usually entails close monitoring.

In an effort to better characterize breast cancer risk using a combination of pathogenic variants found in broad multi-gene cancer predisposition panels, researchers have developed a method to combine risks in a “polygenic risk score” (PRS) that can be used to counsel women (see “What is a polygenic risk score for breast cancer?” on page 203).19-21PRS predicts an additional 18% of genetic risk in women of European descent.21

SIDEBAR
What is a polygenic risk score for breast cancer?

  • A polygenic risk score (PRS) is a mathematical method to combine results from a variety of different single nucleotide polymorphisms (SNPs; ie, single base pair variants) into a prediction tool that can estimate a woman’s lifetime risk of breast cancer.
  • A PRS may be most accurate in determining risk for women with intermediate pathogenic variants, such as ATM and CHEK2. 19,20
  • PRS has not been studied in non-White women.21

Continue to: CASE

 

 

CASE

Using the assessment results, the clinician talks to Ms. P about her lifetime risk for breast cancer. The Gail model indicates her lifetime risk is 13.3%, just slightly higher than the average (12.5%), and her 5-year risk is 0.5% (average, 0.4%). The IBIS or Tyrer-­Cuzick model, which takes into account her second-degree relatives with breast and ovarian cancer and her Ashkenazi ethnicity (which confers increased risk due to elevated risk of BRCA mutations), predicts her lifetime risk of breast cancer to be 20.4%. This categorizes Ms. P as high risk.

Enhanced screening recommendations for women at high risk

TABLE 48,13,22 summarizes screening recommendations for women deemed to be at high risk for breast cancer. The American Cancer Society (ACS), NCCN, and the American College of Radiology (ACR) recommend that women with at least a 20% lifetime risk have yearly magnetic resonance imaging (MRI) and mammography (staggered so that the patient has 1 test every 6 months) starting 10 years before the age of onset for the youngest affected relative but not before age 30.8 For carriers of high-risk (as well as intermediate-risk) genes, NCCN recommends annual MRI screening starting at age 40.13BRCA1/2 screening includes annual MRI starting at age 25 and annual mammography every 6 months starting at age 30.22 Clinicians should counsel women with moderate risk factors (elevated breast density; personal history of ADH, LCIS, or DCIS) about the potential risks and benefits of enhanced screening and chemoprophylaxis.

Screening recommendations for women at high risk

Risk-reduction strategies

Chemoprophylaxis

The US Preventive Services Task Force (USPSTF) recommends that all women at increased risk for breast cancer consider chemoprophylaxis (B recommendation)23 based on convincing evidence that 5 years of treatment with either a synthetic estrogen reuptake modulator (SERM) or an aromatase inhibitor (AI) decreases the incidence of estrogen receptor positive breast cancers. (See TABLE 57,23,24 for absolute risk reduction.) There is no benefit for chemoprophylaxis in women at average risk (D recommendation).23 It is unclear whether chemoprophylaxis is indicated in women with moderate increased risk (ie, who do not meet the 20% lifetime risk criteria). Chemoprophylaxis may not be effective in women with BRCA1 mutations, as they often develop triple-negative breast cancers.

Chemoprophylaxis regimens for prevention of breast cancer

Accurate risk assessment and shared decision-making enable the clinician and patient to discuss the potential risks and benefits of chemoprophylaxis.7,24 The USPSTF did not find that any 1 risk prediction tool was better than another to identify women who should be counseled about chemoprophylaxis. Clinicians should counsel all women taking AIs about optimizing bone health with adequate calcium and vitamin D intake and routine bone density tests.

Surgical risk reduction

The NCCN guidelines state that risk-reducing bilateral mastectomy is reserved for individuals with high-risk gene variants and individuals with prior chest radiation between ages 10 and 30.25 NCCN also recommends discussing risk-reducing mastectomy with all women with BRCA mutations.22

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer.

Bilateral mastectomy is the most effective method to reduce breast cancer risk and should be discussed after age 25 in women with BRCA mutations and at least 8 years after chest radiation is completed.26 There is a reduction in breast cancer incidence of 90%.25 Breast imaging for screening (mammography or MRI) is not indicated after risk-reducing mastectomy. However, clinical breast examinations of the surgical site are important, because there is a small risk of developing breast cancer in that area.26

Risk-reducing oophorectomy is the standard of care for women with BRCA mutations to reduce the risk of ovarian cancer. It can also reduce the risk of breast cancer in women with BRCA mutations.27

Continue to: CASE

 

 

CASE

Based on her risk assessment results, family history, and genetic heritage, Ms. P qualifies for referral to a genetic counselor for discussion of BRCA testing. The clinician discusses adding annual MRI to Ms. P’s breast cancer screening regimen, based on ACS, NCCN, and ACR recommendations, due to her 20.4% lifetime risk. Discussion of whether and when to start chemoprophylaxis is typically based on breast cancer risk, projected benefit, and the potential impact of medication adverse effects. A high-risk woman is eligible for 5 years of chemoprophylaxis (tamoxifen if premenopausal) based on her lifetime risk. The clinician discusses timing with Ms. P, and even though she is finished with childbearing, she would like to wait until she is age 45, which is before the age at which her aunt was given a diagnosis of breast cancer.

Conclusion

Primary care clinicians are well positioned to identify women with an elevated risk of breast cancer and refer them for enhanced screening and chemoprophylaxis (see ALGORITHM). Shared decision-making with the inclusion of patient decision aids (https://decisionaid.ohri.ca/AZsearch.php?criteria=breast+cancer) about genetic testing, chemoprophylaxis, and prophylactic mastectomy or oophorectomy may help women at intermediate or high risk of breast cancer feel empowered to make decisions about their breast—and overall—health.

CORRESPONDENCE
Sarina Schrager, MD, MS, Professor, Department of Family Medicine and Community Health, University of Wisconsin, 1100 Delaplaine Court, Madison, WI 53715; sbschrag@wisc.edu

References

1. National Cancer Institute. Cancer stat facts: female breast cancer. Accessed May 13, 2022. https://seer.cancer.gov/statfacts/html/breast.html

2. Guerra CE, Sherman M, Armstrong K. Diffusion of breast cancer risk assessment in primary care. J Am Board Fam Med. 2009;22:272-279. doi:10.3122/jabfm.2009.03.080153

3. Hamilton JG, Abdiwahab E, Edwards HM, et al. Primary care providers’ cancer genetic testing-related knowledge, attitudes, and communication behaviors: a systematic review and research agenda. J Gen Intern Med. 2017;32:315-324. doi:10.1007/s11606-016-3943-4

4. Eden KB, Ivlev I, Bensching KL, et al. Use of an online breast cancer risk assessment and patient decision aid in primary care practices. J Womens Health (Larchmt). 2020;29:763-769. doi: 10.1089/jwh.2019.8143

5. Kleibl Z, Kristensen VN. Women at high risk of breast cancer: molecular characteristics, clinical presentation and management. Breast. 2016;28:136-44. doi: 10.1016/j.breast.2016.05.006

6. Sciaraffa T, Guido B, Khan SA, et al. Breast cancer risk assessment and management programs: a practical guide. Breast J. 2020;26:1556-1564. doi: 10.1111/tbj.13967

7. Farkas A, Vanderberg R, Merriam S, et al. Breast cancer chemoprevention: a practical guide for the primary care provider. J Womens Health (Larchmt). 2020;29:46-56. doi: 10.1089/jwh.2018.7643

8. McClintock AH, Golob AL, Laya MB. Breast cancer risk assessment: a step-wise approach for primary care providers on the front lines of shared decision making. Mayo Clin Proc. 2020;95:1268-1275. doi: 10.1016/j.mayocp.2020.04.017

9. Catana A, Apostu AP, Antemie RG. Multi gene panel testing for hereditary breast cancer - is it ready to be used? Med Pharm Rep. 2019;92:220-225. doi: 10.15386/mpr-1083

10. Barke LD, Freivogel ME. Breast cancer risk assessment models and high-risk screening. Radiol Clin North Am. 2017;55:457-474. doi: 10.1016/j.rcl.2016.12.013

11. Amir E, Freedman OC, Seruga B, et al. Assessing women at high risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst. 2010;102:680-91. doi: 10.1093/jnci/djq088

12. Kim G, Bahl M. Assessing risk of breast cancer: a review of risk prediction models. J Breast Imaging. 2021;3:144-155. doi: 10.1093/jbi/wbab001

13. Narod SA. Which genes for hereditary breast cancer? N Engl J Med. 2021;384:471-473. doi: 10.1056/NEJMe2035083

14. Couch FJ, Shimelis H, Hu C, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 2017;3:1190-1196. doi: 10.1001/jamaoncol.2017.0424

15. Obeid EI, Hall MJ, Daly MB. Multigene panel testing and breast cancer risk: is it time to scale down? JAMA Oncol. 2017;3:1176-1177. doi: 10.1001/jamaoncol.2017.0342

16. Michailidou K, Lindström S, Dennis J, et al. Association analysis identifies 65 new breast cancer risk loci. Nature. 2017;551:92-94. doi: 10.1038/nature24284

17. Shiovitz S, Korde LA. Genetics of breast cancer: a topic in evolution. Ann Oncol. 2015;26:1291-1299. doi: 10.1093/annonc/mdv022

18. Hu C, Hart SN, Gnanaolivu R, et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med. 2021;384:440-451. doi: 10.1056/NEJMoa2005936

19. Gao C, Polley EC, Hart SN, et al. Risk of breast cancer among carriers of pathogenic variants in breast cancer predisposition genes varies by polygenic risk score. J Clin Oncol. 2021;39:2564-2573. doi: 10.1200/JCO.20.01992

20. Gallagher S, Hughes E, Wagner S, et al. Association of a polygenic risk score with breast cancer among women carriers of high- and moderate-risk breast cancer genes. JAMA Netw Open. 2020;3:e208501. doi: 10.1001/jamanetworkopen.2020.8501

21. Yanes T, Young MA, Meiser B, et al. Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field. Breast Cancer Res. 2020;22:21. doi: 10.1186/s13058-020-01260-3

22. Schrager S, Torell E, Ledford K, et al. Managing a woman with BRCA mutations? Shared decision-making is key. J Fam Pract. 2020;69:237-243

23. US Preventive Services Task Force; Owens DK, Davidson KW, Krist AH, et al. Medication use to reduce risk of breast cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322:857-867. doi: 10.1001/jama.2019.11885

24. Pruthi S, Heisey RE, Bevers TB. Chemoprevention for breast cancer. Ann Surg Oncol 2015;22:3230-3235. doi: 10.1245/s10434-015-4715-9

25. Britt KL, Cuzick J, Phillips KA. Key steps for effective breast cancer prevention. Nat Rev Cancer. 2020;20:417-436. doi: 10.1038/s41568-020-0266-x

26. Jatoi I, Kemp Z. Risk-reducing mastectomy. JAMA. 2021;325:1781-1782. doi: 10.1001/jama.2020.22414

27. Choi Y, Terry MB, Daly MB, et al. Association of risk-reducing salpingo-oophorectomy with breast cancer risk in women with BRCA1 and BRCA2 pathogenic variants. JAMA Oncol. 2021;7:585-592. doi:10.1001/jamaoncol.2020.7995

References

1. National Cancer Institute. Cancer stat facts: female breast cancer. Accessed May 13, 2022. https://seer.cancer.gov/statfacts/html/breast.html

2. Guerra CE, Sherman M, Armstrong K. Diffusion of breast cancer risk assessment in primary care. J Am Board Fam Med. 2009;22:272-279. doi:10.3122/jabfm.2009.03.080153

3. Hamilton JG, Abdiwahab E, Edwards HM, et al. Primary care providers’ cancer genetic testing-related knowledge, attitudes, and communication behaviors: a systematic review and research agenda. J Gen Intern Med. 2017;32:315-324. doi:10.1007/s11606-016-3943-4

4. Eden KB, Ivlev I, Bensching KL, et al. Use of an online breast cancer risk assessment and patient decision aid in primary care practices. J Womens Health (Larchmt). 2020;29:763-769. doi: 10.1089/jwh.2019.8143

5. Kleibl Z, Kristensen VN. Women at high risk of breast cancer: molecular characteristics, clinical presentation and management. Breast. 2016;28:136-44. doi: 10.1016/j.breast.2016.05.006

6. Sciaraffa T, Guido B, Khan SA, et al. Breast cancer risk assessment and management programs: a practical guide. Breast J. 2020;26:1556-1564. doi: 10.1111/tbj.13967

7. Farkas A, Vanderberg R, Merriam S, et al. Breast cancer chemoprevention: a practical guide for the primary care provider. J Womens Health (Larchmt). 2020;29:46-56. doi: 10.1089/jwh.2018.7643

8. McClintock AH, Golob AL, Laya MB. Breast cancer risk assessment: a step-wise approach for primary care providers on the front lines of shared decision making. Mayo Clin Proc. 2020;95:1268-1275. doi: 10.1016/j.mayocp.2020.04.017

9. Catana A, Apostu AP, Antemie RG. Multi gene panel testing for hereditary breast cancer - is it ready to be used? Med Pharm Rep. 2019;92:220-225. doi: 10.15386/mpr-1083

10. Barke LD, Freivogel ME. Breast cancer risk assessment models and high-risk screening. Radiol Clin North Am. 2017;55:457-474. doi: 10.1016/j.rcl.2016.12.013

11. Amir E, Freedman OC, Seruga B, et al. Assessing women at high risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst. 2010;102:680-91. doi: 10.1093/jnci/djq088

12. Kim G, Bahl M. Assessing risk of breast cancer: a review of risk prediction models. J Breast Imaging. 2021;3:144-155. doi: 10.1093/jbi/wbab001

13. Narod SA. Which genes for hereditary breast cancer? N Engl J Med. 2021;384:471-473. doi: 10.1056/NEJMe2035083

14. Couch FJ, Shimelis H, Hu C, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 2017;3:1190-1196. doi: 10.1001/jamaoncol.2017.0424

15. Obeid EI, Hall MJ, Daly MB. Multigene panel testing and breast cancer risk: is it time to scale down? JAMA Oncol. 2017;3:1176-1177. doi: 10.1001/jamaoncol.2017.0342

16. Michailidou K, Lindström S, Dennis J, et al. Association analysis identifies 65 new breast cancer risk loci. Nature. 2017;551:92-94. doi: 10.1038/nature24284

17. Shiovitz S, Korde LA. Genetics of breast cancer: a topic in evolution. Ann Oncol. 2015;26:1291-1299. doi: 10.1093/annonc/mdv022

18. Hu C, Hart SN, Gnanaolivu R, et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med. 2021;384:440-451. doi: 10.1056/NEJMoa2005936

19. Gao C, Polley EC, Hart SN, et al. Risk of breast cancer among carriers of pathogenic variants in breast cancer predisposition genes varies by polygenic risk score. J Clin Oncol. 2021;39:2564-2573. doi: 10.1200/JCO.20.01992

20. Gallagher S, Hughes E, Wagner S, et al. Association of a polygenic risk score with breast cancer among women carriers of high- and moderate-risk breast cancer genes. JAMA Netw Open. 2020;3:e208501. doi: 10.1001/jamanetworkopen.2020.8501

21. Yanes T, Young MA, Meiser B, et al. Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field. Breast Cancer Res. 2020;22:21. doi: 10.1186/s13058-020-01260-3

22. Schrager S, Torell E, Ledford K, et al. Managing a woman with BRCA mutations? Shared decision-making is key. J Fam Pract. 2020;69:237-243

23. US Preventive Services Task Force; Owens DK, Davidson KW, Krist AH, et al. Medication use to reduce risk of breast cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322:857-867. doi: 10.1001/jama.2019.11885

24. Pruthi S, Heisey RE, Bevers TB. Chemoprevention for breast cancer. Ann Surg Oncol 2015;22:3230-3235. doi: 10.1245/s10434-015-4715-9

25. Britt KL, Cuzick J, Phillips KA. Key steps for effective breast cancer prevention. Nat Rev Cancer. 2020;20:417-436. doi: 10.1038/s41568-020-0266-x

26. Jatoi I, Kemp Z. Risk-reducing mastectomy. JAMA. 2021;325:1781-1782. doi: 10.1001/jama.2020.22414

27. Choi Y, Terry MB, Daly MB, et al. Association of risk-reducing salpingo-oophorectomy with breast cancer risk in women with BRCA1 and BRCA2 pathogenic variants. JAMA Oncol. 2021;7:585-592. doi:10.1001/jamaoncol.2020.7995

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PRACTICE RECOMMENDATIONS

› Assess breast cancer risk in all women starting at age 35. C

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Patients asking about APOE gene test results? Here’s what to tell them

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Patients asking about APOE gene test results? Here’s what to tell them

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.1 Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),2 and direct-to-consumer (DTC) services that provide these results as part of large panels.3 Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.3 A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 14), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

Risk for MCI or dementia due to AD based on APOE genotype

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).5 That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).6 In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway10).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.11 While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.12

Continue to: 7 clinical scenarios and how to approach them

 

 

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 213-16.

How to address APOE genetic test results with older adults in primary care

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 14 for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.17 For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,4 estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

 

 

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.18 But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

 

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.2

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.21 Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

 

 

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.24 Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.27

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.28 Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.29 Interventions that personalize and validate an individual’s experience can help address internalized stigma.30 Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.31 It would be prudent to address proper blood pressure control32 and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.33 But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

 

 

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).34 Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.35 Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; Stites@UPenn.edu

References

1. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2018;14:535-562. doi: 10.1016/j.jalz.2018.02.018 PMCID:PMC5958625

2. Langlois CM, Bradbury A, Wood EM, et al. Alzheimer’s Prevention Initiative Generation Program: development of an APOE genetic counseling and disclosure process in the context of clinical trials. Alzheimers Dement Transl Res Clin Interv. 2019;5:705-716. doi: 10.1016/j.trci.2019.09.013

3. Frank L, Wesson Ashford J, Bayley PJ, et al. Genetic risk of Alzheimer’s disease: three wishes now that the genie is out of the bottle. J Alzheimers Dis. 2018;66:421-423. doi: 10.3233/JAD-180629

4. Qian J, Wolters FJ, Beiser A, et al. APOE-related risk of mild cognitive impairment and dementia for prevention trials: an analysis of four cohorts. PLOS Med. 2017;14:e1002254. doi: 10.1371/journal.pmed.1002254

5. Sperling RA, Jack CR, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367-385. doi: 10.1016/j.jalz.2011.05.2351

6. FDA. November 6, 2020: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement. Published November 12, 2020. Accessed January 14, 2021. www.fda.gov/advisory-committees/advisory-committee-calendar/november-6-2020-meeting-peripheral-and-central-nervous-system-drugs-advisory-committee-meeting

7. Cummings J. Why aducanumab is important. Nat Med. 2021;27:1498-1498. doi: 10.1038/s41591-021-01478-4

8. Alexander GC, Karlawish J. The problem of aducanumab for the treatment of Alzheimer disease. Ann Intern Med. 2021;174:1303-1304. doi: 10.7326/M21-2603

9. Mullard A. More Alzheimer’s drugs head for FDA review: what scientists are watching. Nature. 2021;599:544-545. doi: 10.1038/d41586-021-03410-9

10. Rosenberg A, Mangialasche F, Ngandu T, et al. Multidomain interventions to prevent cognitive impairment, Alzheimer’s disease, and dementia: from finger to world-wide fingers. J Prev Alzheimers Dis. 2019:1-8. doi: 10.14283/jpad.2019.41

11. FDA. Commissioner of the FDA allows marketing of first direct-to-consumer tests that provide genetic risk information for certain conditions. Published March 24, 2020. Accessed November 7, 2020. www.fda.gov/news-events/press-announcements/fda-allows-marketing-first-direct-consumer-tests-provide-genetic-risk-information-certain-conditions

12. Blell M, Hunter MA. Direct-to-consumer genetic testing’s red herring: “genetic ancestry” and personalized medicine. Front Med. 2019;6:48. doi: 10.3389/fmed.2019.00048

13. Ekstrand B, Scheers N, Rasmussen MK, et al. Brain foods - the role of diet in brain performance and health. Nutr Rev. 2021;79:693-708. doi: 10.1093/nutrit/nuaa091

14. Cherian L, Wang Y, Fakuda K, et al. Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet slows cognitive decline after stroke. J Prev Alzheimers Dis. 2019;6:267-273. doi: 10.14283/jpad.2019.28

15. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet. 2020;396:413-446. doi: 10.1016/S0140-6736(20)30367-6

16. Livingston PG, Sommerlad A, Orgeta V, et al. The Lancet International Commission on Dementia Prevention and Care. 2017. Accessed March 30, 2022. https://discovery.ucl.ac.uk/id/eprint/1567635/1/Livingston_Dementia_prevention_intervention_care.pdf

17. Peters U. What is the function of confirmation bias? Erkenntnis. April 2020. doi: 10.1007/s10670-020-00252-1

18. Barnes LL, Bennett DA. Cognitive resilience in APOE*ε4 carriers—is race important? Nat Rev Neurol. 2015;11:190-191. doi: 10.1038/nrneurol.2015.38

19. Farrer LA. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA. 1997;278:1349. doi: 10.1001/jama.1997.03550160069041

20. Evans DA, Bennett DA, Wilson RS, et al. Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol. 2003;60:185. doi: 10.1001/archneur.60.2.185

21. Chung WW, Chen CA, Cupples LA, et al. A new scale measuring psychologic impact of genetic susceptibility testing for Alzheimer disease. Alzheimer Dis Assoc Disord. 2009;23:50-56. doi: 10.1097/WAD.0b013e318188429e

22. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606-613. doi: 10.1046/j.1525-1497.2001.016009606.x

23. Yesavage JA, Sheikh JI. 9/Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986;5:165-173. doi: 10.1300/J018v05n01_09

24. Green RC, Roberts JS, Cupples LA, et al. Disclosure of APOE genotype for risk of Alzheimer’s disease. N Engl J Med. 2009;361:245-254. doi: 10.1056/NEJMoa0809578

25. Lineweaver TT, Bondi MW, Galasko D, et al. Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults. Am J Psychiatry. 2014;171:201-208. doi: 10.1176/appi.ajp.2013.12121590

26. Karlawish J. Understanding the impact of learning an amyloid PET scan result: preliminary findings from the SOKRATES study. Alzheimers Dement J Alzheimers Assoc. 2016;12:P325. doi: 10.1016/j.jalz.2016.06.594

27. Stites SD. Cognitively healthy individuals want to know their risk for Alzheimer’s disease: what should we do? J Alzheimers Dis. 2018;62:499-502. doi: 10.3233/JAD-171089

28. Milne S, Lomax C, Freeston MH. A review of the relationship between intolerance of uncertainty and threat appraisal in anxiety. Cogn Behav Ther. 2019;12:e38. doi: 10.1017/S1754470X19000230

29. Hebert EA, Dugas MJ. Behavioral experiments for intolerance of uncertainty: challenging the unknown in the treatment of generalized anxiety disorder. Cogn Behav Pract. 2019;26:421-436. doi: 10.1016/j.cbpra.2018.07.007

30. Stites SD, Karlawish, J. Stigma of Alzheimer’s disease dementia: considerations for practice. Pract Neurol. Published June 2018. Accessed January 31, 2019. http://practicalneurology.com/2018/06/stigma-of-alzheimers-disease-dementia/

31. Solomon A, Turunen H, Ngandu T, et al. Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: a subgroup analysis of a randomized clinical trial. JAMA Neurol. 2018;75:462. doi: 10.1001/jamaneurol.2017.4365

32. Peters R, Warwick J, Anstey KJ, et al. Blood pressure and dementia: what the SPRINT-MIND trial adds and what we still need to know. Neurology. 2019;92:1017-1018. doi: 10.1212/WNL.0000000000007543

33. Musunuru K, Hershberger RE, Day SM, et al. Genetic testing for inherited cardiovascular diseases: a Scientific Statement from the American Heart Association. Circ Genom Precis Med. 2020;13: e000067. doi: 10.1161/HCG.0000000000000067

34. Margaglione M, Seripa D, Gravina C, et al. Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke. Stroke. 1998;29:399-403. doi: 10.1161/01.STR.29.2.399

35. National Institute on Aging. Alzheimer’s disease genetics fact sheet. Reviewed December 24, 2019. Accessed April 10, 2022. www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet

36. Belluck P, Kaplan S, Robbins R. How Aduhelm, an unproven Alzheimer’s drug, got approved. The New York Times. Published July 19, 2021. Updated Oct. 20, 2021. Accessed December 1, 2021. www.nytimes.com/2021/07/19/health/alzheimers-drug-aduhelm-fda.html

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Stites@UPenn.edu

The authors reported no potential conflict of interest relevant to this article. Dr. Stites is supported by the Alzheimer’s Association (AARF-17-528934) and the National Institute on Aging (K23AG065442).

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Stites@UPenn.edu

The authors reported no potential conflict of interest relevant to this article. Dr. Stites is supported by the Alzheimer’s Association (AARF-17-528934) and the National Institute on Aging (K23AG065442).

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Stites@UPenn.edu

The authors reported no potential conflict of interest relevant to this article. Dr. Stites is supported by the Alzheimer’s Association (AARF-17-528934) and the National Institute on Aging (K23AG065442).

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Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.1 Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),2 and direct-to-consumer (DTC) services that provide these results as part of large panels.3 Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.3 A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 14), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

Risk for MCI or dementia due to AD based on APOE genotype

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).5 That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).6 In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway10).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.11 While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.12

Continue to: 7 clinical scenarios and how to approach them

 

 

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 213-16.

How to address APOE genetic test results with older adults in primary care

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 14 for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.17 For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,4 estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

 

 

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.18 But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

 

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.2

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.21 Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

 

 

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.24 Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.27

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.28 Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.29 Interventions that personalize and validate an individual’s experience can help address internalized stigma.30 Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.31 It would be prudent to address proper blood pressure control32 and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.33 But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

 

 

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).34 Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.35 Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; Stites@UPenn.edu

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.1 Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),2 and direct-to-consumer (DTC) services that provide these results as part of large panels.3 Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.3 A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 14), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

Risk for MCI or dementia due to AD based on APOE genotype

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).5 That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).6 In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway10).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.11 While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.12

Continue to: 7 clinical scenarios and how to approach them

 

 

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 213-16.

How to address APOE genetic test results with older adults in primary care

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 14 for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.17 For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,4 estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

 

 

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.18 But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

 

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.2

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.21 Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

 

 

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.24 Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.27

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.28 Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.29 Interventions that personalize and validate an individual’s experience can help address internalized stigma.30 Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.31 It would be prudent to address proper blood pressure control32 and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.33 But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

 

 

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).34 Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.35 Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; Stites@UPenn.edu

References

1. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2018;14:535-562. doi: 10.1016/j.jalz.2018.02.018 PMCID:PMC5958625

2. Langlois CM, Bradbury A, Wood EM, et al. Alzheimer’s Prevention Initiative Generation Program: development of an APOE genetic counseling and disclosure process in the context of clinical trials. Alzheimers Dement Transl Res Clin Interv. 2019;5:705-716. doi: 10.1016/j.trci.2019.09.013

3. Frank L, Wesson Ashford J, Bayley PJ, et al. Genetic risk of Alzheimer’s disease: three wishes now that the genie is out of the bottle. J Alzheimers Dis. 2018;66:421-423. doi: 10.3233/JAD-180629

4. Qian J, Wolters FJ, Beiser A, et al. APOE-related risk of mild cognitive impairment and dementia for prevention trials: an analysis of four cohorts. PLOS Med. 2017;14:e1002254. doi: 10.1371/journal.pmed.1002254

5. Sperling RA, Jack CR, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367-385. doi: 10.1016/j.jalz.2011.05.2351

6. FDA. November 6, 2020: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement. Published November 12, 2020. Accessed January 14, 2021. www.fda.gov/advisory-committees/advisory-committee-calendar/november-6-2020-meeting-peripheral-and-central-nervous-system-drugs-advisory-committee-meeting

7. Cummings J. Why aducanumab is important. Nat Med. 2021;27:1498-1498. doi: 10.1038/s41591-021-01478-4

8. Alexander GC, Karlawish J. The problem of aducanumab for the treatment of Alzheimer disease. Ann Intern Med. 2021;174:1303-1304. doi: 10.7326/M21-2603

9. Mullard A. More Alzheimer’s drugs head for FDA review: what scientists are watching. Nature. 2021;599:544-545. doi: 10.1038/d41586-021-03410-9

10. Rosenberg A, Mangialasche F, Ngandu T, et al. Multidomain interventions to prevent cognitive impairment, Alzheimer’s disease, and dementia: from finger to world-wide fingers. J Prev Alzheimers Dis. 2019:1-8. doi: 10.14283/jpad.2019.41

11. FDA. Commissioner of the FDA allows marketing of first direct-to-consumer tests that provide genetic risk information for certain conditions. Published March 24, 2020. Accessed November 7, 2020. www.fda.gov/news-events/press-announcements/fda-allows-marketing-first-direct-consumer-tests-provide-genetic-risk-information-certain-conditions

12. Blell M, Hunter MA. Direct-to-consumer genetic testing’s red herring: “genetic ancestry” and personalized medicine. Front Med. 2019;6:48. doi: 10.3389/fmed.2019.00048

13. Ekstrand B, Scheers N, Rasmussen MK, et al. Brain foods - the role of diet in brain performance and health. Nutr Rev. 2021;79:693-708. doi: 10.1093/nutrit/nuaa091

14. Cherian L, Wang Y, Fakuda K, et al. Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet slows cognitive decline after stroke. J Prev Alzheimers Dis. 2019;6:267-273. doi: 10.14283/jpad.2019.28

15. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet. 2020;396:413-446. doi: 10.1016/S0140-6736(20)30367-6

16. Livingston PG, Sommerlad A, Orgeta V, et al. The Lancet International Commission on Dementia Prevention and Care. 2017. Accessed March 30, 2022. https://discovery.ucl.ac.uk/id/eprint/1567635/1/Livingston_Dementia_prevention_intervention_care.pdf

17. Peters U. What is the function of confirmation bias? Erkenntnis. April 2020. doi: 10.1007/s10670-020-00252-1

18. Barnes LL, Bennett DA. Cognitive resilience in APOE*ε4 carriers—is race important? Nat Rev Neurol. 2015;11:190-191. doi: 10.1038/nrneurol.2015.38

19. Farrer LA. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA. 1997;278:1349. doi: 10.1001/jama.1997.03550160069041

20. Evans DA, Bennett DA, Wilson RS, et al. Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol. 2003;60:185. doi: 10.1001/archneur.60.2.185

21. Chung WW, Chen CA, Cupples LA, et al. A new scale measuring psychologic impact of genetic susceptibility testing for Alzheimer disease. Alzheimer Dis Assoc Disord. 2009;23:50-56. doi: 10.1097/WAD.0b013e318188429e

22. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606-613. doi: 10.1046/j.1525-1497.2001.016009606.x

23. Yesavage JA, Sheikh JI. 9/Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986;5:165-173. doi: 10.1300/J018v05n01_09

24. Green RC, Roberts JS, Cupples LA, et al. Disclosure of APOE genotype for risk of Alzheimer’s disease. N Engl J Med. 2009;361:245-254. doi: 10.1056/NEJMoa0809578

25. Lineweaver TT, Bondi MW, Galasko D, et al. Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults. Am J Psychiatry. 2014;171:201-208. doi: 10.1176/appi.ajp.2013.12121590

26. Karlawish J. Understanding the impact of learning an amyloid PET scan result: preliminary findings from the SOKRATES study. Alzheimers Dement J Alzheimers Assoc. 2016;12:P325. doi: 10.1016/j.jalz.2016.06.594

27. Stites SD. Cognitively healthy individuals want to know their risk for Alzheimer’s disease: what should we do? J Alzheimers Dis. 2018;62:499-502. doi: 10.3233/JAD-171089

28. Milne S, Lomax C, Freeston MH. A review of the relationship between intolerance of uncertainty and threat appraisal in anxiety. Cogn Behav Ther. 2019;12:e38. doi: 10.1017/S1754470X19000230

29. Hebert EA, Dugas MJ. Behavioral experiments for intolerance of uncertainty: challenging the unknown in the treatment of generalized anxiety disorder. Cogn Behav Pract. 2019;26:421-436. doi: 10.1016/j.cbpra.2018.07.007

30. Stites SD, Karlawish, J. Stigma of Alzheimer’s disease dementia: considerations for practice. Pract Neurol. Published June 2018. Accessed January 31, 2019. http://practicalneurology.com/2018/06/stigma-of-alzheimers-disease-dementia/

31. Solomon A, Turunen H, Ngandu T, et al. Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: a subgroup analysis of a randomized clinical trial. JAMA Neurol. 2018;75:462. doi: 10.1001/jamaneurol.2017.4365

32. Peters R, Warwick J, Anstey KJ, et al. Blood pressure and dementia: what the SPRINT-MIND trial adds and what we still need to know. Neurology. 2019;92:1017-1018. doi: 10.1212/WNL.0000000000007543

33. Musunuru K, Hershberger RE, Day SM, et al. Genetic testing for inherited cardiovascular diseases: a Scientific Statement from the American Heart Association. Circ Genom Precis Med. 2020;13: e000067. doi: 10.1161/HCG.0000000000000067

34. Margaglione M, Seripa D, Gravina C, et al. Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke. Stroke. 1998;29:399-403. doi: 10.1161/01.STR.29.2.399

35. National Institute on Aging. Alzheimer’s disease genetics fact sheet. Reviewed December 24, 2019. Accessed April 10, 2022. www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet

36. Belluck P, Kaplan S, Robbins R. How Aduhelm, an unproven Alzheimer’s drug, got approved. The New York Times. Published July 19, 2021. Updated Oct. 20, 2021. Accessed December 1, 2021. www.nytimes.com/2021/07/19/health/alzheimers-drug-aduhelm-fda.html

References

1. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2018;14:535-562. doi: 10.1016/j.jalz.2018.02.018 PMCID:PMC5958625

2. Langlois CM, Bradbury A, Wood EM, et al. Alzheimer’s Prevention Initiative Generation Program: development of an APOE genetic counseling and disclosure process in the context of clinical trials. Alzheimers Dement Transl Res Clin Interv. 2019;5:705-716. doi: 10.1016/j.trci.2019.09.013

3. Frank L, Wesson Ashford J, Bayley PJ, et al. Genetic risk of Alzheimer’s disease: three wishes now that the genie is out of the bottle. J Alzheimers Dis. 2018;66:421-423. doi: 10.3233/JAD-180629

4. Qian J, Wolters FJ, Beiser A, et al. APOE-related risk of mild cognitive impairment and dementia for prevention trials: an analysis of four cohorts. PLOS Med. 2017;14:e1002254. doi: 10.1371/journal.pmed.1002254

5. Sperling RA, Jack CR, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367-385. doi: 10.1016/j.jalz.2011.05.2351

6. FDA. November 6, 2020: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement. Published November 12, 2020. Accessed January 14, 2021. www.fda.gov/advisory-committees/advisory-committee-calendar/november-6-2020-meeting-peripheral-and-central-nervous-system-drugs-advisory-committee-meeting

7. Cummings J. Why aducanumab is important. Nat Med. 2021;27:1498-1498. doi: 10.1038/s41591-021-01478-4

8. Alexander GC, Karlawish J. The problem of aducanumab for the treatment of Alzheimer disease. Ann Intern Med. 2021;174:1303-1304. doi: 10.7326/M21-2603

9. Mullard A. More Alzheimer’s drugs head for FDA review: what scientists are watching. Nature. 2021;599:544-545. doi: 10.1038/d41586-021-03410-9

10. Rosenberg A, Mangialasche F, Ngandu T, et al. Multidomain interventions to prevent cognitive impairment, Alzheimer’s disease, and dementia: from finger to world-wide fingers. J Prev Alzheimers Dis. 2019:1-8. doi: 10.14283/jpad.2019.41

11. FDA. Commissioner of the FDA allows marketing of first direct-to-consumer tests that provide genetic risk information for certain conditions. Published March 24, 2020. Accessed November 7, 2020. www.fda.gov/news-events/press-announcements/fda-allows-marketing-first-direct-consumer-tests-provide-genetic-risk-information-certain-conditions

12. Blell M, Hunter MA. Direct-to-consumer genetic testing’s red herring: “genetic ancestry” and personalized medicine. Front Med. 2019;6:48. doi: 10.3389/fmed.2019.00048

13. Ekstrand B, Scheers N, Rasmussen MK, et al. Brain foods - the role of diet in brain performance and health. Nutr Rev. 2021;79:693-708. doi: 10.1093/nutrit/nuaa091

14. Cherian L, Wang Y, Fakuda K, et al. Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet slows cognitive decline after stroke. J Prev Alzheimers Dis. 2019;6:267-273. doi: 10.14283/jpad.2019.28

15. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet. 2020;396:413-446. doi: 10.1016/S0140-6736(20)30367-6

16. Livingston PG, Sommerlad A, Orgeta V, et al. The Lancet International Commission on Dementia Prevention and Care. 2017. Accessed March 30, 2022. https://discovery.ucl.ac.uk/id/eprint/1567635/1/Livingston_Dementia_prevention_intervention_care.pdf

17. Peters U. What is the function of confirmation bias? Erkenntnis. April 2020. doi: 10.1007/s10670-020-00252-1

18. Barnes LL, Bennett DA. Cognitive resilience in APOE*ε4 carriers—is race important? Nat Rev Neurol. 2015;11:190-191. doi: 10.1038/nrneurol.2015.38

19. Farrer LA. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA. 1997;278:1349. doi: 10.1001/jama.1997.03550160069041

20. Evans DA, Bennett DA, Wilson RS, et al. Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol. 2003;60:185. doi: 10.1001/archneur.60.2.185

21. Chung WW, Chen CA, Cupples LA, et al. A new scale measuring psychologic impact of genetic susceptibility testing for Alzheimer disease. Alzheimer Dis Assoc Disord. 2009;23:50-56. doi: 10.1097/WAD.0b013e318188429e

22. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606-613. doi: 10.1046/j.1525-1497.2001.016009606.x

23. Yesavage JA, Sheikh JI. 9/Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. Clin Gerontol. 1986;5:165-173. doi: 10.1300/J018v05n01_09

24. Green RC, Roberts JS, Cupples LA, et al. Disclosure of APOE genotype for risk of Alzheimer’s disease. N Engl J Med. 2009;361:245-254. doi: 10.1056/NEJMoa0809578

25. Lineweaver TT, Bondi MW, Galasko D, et al. Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults. Am J Psychiatry. 2014;171:201-208. doi: 10.1176/appi.ajp.2013.12121590

26. Karlawish J. Understanding the impact of learning an amyloid PET scan result: preliminary findings from the SOKRATES study. Alzheimers Dement J Alzheimers Assoc. 2016;12:P325. doi: 10.1016/j.jalz.2016.06.594

27. Stites SD. Cognitively healthy individuals want to know their risk for Alzheimer’s disease: what should we do? J Alzheimers Dis. 2018;62:499-502. doi: 10.3233/JAD-171089

28. Milne S, Lomax C, Freeston MH. A review of the relationship between intolerance of uncertainty and threat appraisal in anxiety. Cogn Behav Ther. 2019;12:e38. doi: 10.1017/S1754470X19000230

29. Hebert EA, Dugas MJ. Behavioral experiments for intolerance of uncertainty: challenging the unknown in the treatment of generalized anxiety disorder. Cogn Behav Pract. 2019;26:421-436. doi: 10.1016/j.cbpra.2018.07.007

30. Stites SD, Karlawish, J. Stigma of Alzheimer’s disease dementia: considerations for practice. Pract Neurol. Published June 2018. Accessed January 31, 2019. http://practicalneurology.com/2018/06/stigma-of-alzheimers-disease-dementia/

31. Solomon A, Turunen H, Ngandu T, et al. Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: a subgroup analysis of a randomized clinical trial. JAMA Neurol. 2018;75:462. doi: 10.1001/jamaneurol.2017.4365

32. Peters R, Warwick J, Anstey KJ, et al. Blood pressure and dementia: what the SPRINT-MIND trial adds and what we still need to know. Neurology. 2019;92:1017-1018. doi: 10.1212/WNL.0000000000007543

33. Musunuru K, Hershberger RE, Day SM, et al. Genetic testing for inherited cardiovascular diseases: a Scientific Statement from the American Heart Association. Circ Genom Precis Med. 2020;13: e000067. doi: 10.1161/HCG.0000000000000067

34. Margaglione M, Seripa D, Gravina C, et al. Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke. Stroke. 1998;29:399-403. doi: 10.1161/01.STR.29.2.399

35. National Institute on Aging. Alzheimer’s disease genetics fact sheet. Reviewed December 24, 2019. Accessed April 10, 2022. www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet

36. Belluck P, Kaplan S, Robbins R. How Aduhelm, an unproven Alzheimer’s drug, got approved. The New York Times. Published July 19, 2021. Updated Oct. 20, 2021. Accessed December 1, 2021. www.nytimes.com/2021/07/19/health/alzheimers-drug-aduhelm-fda.html

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Transitioning patients with developmental disabilities to adult care

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Transitioning patients with developmental disabilities to adult care

Some adults who have an intellectual or other developmental disability (IDD) require extensive subspecialty care; many, however, depend primarily on their family physician for the bulk of their health care. With that reliance in mind, this article provides (1) an overview of important services that family physicians can provide for their adult patients with IDD and (2) pragmatic clinical suggestions for tailoring that care. Note: We highlight only some high-impact areas of clinical focus; refer to the 2018 Canadian consensus guidelines for a comprehensive approach to optimizing primary care for this population.1

CASE

Laura S, a 24-year-old woman with Down syndrome, is visiting your clinic with her mother to establish care. Ms. S has several medical comorbidities, including type 2 diabetes, hyperlipidemia, repaired congenital heart disease, schizoaffective disorder, and hypothyroidism. She is under the care of multiple specialists, including a cardiologist and an endocrinologist. Her medications include the atypical antipsychotic risperidone, which was prescribed for her through the services of a community mental health center.

Developmental disability patient

Ms. S is due for multiple preventive health screenings. She indicates that she feels nervous today talking about these screenings with a new physician.

 

First step in care: Proficiency in the lexicon of IDD

Three core concepts of IDD are impairment, disability, and handicap. According to the World Health Organization2:

  • impairment “is any loss or abnormality of psychological, physiological, or anatomical structure or function.”
  • disability “is any restriction or lack (resulting from an impairment) of ability to perform an activity in the manner or within the range considered normal for a human being.”
  • handicap therefore “represents socialization of an impairment or disability, and as such it reflects the consequences for the individual—cultural, social, economic, and environmental—that stem from the presence of impairment and disability.”

Essential transition: Pediatric to adult health care

Health care transition (HCT) is the planned process of transferring care from a pediatric to an adult-based health care setting,3 comprising 3 phases:

  • preparation
  • transfer from pediatric to adult care
  • integration into adult-based care.

Two critical components of a smooth HCT include initiating the transition early in adolescence and providing transition-support resources, which are often lacking, even in large, integrated health systems.4 Got Transition, created by the National Alliance to Advance Adolescent Health, outlines core elements of an organized HCT process (www.gottransition.org) specific to young adults with IDD, including young adults with autism spectrum disorder.5,6 

Even young people who are served by a family physician and who intend to remain in that family practice as they age into adulthood require HCT services that include6:

  • assessment of readiness to transition to adult care
  • update of the medical history
  • assessment and promotion of self-care skills
  • consent discussions and optimized participation in decision-making
  • transition of specialty care from pediatric to adult specialists.

Continue to: For an ideal HCT...

 

 

For an ideal health care transition, full engagement of the patient, the medical home, and the patient’s family (including the primary caregiver or guardian) is critical.

For an ideal HCT, full engagement of the patient, the medical home (physicians, nursing staff, and care coordinators), and the patient’s family (including the primary caregiver or guardian) is critical. In addition to preventive care visits and management of chronic disease, additional domains that require explicit attention in transitioning young people with IDD include health insurance, transportation, employment, and postsecondary education.

Young people who have special health care needs and receive high-quality HCT demonstrate improvements in adherence to care, disease-specific measures, quality of life, self-care skills, satisfaction with care, and health care utilization.7TABLE 13 lists resources identified by Berens and colleagues that are helpful in facilitating the transition.

Resources for making the health care transition in patients with IDD

 

Teach and practice disability etiquette

Societal prejudice harms people with IDD—leading to self-deprecation, alienation from the larger community, and isolation from others with IDD.8 To promote acceptance and inclusivity in residential communities, the workplace, recreational venues, and clinical settings, disability etiquette should be utilized—a set of guidelines on how to interact with patients with IDD. These include speaking to the patient directly, using clear language in an adult voice, and avoiding stereotypes about people with disabilities.9 The entire health care team, including all front-facing staff (receptionists and care and financial coordinators) and clinical staff (physicians, nurses, medical assistants), need to be educated in, and practice, disability etiquette.

Preparing for in-person visits. Pre-­visit preparation, ideally by means of dialogue between health care staff and the patient or caregiver (or both), typically by telephone and in advance of the scheduled visit, is often critical for a successful first face-to-face encounter. (See “Pre-visit telephone questionnaire and script for a new adult patient with IDD,” page 287, which we developed for use in our office practice.) Outcomes of the pre-visit preparation should include identifying:

  • words or actions that can trigger anxiety or panic
  • de-escalation techniques, such as specific calming words and actions
  • strategies for optimal communication, physical access, and physical examination.

SIDEBAR
Pre-visit telephone questionnaire and script for a new adult patient with IDD

Introduction

Hello! My name is ______________. I’m a nurse [or medical assistant] from [name of practice]. I understand that [name of patient] is coming to our office for an appointment on [date and time]. I am calling to prepare our health care team to make this first appointment successful for [name of patient] and you.

  • How would [name of patient] prefer to be called?
  • Who will be accompanying [name of patient] to the appointment? What parts of the appointment will that person remain for?

Describe what to expect, what the patient or caregiver should bring to the appointment, and how long the appointment will last.

  • What makes [name of patient] anxious or fearful so that we might avoid doing that? Should we avoid bringing up certain topics? Should we avoid performing any procedures that are customary during a first appointment?
  • Does [name of patient] have sensitivities—to light, sound, touch, etc—that we should be aware of?

Offer to have a room ready upon the patient’s arrival if remaining in the waiting area would cause too much anxiety.

  • What helps calm [name of patient]? Are there some topics that put [name of patient] at ease?
  • How does [name of patient] best communicate?
  • Is there anything else the health care team might do to prepare for the appointment?
  • Does [name of patient] need personal protective equipment, a wheelchair, oxygen, or other medical equipment upon arrival?
  • What would make for a successful first appointment?
  • What strategies or techniques have [name of patient’s] providers used in the past that have helped make health care visits successful?
  • Is there anything else you want me to know that we haven’t talked about?
  • Would it be helpful if I talked with [name of patient] now about their upcoming appointment?

Initial appointments should focus on building trust and rapport with the health care team and desensitizing the patient to the clinical environment.10 Examination techniques used with pediatric patients can be applied to this population: for example, demonstrating an examination maneuver first on the parent or caregiver; beginning the examination with the least invasive or anxiety-­provoking components; and stating what you plan to do next—before you do it.

Continue to: Systematic health checks provide great value

 

 

Systematic health checks provide great value

A health check is a systematic and comprehensive health assessment that is provided annually to adults with IDD, and includes:

  • specific review of signs and symptoms of health conditions that often co-­occur in adults with IDD (TABLE 2Calibri11)
  • screening for changes in adaptive functioning and secondary disability
  • lifestyle counseling
  • medication review and counseling
  • immunization update
  • discussion of caregiver concerns.

Commonly co-occurring medical conditions in adults with IDD

Successful implementation of preventive health screening tests for a patient with IDD often requires ingenuity and creativity to allay fears and anxieties.

Regarding the last point: Many caregivers are the aging parents of the adult patient with IDD—people who have their own emerging health and support needs. You should initiate conversations about advanced planning for the needs of patients, which often involves engaging siblings and other family members to assume a greater role in caregiving.12

Benefits of the health check. A systematic review of 38 studies, comprising more than 5000 patients with IDD, found that health checks increased the detection of serious conditions, improved screening for sensory impairments, and increased the immunization rate.13 Although many patients with IDD generally understand the need for a periodic health examination, you can enhance their experience by better explaining the rationale for the health check; scheduling sufficient time for the appointment, based on the individual clinical situation; and discussing the value of laboratory testing and referrals to specialists.14

Tailoring preventive care

Many of the preventive services recommendations typically utilized by family physicians, such as guidelines from the US Preventive Services Task Force, have been developed for the general population at average risk of conditions of interest.15 Adults with IDD, depending on the cause of their developmental disability and their behavioral risk profile, might be at significantly higher (or lower) risk of cancer, heart disease, or other conditions than the general population. To address these differences, preventive care guidelines tailored to patients with certain developmental disabilities have been created, including guidelines specific to adults with Down syndrome, fragile X syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, and 22q11.2 deletion (DiGeorge) syndrome.16

Clarifying the molecular genetic etiology of many developmental disabilities has led to more precise understandings about physical and behavioral health issues associated with specific developmental disabilities. For that reason, patients without a known cause for their IDD might benefit from referral to a geneticist—even in early or middle adulthood. Variables generally associated with a higher likelihood of an abnormal genetic test result include17:

  • a family history of developmental disability
  • a congenital malformation or dysmorphic features
  • a dual diagnosis of developmental disability and co-occurring mental illness
  • hypotonia
  • severe or profound IDD.

Continue to: Successful implementation of preventive health screening tests...

 

 

Successful implementation of preventive health screening tests often requires ingenuity and the collective creativity of the patient, family members, staff, and family physician to allay fears and anxieties. Examples: Women who have been advised to undergo screening mammography might feel less anxious by undergoing tandem screening with their sister or mother, and colorectal cancer screening might be more easily accomplished using a fecal DNA test rather than by colonoscopy. Procedural desensitization strategies and preventive care instructional materials targeting people with IDD are posted on YouTube (for example, the “DD CARES Best Practices” series [see www.youtube.com/watch?v=EPJy4zvg4io]) and other websites.

Management of chronic disease

Evidence of health disparities in patients with IDD includes suboptimal management of chronic diseases, such as diabetes18 and hypertension,19 despite contact with a primary care physician. Nonadherence to a medication regimen might be more common in patients who live with their family or in a residential setting where there is a lower degree of supervision—that is, compared to a residence that maintains 24-hour staffing with daily nursing care and supervision. For a patient who is not so closely supervised, reviewing the medication refill history with the pharmacy, or using the so-called brown-bag technique of counting pill bottles brought to appointments, can ensure medication adherence.

 

CASE

As you interview Ms. S, you note that she is shy, avoids eye contact, and appears generally anxious. You calm her by noticing and complimenting her jewelry and fingernail polish. Ms. S smiles and talks about her favorite polish colors.

Evaluation of suspected mental and behavioral health issues begins with assessment for medical conditions that might be causing pain and distress or stereotypies.

Her mother reports that, when Ms. S is stressed, she talks to herself alone in her bedroom. However, you do not observe evidence of schizoaffective disorder, and begin to wonder whether she needs to be taking risperidone.

Essentials of mental health care

It is estimated that one-third of adults with IDD have significant mental and behavioral health care needs.20 Patients with IDD suffer the same psychiatric disorders as the general population; some also engage in problematic behaviors, such as self-injurious actions, physical or verbal aggression (or both), property destruction, and resistance to caregiving assistance.

Continue to: Mental and behavioral health problems...

 

 

Mental and behavioral health problems can have a profound impact on the quality of life of patients with IDD, their peers, and their family and other caregivers. If untreated, these problems can lead to premature institutionalization, loss of employment or desired program participation, fractured social relationships, and caregiver withdrawal and burnout.

Initial evaluation of suspected mental and behavioral health problems begins with careful assessment for medical conditions that might be causing pain and distress, stereotypies, and other problematic behaviors. Common sources of pain and discomfort include dental and other oral disease, dysphagia, gastroesophageal reflux disease, gastritis, constipation, allergic disease, headache, musculoskeletal pathology, lower urinary tract disease, and gynecologic disorders.11 Identification and optimal treatment of medical conditions might not eliminate problematic behaviors but often decrease their frequency and intensity.

Psychoactive medications are prescribed for many patients with IDD. Many have behavioral adverse effects, such as akathisia, aggression, and disinhibition—leading to a prescribing cascade of psychoactive medication polypharmacy and escalating dosages.21 Antipsychotic medications are often initiated without a careful diagnosis, explicit outcome targets, or adequate clinical monitoring for effectiveness; in addition, they often lead to insulin resistance, metabolic syndrome, and massive weight gain.21 Even a family physician who is not the prescriber can perform an important advocacy role by critically reviewing psychoactive medications, documenting adverse effects, insisting on a clear therapeutic target, and calling for discontinuation of medications that appear to be ineffective.

Evaluation of mental and behavioral health problems requires a developmental perspective to interpret specific, observable behaviors with a proper clinical lens. For example, many patients with IDD engage in self-talk (soliloquizing) as a means of processing the world around them. This practice might escalate during a time of physical or psychological stress, and the unwary clinician might misinterpret this behavior as psychotic, leading to inappropriate prescribing of antipsychotic medication. Other psychotoform behaviors that, superficially, mimic but are typically not truly psychotic, include talk with or about imaginary friends and repetitive retelling of sometimes elaborate or grandiose tales or assertions. The failure of clinicians to recognize developmentally determined expressions of distress often leads to a misdiagnosis of schizophrenia or other psychotic illness and, consequently, inappropriate psychopharmacotherapy. 

Family physicians, familiar with the use of psychiatric scales for diagnosis and treatment monitoring, should use similar scales that have been developed specifically for patients with IDD (TABLE 311). In addition, a psychiatric diagnosis manual, the Diagnostic Manual—Intellectual Disability 2, specific to people with IDD (and analogous to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) provides modification of diagnostic criteria to account for patients who have difficulty articulating their internal emotional state and inner thoughts.22

Screening and monitoring tools for co-occurring mental and behavioral health problems in patients with IDD

Continue to: Problematic behaviors

 

 

Problematic behaviors that are not features of a bona fide psychiatric disorder are often best understood through functional behavioral analysis, which examines antecedents and consequences of problematic behaviors and identifies their predictable outcomes, such as gaining attention, avoiding a task, or securing a desired item. Rather than being given a prescription for psychoactive medication, many adult patients with IDD and problematic behaviors might be best served by having you order consultation with a certified behavior analyst. The analyst will conduct an evaluation and, along with family or residential staff and the patient, craft a behavioral support plan to address core drivers of the undesired behavior. Behavioral support plans might be enriched by multidisciplinary input from a speech and language pathologist, habilitation professionals, occupational and physical therapists, a neuropsychologist, and others.23

Antipsychotic medications are often initiated without a careful diagnosis. In addition, they often lead to insulin resistance, metabolic syndrome, and massive weight gain.

Resources to help you address the physical, mental, and behavioral health problems of these patients are available online through Vanderbilt Kennedy Center’s “Toolkit for primary care providers” (https://iddtoolkit.vkcsites.org).

CASE

During your examination, you review Ms. S’s vital signs, including body mass index (BMI). You calculate that she is morbidly obese—BMI, 37—in the setting of a known comorbidity, diabetes.

Ms. S tells you that she is interested in having a healthy lifestyle, but feels frustrated because she does not know how to make the necessary changes. You discuss with her how some medications, including risperidone, can promote weight gain, and that it is important for her mental health provider to carefully reassess whether she needs to continue the drug.

Weight management in a patient population that tends to be sedentary

Patients with IDD are more likely to live a sedentary lifestyle. Compared to adults who do not have IDD, adults with IDD—especially women and patients with Down syndrome—are reported to have a higher prevalence of obesity.24

Continue to: As in the general population...

 

 

As in the general population, the greatest success in weight management involves multidisciplinary treatment, including nutritional support, physical activity, behavioral changes, and close follow-up. The importance of such an approach was borne out by the findings of a randomized controlled trial in which a multicomponent intervention—an energy-reduced diet, physical activity, and behavioral sessions—delivered to participants or their caregivers during monthly visits produced clinically meaningful 6-month weight loss.25 Health-promoting behavioral interventions that rely on a dyadic strategy, such as peer health coaches (ie, people with IDD who have been trained as a health coach) or mentors (IDD staff trained as a health coach), might be more successful at changing health behaviors among patients with IDD than traditional office-based, individual patient education and counseling.26

Similarly, undesired weight loss demands careful evaluation and management because such loss can reflect a medically significant condition, such as gastroesophageal reflux, constipation, dysphagia, neglect, and cancer.27

Boosting the amount and effectiveness of physical activity

Young people with IDD participate in physical activity less often than their neurotypical peers; as a result, they tend to be less fit and have a higher prevalence of obesity.28 Based on a meta-analysis, interventions that focus on sport and movement skills training, such as soccer, basketball, and ball-throwing programs, might be more effective than general physical activity programs.28 In addition to year-round sports training and athletic competitions, Special Olympics conducts vital health screenings of athletes and supports community-based initiatives that address bias against patients with IDD, promote inclusion, and foster social relationships (www.specialolympics.org/our-work/inclusive-health?locale=en).

Success in weight management involves multidisciplinary treatment, including nutritional support, physical activity, behavioral changes, and close follow-up.

Emphasize regular activity. In adulthood, fewer than 10% of patients with IDD exercise regularly.21 According to the second edition of Physical Activity Guidelines for Americans,29 “all adults, with or without a disability, should get at least 150 minutes of aerobic physical activity a week. Activities can be broken down into smaller amounts, such as about 25 minutes a day every day.”30 Supplementation with muscle-strengthening activities (eg, yoga, weight training, and resistance-band training) provides further health benefit, such as improvement in posture and prevention of future injury.31 An ideal exercise program proposed by Tyler and Baker is based on a daily, “3-2-1” schedule (ie, of every hour of activity, 30 minutes should be of aerobic exercise; 20 minutes, of strength building; and 10 minutes, of flexibility).11 By participating in any type of physical activity, there is potential for considerable health benefit in reducing psychosocial stressors, improving mental health, counteracting metabolic syndromes, and, ultimately, reducing morbidity and mortality related to physical inactivity.

CASE

With permission from Ms. S, you send your progress notes by fax to her mental health provider at the community mental health center and request a call to discuss her case—in particular, to examine potential alternatives to risperidone. With Ms. S’s input, you also co-create an exercise prescription that includes a daily 20-minute walking program with her mother.

At the follow-up visit that is scheduled in 3 months, you anticipate adding a resistance component and balance activity to the exercise prescription to enrich Ms. S’s physical activity regimen.

CORRESPONDENCE
Carl V. Tyler Jr., MD, 14601 Detroit Avenue, Lakewood, OH, 44107; catyle@ccf.org

References

1. Sullivan WF, Diepstra H, Heng J, et al. Primary care of adults with intellectual and developmental disabilities: 2018 Canadian consensus guidelines. Can Fam Physician. 2018;64:254-279.

2. World Health Organization. International Classification of Impairments, Disabilities, and Handicaps: A Manual of Classification Relating to the Consequences of Disease. May 1980. Accessed May 27, 2021. https://apps.who.int/iris/bitstream/handle/10665/41003/9241541261_eng.pdf?sequence=1&isAllowed=y

3. Berens J, Wozow C, Peacock C. Transition to adult care. Phys Med Rehabil Clin N Am. 2020;31:159-170. doi:10.1016/j.pmr.2019.09.004

4. American Academy of Pediatrics; American Academy of Family Physicians; American College of Physicians; Transitions Clinical Report Authoring Group; Cooley WC, Sagerman PJ. Supporting the health care transition from adolescence to adulthood in the medical home. Pediatrics. 2011;128:182-200. doi:10.1542/peds.2011-0969

5. Dressler PB, Nguyen TK, Moody EJ, et al. Use of transition resources by primary care providers for youth with intellectual and developmental disabilities. Intellect Dev Disabil. 2018;56:56-68. doi:10.1352/1934-9556-56.1.56

6. The National Alliance to Advance Adolescent Health. Six Core Elements of Health Care Transition.™ Got Transition website. Accessed May 27, 2021. www.gottransition.org

7. Schmidt A, Ilango SM, McManus MA, et al. Outcomes of pediatric to adult health care transition interventions: an updated systematic review. J Pediatr Nurs. 2020; 51:92-107. doi: 10.1016/j.pedn.2020.01.002

8. Keith JM, Bennetto L, Rogge RD. The relationship between contact and attitudes: reducing prejudice toward individuals with intellectual and developmental disabilities. Res Dev Disabil. 2015;47:14-26. doi:10.1016/j.ridd.2015.07.032

9. United Spinal Association. Disability Etiquette: Tips on Interacting With People With Disabilities. 2015. Accessed June 9, 2021. www.unitedspinal.org/pdf/DisabilityEtiquette.pdf

10. Nathawad R, Hanks C. Optimizing the office visit for adolescents with special health care needs. Curr Probl Pediatr Adolesc Health Care. 2017;47:182-189. doi:10.1016/j.cppeds.2017.07.002

11. Tyler CV, Baker S. Intellectual Disabilities at Your Fingertips: A Health Care Resource. High Tide Press; 2009.

12. Williamson HJ, Perkins EA. Family caregivers of adults with intellectual and developmental disabilities: outcomes associated with U.S. services and supports. Intellect Dev Disabil. 2014;52:147-159. doi: 10.1352/1934-9556-52.2.147

13. Robertson J, Hatton C, Emerson E, et al. The impact of health checks for people with intellectual disabilities: an updated systematic review of evidence. Res Dev Disabil. 2014;35:2450-2462. doi:10.1016/j.ridd.2014.06.007

14. Perry J, Felce D, Kerr M, et al. Contact with primary care: the experience of people with intellectual disabilities. J Appl Res Intellect Disabil. 2014;27:200-211. doi: 10.1111/jar.12072

15. Recommendation topics. United States Preventive Services Task Force website. 2020. Accessed May 27, 2021. www.uspreventiveservicestaskforce.org

16. Developmental Disabilities Primary Care Initiative. Tools for the Primary Care of People with Developmental Disabilities. 1st ed. MUMS Guideline Clearinghouse; 2011.

17. Jang W, Kim Y, Han E, et al. Chromosomal microarray analysis as a first-tier clinical diagnostic test in patients with developmental delay/intellectual disability, autism spectrum disorders, and multiple congenital anomalies: a prospective multicenter study in Korea. Ann Lab Med. 2019;39:299-310. doi:10.3343/alm.2019.39.3.299

18. Shireman TI, Reichard A, Nazir N, et al. Quality of diabetes care for adults with developmental disabilities. Disabil Health J. 2010;3:179-185. doi:10.1016/j.dhjo.2009.10.004

19. Cyrus AC, Royer J, Carroll DD, et al. Anti-hypertensive medication use and actors related to adherence among adults with intellectual and developmental disabilities. Am J Intellect Dev Disabil. 2019;124:248-262. doi:10.1352/1944-7558-124.3.248

20. IDD/MI diagnosis. National Association for the Dually Diagnosed (NADD) website. 2019. Accessed May 27, 2021. https://thenadd.org/idd-mi-diagnosis

21. Matson JL, Mayville EA, Bielecki J, et al. Reliability of the Matson Evaluation of Drug Side Effects Scale (MEDS). Res Dev Disabil. 1998;19:501-506. doi:10.1016/s0891-4222(98)00021-3

22. Fletcher R, Barnhill J, Cooper SA. (2017). Diagnostic Manual-Intellectual Disability: A Textbook of Diagnosis of Mental Disorders in Persons with Intellectual Disability. 2nd ed. National Association for the Dually Diagnosed (NADD); 2017.

23. Marrus N, Hall L. Intellectual disability and language disorder. Child Adolesc Psychiatr Clin N Am. 2017;26:539-554. doi:10.1016/j.chc.2017.03.001

24. Rimmer JH, Yamaki K. Obesity and intellectual disability. Ment Retard Dev Disabil Res Rev. 2006;12;22-7. doi: 10.1002/mrdd.20091

25. Ptomey LT, Saunders RR, Saunders M, et al. Weight management in adults with intellectual and developmental disabilities: a randomized controlled trial of two dietary approaches. J Appl Res Intellect Disabil. 2018;31(suppl 1):82-96. doi:10.1111/jar.12348

26. Marks B, Sisirak J, Magallanes R, et al. Effectiveness of a HealthMessages peer-to-peer program for people with intellectual and developmental disabilities. Intellect Dev Disabil. 2019;57:242-258. doi:10.1352/1934-9556-57.3.242

27. Escudé C. Clinical Pearls in IDD Health care. HRS, Inc; 2020.

28. Kapsal NJ, Dicke T, Morin AJS, et al. Effects of physical activity on the physical and psychosocial health of youth with intellectual disabilities: a systematic review and meta-analysis. J Phys Act Health. 2019;16:1187-1195. doi:10.1123/jpah.2018-0675

29. Physical Activity Guidelines for Americans. 2nd ed. US Department of Health and Human Services; 2018. Accessed May 29, 2021. https://health.gov/sites/default/files/2019-09/Physical_Activity_Guidelines_2nd_edition.pdf

30. National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. Physical activity for people with disability. September 2020. Accessed May 27, 2021. www.cdc.gov/ncbddd/disabilityandhealth/features/physical-activity-for-all.html

31. Introduction to strengthening exercises. National Center on Health, Physical Activity and Disability (NCHPAD). 2020. Accessed May 27, 2021. www.nchpad.org/374/2096/Strengthening~Exercises

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Dr. Tyler receives royalties from the sale of his book, Intellectual Disabilities at Your Fingertips: A Health Care Resource, referenced in this article. Dr. McDermott reported no potential conflict of interest relevant to this article.

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Dr. Tyler receives royalties from the sale of his book, Intellectual Disabilities at Your Fingertips: A Health Care Resource, referenced in this article. Dr. McDermott reported no potential conflict of interest relevant to this article.

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Some adults who have an intellectual or other developmental disability (IDD) require extensive subspecialty care; many, however, depend primarily on their family physician for the bulk of their health care. With that reliance in mind, this article provides (1) an overview of important services that family physicians can provide for their adult patients with IDD and (2) pragmatic clinical suggestions for tailoring that care. Note: We highlight only some high-impact areas of clinical focus; refer to the 2018 Canadian consensus guidelines for a comprehensive approach to optimizing primary care for this population.1

CASE

Laura S, a 24-year-old woman with Down syndrome, is visiting your clinic with her mother to establish care. Ms. S has several medical comorbidities, including type 2 diabetes, hyperlipidemia, repaired congenital heart disease, schizoaffective disorder, and hypothyroidism. She is under the care of multiple specialists, including a cardiologist and an endocrinologist. Her medications include the atypical antipsychotic risperidone, which was prescribed for her through the services of a community mental health center.

Developmental disability patient

Ms. S is due for multiple preventive health screenings. She indicates that she feels nervous today talking about these screenings with a new physician.

 

First step in care: Proficiency in the lexicon of IDD

Three core concepts of IDD are impairment, disability, and handicap. According to the World Health Organization2:

  • impairment “is any loss or abnormality of psychological, physiological, or anatomical structure or function.”
  • disability “is any restriction or lack (resulting from an impairment) of ability to perform an activity in the manner or within the range considered normal for a human being.”
  • handicap therefore “represents socialization of an impairment or disability, and as such it reflects the consequences for the individual—cultural, social, economic, and environmental—that stem from the presence of impairment and disability.”

Essential transition: Pediatric to adult health care

Health care transition (HCT) is the planned process of transferring care from a pediatric to an adult-based health care setting,3 comprising 3 phases:

  • preparation
  • transfer from pediatric to adult care
  • integration into adult-based care.

Two critical components of a smooth HCT include initiating the transition early in adolescence and providing transition-support resources, which are often lacking, even in large, integrated health systems.4 Got Transition, created by the National Alliance to Advance Adolescent Health, outlines core elements of an organized HCT process (www.gottransition.org) specific to young adults with IDD, including young adults with autism spectrum disorder.5,6 

Even young people who are served by a family physician and who intend to remain in that family practice as they age into adulthood require HCT services that include6:

  • assessment of readiness to transition to adult care
  • update of the medical history
  • assessment and promotion of self-care skills
  • consent discussions and optimized participation in decision-making
  • transition of specialty care from pediatric to adult specialists.

Continue to: For an ideal HCT...

 

 

For an ideal health care transition, full engagement of the patient, the medical home, and the patient’s family (including the primary caregiver or guardian) is critical.

For an ideal HCT, full engagement of the patient, the medical home (physicians, nursing staff, and care coordinators), and the patient’s family (including the primary caregiver or guardian) is critical. In addition to preventive care visits and management of chronic disease, additional domains that require explicit attention in transitioning young people with IDD include health insurance, transportation, employment, and postsecondary education.

Young people who have special health care needs and receive high-quality HCT demonstrate improvements in adherence to care, disease-specific measures, quality of life, self-care skills, satisfaction with care, and health care utilization.7TABLE 13 lists resources identified by Berens and colleagues that are helpful in facilitating the transition.

Resources for making the health care transition in patients with IDD

 

Teach and practice disability etiquette

Societal prejudice harms people with IDD—leading to self-deprecation, alienation from the larger community, and isolation from others with IDD.8 To promote acceptance and inclusivity in residential communities, the workplace, recreational venues, and clinical settings, disability etiquette should be utilized—a set of guidelines on how to interact with patients with IDD. These include speaking to the patient directly, using clear language in an adult voice, and avoiding stereotypes about people with disabilities.9 The entire health care team, including all front-facing staff (receptionists and care and financial coordinators) and clinical staff (physicians, nurses, medical assistants), need to be educated in, and practice, disability etiquette.

Preparing for in-person visits. Pre-­visit preparation, ideally by means of dialogue between health care staff and the patient or caregiver (or both), typically by telephone and in advance of the scheduled visit, is often critical for a successful first face-to-face encounter. (See “Pre-visit telephone questionnaire and script for a new adult patient with IDD,” page 287, which we developed for use in our office practice.) Outcomes of the pre-visit preparation should include identifying:

  • words or actions that can trigger anxiety or panic
  • de-escalation techniques, such as specific calming words and actions
  • strategies for optimal communication, physical access, and physical examination.

SIDEBAR
Pre-visit telephone questionnaire and script for a new adult patient with IDD

Introduction

Hello! My name is ______________. I’m a nurse [or medical assistant] from [name of practice]. I understand that [name of patient] is coming to our office for an appointment on [date and time]. I am calling to prepare our health care team to make this first appointment successful for [name of patient] and you.

  • How would [name of patient] prefer to be called?
  • Who will be accompanying [name of patient] to the appointment? What parts of the appointment will that person remain for?

Describe what to expect, what the patient or caregiver should bring to the appointment, and how long the appointment will last.

  • What makes [name of patient] anxious or fearful so that we might avoid doing that? Should we avoid bringing up certain topics? Should we avoid performing any procedures that are customary during a first appointment?
  • Does [name of patient] have sensitivities—to light, sound, touch, etc—that we should be aware of?

Offer to have a room ready upon the patient’s arrival if remaining in the waiting area would cause too much anxiety.

  • What helps calm [name of patient]? Are there some topics that put [name of patient] at ease?
  • How does [name of patient] best communicate?
  • Is there anything else the health care team might do to prepare for the appointment?
  • Does [name of patient] need personal protective equipment, a wheelchair, oxygen, or other medical equipment upon arrival?
  • What would make for a successful first appointment?
  • What strategies or techniques have [name of patient’s] providers used in the past that have helped make health care visits successful?
  • Is there anything else you want me to know that we haven’t talked about?
  • Would it be helpful if I talked with [name of patient] now about their upcoming appointment?

Initial appointments should focus on building trust and rapport with the health care team and desensitizing the patient to the clinical environment.10 Examination techniques used with pediatric patients can be applied to this population: for example, demonstrating an examination maneuver first on the parent or caregiver; beginning the examination with the least invasive or anxiety-­provoking components; and stating what you plan to do next—before you do it.

Continue to: Systematic health checks provide great value

 

 

Systematic health checks provide great value

A health check is a systematic and comprehensive health assessment that is provided annually to adults with IDD, and includes:

  • specific review of signs and symptoms of health conditions that often co-­occur in adults with IDD (TABLE 2Calibri11)
  • screening for changes in adaptive functioning and secondary disability
  • lifestyle counseling
  • medication review and counseling
  • immunization update
  • discussion of caregiver concerns.

Commonly co-occurring medical conditions in adults with IDD

Successful implementation of preventive health screening tests for a patient with IDD often requires ingenuity and creativity to allay fears and anxieties.

Regarding the last point: Many caregivers are the aging parents of the adult patient with IDD—people who have their own emerging health and support needs. You should initiate conversations about advanced planning for the needs of patients, which often involves engaging siblings and other family members to assume a greater role in caregiving.12

Benefits of the health check. A systematic review of 38 studies, comprising more than 5000 patients with IDD, found that health checks increased the detection of serious conditions, improved screening for sensory impairments, and increased the immunization rate.13 Although many patients with IDD generally understand the need for a periodic health examination, you can enhance their experience by better explaining the rationale for the health check; scheduling sufficient time for the appointment, based on the individual clinical situation; and discussing the value of laboratory testing and referrals to specialists.14

Tailoring preventive care

Many of the preventive services recommendations typically utilized by family physicians, such as guidelines from the US Preventive Services Task Force, have been developed for the general population at average risk of conditions of interest.15 Adults with IDD, depending on the cause of their developmental disability and their behavioral risk profile, might be at significantly higher (or lower) risk of cancer, heart disease, or other conditions than the general population. To address these differences, preventive care guidelines tailored to patients with certain developmental disabilities have been created, including guidelines specific to adults with Down syndrome, fragile X syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, and 22q11.2 deletion (DiGeorge) syndrome.16

Clarifying the molecular genetic etiology of many developmental disabilities has led to more precise understandings about physical and behavioral health issues associated with specific developmental disabilities. For that reason, patients without a known cause for their IDD might benefit from referral to a geneticist—even in early or middle adulthood. Variables generally associated with a higher likelihood of an abnormal genetic test result include17:

  • a family history of developmental disability
  • a congenital malformation or dysmorphic features
  • a dual diagnosis of developmental disability and co-occurring mental illness
  • hypotonia
  • severe or profound IDD.

Continue to: Successful implementation of preventive health screening tests...

 

 

Successful implementation of preventive health screening tests often requires ingenuity and the collective creativity of the patient, family members, staff, and family physician to allay fears and anxieties. Examples: Women who have been advised to undergo screening mammography might feel less anxious by undergoing tandem screening with their sister or mother, and colorectal cancer screening might be more easily accomplished using a fecal DNA test rather than by colonoscopy. Procedural desensitization strategies and preventive care instructional materials targeting people with IDD are posted on YouTube (for example, the “DD CARES Best Practices” series [see www.youtube.com/watch?v=EPJy4zvg4io]) and other websites.

Management of chronic disease

Evidence of health disparities in patients with IDD includes suboptimal management of chronic diseases, such as diabetes18 and hypertension,19 despite contact with a primary care physician. Nonadherence to a medication regimen might be more common in patients who live with their family or in a residential setting where there is a lower degree of supervision—that is, compared to a residence that maintains 24-hour staffing with daily nursing care and supervision. For a patient who is not so closely supervised, reviewing the medication refill history with the pharmacy, or using the so-called brown-bag technique of counting pill bottles brought to appointments, can ensure medication adherence.

 

CASE

As you interview Ms. S, you note that she is shy, avoids eye contact, and appears generally anxious. You calm her by noticing and complimenting her jewelry and fingernail polish. Ms. S smiles and talks about her favorite polish colors.

Evaluation of suspected mental and behavioral health issues begins with assessment for medical conditions that might be causing pain and distress or stereotypies.

Her mother reports that, when Ms. S is stressed, she talks to herself alone in her bedroom. However, you do not observe evidence of schizoaffective disorder, and begin to wonder whether she needs to be taking risperidone.

Essentials of mental health care

It is estimated that one-third of adults with IDD have significant mental and behavioral health care needs.20 Patients with IDD suffer the same psychiatric disorders as the general population; some also engage in problematic behaviors, such as self-injurious actions, physical or verbal aggression (or both), property destruction, and resistance to caregiving assistance.

Continue to: Mental and behavioral health problems...

 

 

Mental and behavioral health problems can have a profound impact on the quality of life of patients with IDD, their peers, and their family and other caregivers. If untreated, these problems can lead to premature institutionalization, loss of employment or desired program participation, fractured social relationships, and caregiver withdrawal and burnout.

Initial evaluation of suspected mental and behavioral health problems begins with careful assessment for medical conditions that might be causing pain and distress, stereotypies, and other problematic behaviors. Common sources of pain and discomfort include dental and other oral disease, dysphagia, gastroesophageal reflux disease, gastritis, constipation, allergic disease, headache, musculoskeletal pathology, lower urinary tract disease, and gynecologic disorders.11 Identification and optimal treatment of medical conditions might not eliminate problematic behaviors but often decrease their frequency and intensity.

Psychoactive medications are prescribed for many patients with IDD. Many have behavioral adverse effects, such as akathisia, aggression, and disinhibition—leading to a prescribing cascade of psychoactive medication polypharmacy and escalating dosages.21 Antipsychotic medications are often initiated without a careful diagnosis, explicit outcome targets, or adequate clinical monitoring for effectiveness; in addition, they often lead to insulin resistance, metabolic syndrome, and massive weight gain.21 Even a family physician who is not the prescriber can perform an important advocacy role by critically reviewing psychoactive medications, documenting adverse effects, insisting on a clear therapeutic target, and calling for discontinuation of medications that appear to be ineffective.

Evaluation of mental and behavioral health problems requires a developmental perspective to interpret specific, observable behaviors with a proper clinical lens. For example, many patients with IDD engage in self-talk (soliloquizing) as a means of processing the world around them. This practice might escalate during a time of physical or psychological stress, and the unwary clinician might misinterpret this behavior as psychotic, leading to inappropriate prescribing of antipsychotic medication. Other psychotoform behaviors that, superficially, mimic but are typically not truly psychotic, include talk with or about imaginary friends and repetitive retelling of sometimes elaborate or grandiose tales or assertions. The failure of clinicians to recognize developmentally determined expressions of distress often leads to a misdiagnosis of schizophrenia or other psychotic illness and, consequently, inappropriate psychopharmacotherapy. 

Family physicians, familiar with the use of psychiatric scales for diagnosis and treatment monitoring, should use similar scales that have been developed specifically for patients with IDD (TABLE 311). In addition, a psychiatric diagnosis manual, the Diagnostic Manual—Intellectual Disability 2, specific to people with IDD (and analogous to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) provides modification of diagnostic criteria to account for patients who have difficulty articulating their internal emotional state and inner thoughts.22

Screening and monitoring tools for co-occurring mental and behavioral health problems in patients with IDD

Continue to: Problematic behaviors

 

 

Problematic behaviors that are not features of a bona fide psychiatric disorder are often best understood through functional behavioral analysis, which examines antecedents and consequences of problematic behaviors and identifies their predictable outcomes, such as gaining attention, avoiding a task, or securing a desired item. Rather than being given a prescription for psychoactive medication, many adult patients with IDD and problematic behaviors might be best served by having you order consultation with a certified behavior analyst. The analyst will conduct an evaluation and, along with family or residential staff and the patient, craft a behavioral support plan to address core drivers of the undesired behavior. Behavioral support plans might be enriched by multidisciplinary input from a speech and language pathologist, habilitation professionals, occupational and physical therapists, a neuropsychologist, and others.23

Antipsychotic medications are often initiated without a careful diagnosis. In addition, they often lead to insulin resistance, metabolic syndrome, and massive weight gain.

Resources to help you address the physical, mental, and behavioral health problems of these patients are available online through Vanderbilt Kennedy Center’s “Toolkit for primary care providers” (https://iddtoolkit.vkcsites.org).

CASE

During your examination, you review Ms. S’s vital signs, including body mass index (BMI). You calculate that she is morbidly obese—BMI, 37—in the setting of a known comorbidity, diabetes.

Ms. S tells you that she is interested in having a healthy lifestyle, but feels frustrated because she does not know how to make the necessary changes. You discuss with her how some medications, including risperidone, can promote weight gain, and that it is important for her mental health provider to carefully reassess whether she needs to continue the drug.

Weight management in a patient population that tends to be sedentary

Patients with IDD are more likely to live a sedentary lifestyle. Compared to adults who do not have IDD, adults with IDD—especially women and patients with Down syndrome—are reported to have a higher prevalence of obesity.24

Continue to: As in the general population...

 

 

As in the general population, the greatest success in weight management involves multidisciplinary treatment, including nutritional support, physical activity, behavioral changes, and close follow-up. The importance of such an approach was borne out by the findings of a randomized controlled trial in which a multicomponent intervention—an energy-reduced diet, physical activity, and behavioral sessions—delivered to participants or their caregivers during monthly visits produced clinically meaningful 6-month weight loss.25 Health-promoting behavioral interventions that rely on a dyadic strategy, such as peer health coaches (ie, people with IDD who have been trained as a health coach) or mentors (IDD staff trained as a health coach), might be more successful at changing health behaviors among patients with IDD than traditional office-based, individual patient education and counseling.26

Similarly, undesired weight loss demands careful evaluation and management because such loss can reflect a medically significant condition, such as gastroesophageal reflux, constipation, dysphagia, neglect, and cancer.27

Boosting the amount and effectiveness of physical activity

Young people with IDD participate in physical activity less often than their neurotypical peers; as a result, they tend to be less fit and have a higher prevalence of obesity.28 Based on a meta-analysis, interventions that focus on sport and movement skills training, such as soccer, basketball, and ball-throwing programs, might be more effective than general physical activity programs.28 In addition to year-round sports training and athletic competitions, Special Olympics conducts vital health screenings of athletes and supports community-based initiatives that address bias against patients with IDD, promote inclusion, and foster social relationships (www.specialolympics.org/our-work/inclusive-health?locale=en).

Success in weight management involves multidisciplinary treatment, including nutritional support, physical activity, behavioral changes, and close follow-up.

Emphasize regular activity. In adulthood, fewer than 10% of patients with IDD exercise regularly.21 According to the second edition of Physical Activity Guidelines for Americans,29 “all adults, with or without a disability, should get at least 150 minutes of aerobic physical activity a week. Activities can be broken down into smaller amounts, such as about 25 minutes a day every day.”30 Supplementation with muscle-strengthening activities (eg, yoga, weight training, and resistance-band training) provides further health benefit, such as improvement in posture and prevention of future injury.31 An ideal exercise program proposed by Tyler and Baker is based on a daily, “3-2-1” schedule (ie, of every hour of activity, 30 minutes should be of aerobic exercise; 20 minutes, of strength building; and 10 minutes, of flexibility).11 By participating in any type of physical activity, there is potential for considerable health benefit in reducing psychosocial stressors, improving mental health, counteracting metabolic syndromes, and, ultimately, reducing morbidity and mortality related to physical inactivity.

CASE

With permission from Ms. S, you send your progress notes by fax to her mental health provider at the community mental health center and request a call to discuss her case—in particular, to examine potential alternatives to risperidone. With Ms. S’s input, you also co-create an exercise prescription that includes a daily 20-minute walking program with her mother.

At the follow-up visit that is scheduled in 3 months, you anticipate adding a resistance component and balance activity to the exercise prescription to enrich Ms. S’s physical activity regimen.

CORRESPONDENCE
Carl V. Tyler Jr., MD, 14601 Detroit Avenue, Lakewood, OH, 44107; catyle@ccf.org

Some adults who have an intellectual or other developmental disability (IDD) require extensive subspecialty care; many, however, depend primarily on their family physician for the bulk of their health care. With that reliance in mind, this article provides (1) an overview of important services that family physicians can provide for their adult patients with IDD and (2) pragmatic clinical suggestions for tailoring that care. Note: We highlight only some high-impact areas of clinical focus; refer to the 2018 Canadian consensus guidelines for a comprehensive approach to optimizing primary care for this population.1

CASE

Laura S, a 24-year-old woman with Down syndrome, is visiting your clinic with her mother to establish care. Ms. S has several medical comorbidities, including type 2 diabetes, hyperlipidemia, repaired congenital heart disease, schizoaffective disorder, and hypothyroidism. She is under the care of multiple specialists, including a cardiologist and an endocrinologist. Her medications include the atypical antipsychotic risperidone, which was prescribed for her through the services of a community mental health center.

Developmental disability patient

Ms. S is due for multiple preventive health screenings. She indicates that she feels nervous today talking about these screenings with a new physician.

 

First step in care: Proficiency in the lexicon of IDD

Three core concepts of IDD are impairment, disability, and handicap. According to the World Health Organization2:

  • impairment “is any loss or abnormality of psychological, physiological, or anatomical structure or function.”
  • disability “is any restriction or lack (resulting from an impairment) of ability to perform an activity in the manner or within the range considered normal for a human being.”
  • handicap therefore “represents socialization of an impairment or disability, and as such it reflects the consequences for the individual—cultural, social, economic, and environmental—that stem from the presence of impairment and disability.”

Essential transition: Pediatric to adult health care

Health care transition (HCT) is the planned process of transferring care from a pediatric to an adult-based health care setting,3 comprising 3 phases:

  • preparation
  • transfer from pediatric to adult care
  • integration into adult-based care.

Two critical components of a smooth HCT include initiating the transition early in adolescence and providing transition-support resources, which are often lacking, even in large, integrated health systems.4 Got Transition, created by the National Alliance to Advance Adolescent Health, outlines core elements of an organized HCT process (www.gottransition.org) specific to young adults with IDD, including young adults with autism spectrum disorder.5,6 

Even young people who are served by a family physician and who intend to remain in that family practice as they age into adulthood require HCT services that include6:

  • assessment of readiness to transition to adult care
  • update of the medical history
  • assessment and promotion of self-care skills
  • consent discussions and optimized participation in decision-making
  • transition of specialty care from pediatric to adult specialists.

Continue to: For an ideal HCT...

 

 

For an ideal health care transition, full engagement of the patient, the medical home, and the patient’s family (including the primary caregiver or guardian) is critical.

For an ideal HCT, full engagement of the patient, the medical home (physicians, nursing staff, and care coordinators), and the patient’s family (including the primary caregiver or guardian) is critical. In addition to preventive care visits and management of chronic disease, additional domains that require explicit attention in transitioning young people with IDD include health insurance, transportation, employment, and postsecondary education.

Young people who have special health care needs and receive high-quality HCT demonstrate improvements in adherence to care, disease-specific measures, quality of life, self-care skills, satisfaction with care, and health care utilization.7TABLE 13 lists resources identified by Berens and colleagues that are helpful in facilitating the transition.

Resources for making the health care transition in patients with IDD

 

Teach and practice disability etiquette

Societal prejudice harms people with IDD—leading to self-deprecation, alienation from the larger community, and isolation from others with IDD.8 To promote acceptance and inclusivity in residential communities, the workplace, recreational venues, and clinical settings, disability etiquette should be utilized—a set of guidelines on how to interact with patients with IDD. These include speaking to the patient directly, using clear language in an adult voice, and avoiding stereotypes about people with disabilities.9 The entire health care team, including all front-facing staff (receptionists and care and financial coordinators) and clinical staff (physicians, nurses, medical assistants), need to be educated in, and practice, disability etiquette.

Preparing for in-person visits. Pre-­visit preparation, ideally by means of dialogue between health care staff and the patient or caregiver (or both), typically by telephone and in advance of the scheduled visit, is often critical for a successful first face-to-face encounter. (See “Pre-visit telephone questionnaire and script for a new adult patient with IDD,” page 287, which we developed for use in our office practice.) Outcomes of the pre-visit preparation should include identifying:

  • words or actions that can trigger anxiety or panic
  • de-escalation techniques, such as specific calming words and actions
  • strategies for optimal communication, physical access, and physical examination.

SIDEBAR
Pre-visit telephone questionnaire and script for a new adult patient with IDD

Introduction

Hello! My name is ______________. I’m a nurse [or medical assistant] from [name of practice]. I understand that [name of patient] is coming to our office for an appointment on [date and time]. I am calling to prepare our health care team to make this first appointment successful for [name of patient] and you.

  • How would [name of patient] prefer to be called?
  • Who will be accompanying [name of patient] to the appointment? What parts of the appointment will that person remain for?

Describe what to expect, what the patient or caregiver should bring to the appointment, and how long the appointment will last.

  • What makes [name of patient] anxious or fearful so that we might avoid doing that? Should we avoid bringing up certain topics? Should we avoid performing any procedures that are customary during a first appointment?
  • Does [name of patient] have sensitivities—to light, sound, touch, etc—that we should be aware of?

Offer to have a room ready upon the patient’s arrival if remaining in the waiting area would cause too much anxiety.

  • What helps calm [name of patient]? Are there some topics that put [name of patient] at ease?
  • How does [name of patient] best communicate?
  • Is there anything else the health care team might do to prepare for the appointment?
  • Does [name of patient] need personal protective equipment, a wheelchair, oxygen, or other medical equipment upon arrival?
  • What would make for a successful first appointment?
  • What strategies or techniques have [name of patient’s] providers used in the past that have helped make health care visits successful?
  • Is there anything else you want me to know that we haven’t talked about?
  • Would it be helpful if I talked with [name of patient] now about their upcoming appointment?

Initial appointments should focus on building trust and rapport with the health care team and desensitizing the patient to the clinical environment.10 Examination techniques used with pediatric patients can be applied to this population: for example, demonstrating an examination maneuver first on the parent or caregiver; beginning the examination with the least invasive or anxiety-­provoking components; and stating what you plan to do next—before you do it.

Continue to: Systematic health checks provide great value

 

 

Systematic health checks provide great value

A health check is a systematic and comprehensive health assessment that is provided annually to adults with IDD, and includes:

  • specific review of signs and symptoms of health conditions that often co-­occur in adults with IDD (TABLE 2Calibri11)
  • screening for changes in adaptive functioning and secondary disability
  • lifestyle counseling
  • medication review and counseling
  • immunization update
  • discussion of caregiver concerns.

Commonly co-occurring medical conditions in adults with IDD

Successful implementation of preventive health screening tests for a patient with IDD often requires ingenuity and creativity to allay fears and anxieties.

Regarding the last point: Many caregivers are the aging parents of the adult patient with IDD—people who have their own emerging health and support needs. You should initiate conversations about advanced planning for the needs of patients, which often involves engaging siblings and other family members to assume a greater role in caregiving.12

Benefits of the health check. A systematic review of 38 studies, comprising more than 5000 patients with IDD, found that health checks increased the detection of serious conditions, improved screening for sensory impairments, and increased the immunization rate.13 Although many patients with IDD generally understand the need for a periodic health examination, you can enhance their experience by better explaining the rationale for the health check; scheduling sufficient time for the appointment, based on the individual clinical situation; and discussing the value of laboratory testing and referrals to specialists.14

Tailoring preventive care

Many of the preventive services recommendations typically utilized by family physicians, such as guidelines from the US Preventive Services Task Force, have been developed for the general population at average risk of conditions of interest.15 Adults with IDD, depending on the cause of their developmental disability and their behavioral risk profile, might be at significantly higher (or lower) risk of cancer, heart disease, or other conditions than the general population. To address these differences, preventive care guidelines tailored to patients with certain developmental disabilities have been created, including guidelines specific to adults with Down syndrome, fragile X syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, and 22q11.2 deletion (DiGeorge) syndrome.16

Clarifying the molecular genetic etiology of many developmental disabilities has led to more precise understandings about physical and behavioral health issues associated with specific developmental disabilities. For that reason, patients without a known cause for their IDD might benefit from referral to a geneticist—even in early or middle adulthood. Variables generally associated with a higher likelihood of an abnormal genetic test result include17:

  • a family history of developmental disability
  • a congenital malformation or dysmorphic features
  • a dual diagnosis of developmental disability and co-occurring mental illness
  • hypotonia
  • severe or profound IDD.

Continue to: Successful implementation of preventive health screening tests...

 

 

Successful implementation of preventive health screening tests often requires ingenuity and the collective creativity of the patient, family members, staff, and family physician to allay fears and anxieties. Examples: Women who have been advised to undergo screening mammography might feel less anxious by undergoing tandem screening with their sister or mother, and colorectal cancer screening might be more easily accomplished using a fecal DNA test rather than by colonoscopy. Procedural desensitization strategies and preventive care instructional materials targeting people with IDD are posted on YouTube (for example, the “DD CARES Best Practices” series [see www.youtube.com/watch?v=EPJy4zvg4io]) and other websites.

Management of chronic disease

Evidence of health disparities in patients with IDD includes suboptimal management of chronic diseases, such as diabetes18 and hypertension,19 despite contact with a primary care physician. Nonadherence to a medication regimen might be more common in patients who live with their family or in a residential setting where there is a lower degree of supervision—that is, compared to a residence that maintains 24-hour staffing with daily nursing care and supervision. For a patient who is not so closely supervised, reviewing the medication refill history with the pharmacy, or using the so-called brown-bag technique of counting pill bottles brought to appointments, can ensure medication adherence.

 

CASE

As you interview Ms. S, you note that she is shy, avoids eye contact, and appears generally anxious. You calm her by noticing and complimenting her jewelry and fingernail polish. Ms. S smiles and talks about her favorite polish colors.

Evaluation of suspected mental and behavioral health issues begins with assessment for medical conditions that might be causing pain and distress or stereotypies.

Her mother reports that, when Ms. S is stressed, she talks to herself alone in her bedroom. However, you do not observe evidence of schizoaffective disorder, and begin to wonder whether she needs to be taking risperidone.

Essentials of mental health care

It is estimated that one-third of adults with IDD have significant mental and behavioral health care needs.20 Patients with IDD suffer the same psychiatric disorders as the general population; some also engage in problematic behaviors, such as self-injurious actions, physical or verbal aggression (or both), property destruction, and resistance to caregiving assistance.

Continue to: Mental and behavioral health problems...

 

 

Mental and behavioral health problems can have a profound impact on the quality of life of patients with IDD, their peers, and their family and other caregivers. If untreated, these problems can lead to premature institutionalization, loss of employment or desired program participation, fractured social relationships, and caregiver withdrawal and burnout.

Initial evaluation of suspected mental and behavioral health problems begins with careful assessment for medical conditions that might be causing pain and distress, stereotypies, and other problematic behaviors. Common sources of pain and discomfort include dental and other oral disease, dysphagia, gastroesophageal reflux disease, gastritis, constipation, allergic disease, headache, musculoskeletal pathology, lower urinary tract disease, and gynecologic disorders.11 Identification and optimal treatment of medical conditions might not eliminate problematic behaviors but often decrease their frequency and intensity.

Psychoactive medications are prescribed for many patients with IDD. Many have behavioral adverse effects, such as akathisia, aggression, and disinhibition—leading to a prescribing cascade of psychoactive medication polypharmacy and escalating dosages.21 Antipsychotic medications are often initiated without a careful diagnosis, explicit outcome targets, or adequate clinical monitoring for effectiveness; in addition, they often lead to insulin resistance, metabolic syndrome, and massive weight gain.21 Even a family physician who is not the prescriber can perform an important advocacy role by critically reviewing psychoactive medications, documenting adverse effects, insisting on a clear therapeutic target, and calling for discontinuation of medications that appear to be ineffective.

Evaluation of mental and behavioral health problems requires a developmental perspective to interpret specific, observable behaviors with a proper clinical lens. For example, many patients with IDD engage in self-talk (soliloquizing) as a means of processing the world around them. This practice might escalate during a time of physical or psychological stress, and the unwary clinician might misinterpret this behavior as psychotic, leading to inappropriate prescribing of antipsychotic medication. Other psychotoform behaviors that, superficially, mimic but are typically not truly psychotic, include talk with or about imaginary friends and repetitive retelling of sometimes elaborate or grandiose tales or assertions. The failure of clinicians to recognize developmentally determined expressions of distress often leads to a misdiagnosis of schizophrenia or other psychotic illness and, consequently, inappropriate psychopharmacotherapy. 

Family physicians, familiar with the use of psychiatric scales for diagnosis and treatment monitoring, should use similar scales that have been developed specifically for patients with IDD (TABLE 311). In addition, a psychiatric diagnosis manual, the Diagnostic Manual—Intellectual Disability 2, specific to people with IDD (and analogous to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) provides modification of diagnostic criteria to account for patients who have difficulty articulating their internal emotional state and inner thoughts.22

Screening and monitoring tools for co-occurring mental and behavioral health problems in patients with IDD

Continue to: Problematic behaviors

 

 

Problematic behaviors that are not features of a bona fide psychiatric disorder are often best understood through functional behavioral analysis, which examines antecedents and consequences of problematic behaviors and identifies their predictable outcomes, such as gaining attention, avoiding a task, or securing a desired item. Rather than being given a prescription for psychoactive medication, many adult patients with IDD and problematic behaviors might be best served by having you order consultation with a certified behavior analyst. The analyst will conduct an evaluation and, along with family or residential staff and the patient, craft a behavioral support plan to address core drivers of the undesired behavior. Behavioral support plans might be enriched by multidisciplinary input from a speech and language pathologist, habilitation professionals, occupational and physical therapists, a neuropsychologist, and others.23

Antipsychotic medications are often initiated without a careful diagnosis. In addition, they often lead to insulin resistance, metabolic syndrome, and massive weight gain.

Resources to help you address the physical, mental, and behavioral health problems of these patients are available online through Vanderbilt Kennedy Center’s “Toolkit for primary care providers” (https://iddtoolkit.vkcsites.org).

CASE

During your examination, you review Ms. S’s vital signs, including body mass index (BMI). You calculate that she is morbidly obese—BMI, 37—in the setting of a known comorbidity, diabetes.

Ms. S tells you that she is interested in having a healthy lifestyle, but feels frustrated because she does not know how to make the necessary changes. You discuss with her how some medications, including risperidone, can promote weight gain, and that it is important for her mental health provider to carefully reassess whether she needs to continue the drug.

Weight management in a patient population that tends to be sedentary

Patients with IDD are more likely to live a sedentary lifestyle. Compared to adults who do not have IDD, adults with IDD—especially women and patients with Down syndrome—are reported to have a higher prevalence of obesity.24

Continue to: As in the general population...

 

 

As in the general population, the greatest success in weight management involves multidisciplinary treatment, including nutritional support, physical activity, behavioral changes, and close follow-up. The importance of such an approach was borne out by the findings of a randomized controlled trial in which a multicomponent intervention—an energy-reduced diet, physical activity, and behavioral sessions—delivered to participants or their caregivers during monthly visits produced clinically meaningful 6-month weight loss.25 Health-promoting behavioral interventions that rely on a dyadic strategy, such as peer health coaches (ie, people with IDD who have been trained as a health coach) or mentors (IDD staff trained as a health coach), might be more successful at changing health behaviors among patients with IDD than traditional office-based, individual patient education and counseling.26

Similarly, undesired weight loss demands careful evaluation and management because such loss can reflect a medically significant condition, such as gastroesophageal reflux, constipation, dysphagia, neglect, and cancer.27

Boosting the amount and effectiveness of physical activity

Young people with IDD participate in physical activity less often than their neurotypical peers; as a result, they tend to be less fit and have a higher prevalence of obesity.28 Based on a meta-analysis, interventions that focus on sport and movement skills training, such as soccer, basketball, and ball-throwing programs, might be more effective than general physical activity programs.28 In addition to year-round sports training and athletic competitions, Special Olympics conducts vital health screenings of athletes and supports community-based initiatives that address bias against patients with IDD, promote inclusion, and foster social relationships (www.specialolympics.org/our-work/inclusive-health?locale=en).

Success in weight management involves multidisciplinary treatment, including nutritional support, physical activity, behavioral changes, and close follow-up.

Emphasize regular activity. In adulthood, fewer than 10% of patients with IDD exercise regularly.21 According to the second edition of Physical Activity Guidelines for Americans,29 “all adults, with or without a disability, should get at least 150 minutes of aerobic physical activity a week. Activities can be broken down into smaller amounts, such as about 25 minutes a day every day.”30 Supplementation with muscle-strengthening activities (eg, yoga, weight training, and resistance-band training) provides further health benefit, such as improvement in posture and prevention of future injury.31 An ideal exercise program proposed by Tyler and Baker is based on a daily, “3-2-1” schedule (ie, of every hour of activity, 30 minutes should be of aerobic exercise; 20 minutes, of strength building; and 10 minutes, of flexibility).11 By participating in any type of physical activity, there is potential for considerable health benefit in reducing psychosocial stressors, improving mental health, counteracting metabolic syndromes, and, ultimately, reducing morbidity and mortality related to physical inactivity.

CASE

With permission from Ms. S, you send your progress notes by fax to her mental health provider at the community mental health center and request a call to discuss her case—in particular, to examine potential alternatives to risperidone. With Ms. S’s input, you also co-create an exercise prescription that includes a daily 20-minute walking program with her mother.

At the follow-up visit that is scheduled in 3 months, you anticipate adding a resistance component and balance activity to the exercise prescription to enrich Ms. S’s physical activity regimen.

CORRESPONDENCE
Carl V. Tyler Jr., MD, 14601 Detroit Avenue, Lakewood, OH, 44107; catyle@ccf.org

References

1. Sullivan WF, Diepstra H, Heng J, et al. Primary care of adults with intellectual and developmental disabilities: 2018 Canadian consensus guidelines. Can Fam Physician. 2018;64:254-279.

2. World Health Organization. International Classification of Impairments, Disabilities, and Handicaps: A Manual of Classification Relating to the Consequences of Disease. May 1980. Accessed May 27, 2021. https://apps.who.int/iris/bitstream/handle/10665/41003/9241541261_eng.pdf?sequence=1&isAllowed=y

3. Berens J, Wozow C, Peacock C. Transition to adult care. Phys Med Rehabil Clin N Am. 2020;31:159-170. doi:10.1016/j.pmr.2019.09.004

4. American Academy of Pediatrics; American Academy of Family Physicians; American College of Physicians; Transitions Clinical Report Authoring Group; Cooley WC, Sagerman PJ. Supporting the health care transition from adolescence to adulthood in the medical home. Pediatrics. 2011;128:182-200. doi:10.1542/peds.2011-0969

5. Dressler PB, Nguyen TK, Moody EJ, et al. Use of transition resources by primary care providers for youth with intellectual and developmental disabilities. Intellect Dev Disabil. 2018;56:56-68. doi:10.1352/1934-9556-56.1.56

6. The National Alliance to Advance Adolescent Health. Six Core Elements of Health Care Transition.™ Got Transition website. Accessed May 27, 2021. www.gottransition.org

7. Schmidt A, Ilango SM, McManus MA, et al. Outcomes of pediatric to adult health care transition interventions: an updated systematic review. J Pediatr Nurs. 2020; 51:92-107. doi: 10.1016/j.pedn.2020.01.002

8. Keith JM, Bennetto L, Rogge RD. The relationship between contact and attitudes: reducing prejudice toward individuals with intellectual and developmental disabilities. Res Dev Disabil. 2015;47:14-26. doi:10.1016/j.ridd.2015.07.032

9. United Spinal Association. Disability Etiquette: Tips on Interacting With People With Disabilities. 2015. Accessed June 9, 2021. www.unitedspinal.org/pdf/DisabilityEtiquette.pdf

10. Nathawad R, Hanks C. Optimizing the office visit for adolescents with special health care needs. Curr Probl Pediatr Adolesc Health Care. 2017;47:182-189. doi:10.1016/j.cppeds.2017.07.002

11. Tyler CV, Baker S. Intellectual Disabilities at Your Fingertips: A Health Care Resource. High Tide Press; 2009.

12. Williamson HJ, Perkins EA. Family caregivers of adults with intellectual and developmental disabilities: outcomes associated with U.S. services and supports. Intellect Dev Disabil. 2014;52:147-159. doi: 10.1352/1934-9556-52.2.147

13. Robertson J, Hatton C, Emerson E, et al. The impact of health checks for people with intellectual disabilities: an updated systematic review of evidence. Res Dev Disabil. 2014;35:2450-2462. doi:10.1016/j.ridd.2014.06.007

14. Perry J, Felce D, Kerr M, et al. Contact with primary care: the experience of people with intellectual disabilities. J Appl Res Intellect Disabil. 2014;27:200-211. doi: 10.1111/jar.12072

15. Recommendation topics. United States Preventive Services Task Force website. 2020. Accessed May 27, 2021. www.uspreventiveservicestaskforce.org

16. Developmental Disabilities Primary Care Initiative. Tools for the Primary Care of People with Developmental Disabilities. 1st ed. MUMS Guideline Clearinghouse; 2011.

17. Jang W, Kim Y, Han E, et al. Chromosomal microarray analysis as a first-tier clinical diagnostic test in patients with developmental delay/intellectual disability, autism spectrum disorders, and multiple congenital anomalies: a prospective multicenter study in Korea. Ann Lab Med. 2019;39:299-310. doi:10.3343/alm.2019.39.3.299

18. Shireman TI, Reichard A, Nazir N, et al. Quality of diabetes care for adults with developmental disabilities. Disabil Health J. 2010;3:179-185. doi:10.1016/j.dhjo.2009.10.004

19. Cyrus AC, Royer J, Carroll DD, et al. Anti-hypertensive medication use and actors related to adherence among adults with intellectual and developmental disabilities. Am J Intellect Dev Disabil. 2019;124:248-262. doi:10.1352/1944-7558-124.3.248

20. IDD/MI diagnosis. National Association for the Dually Diagnosed (NADD) website. 2019. Accessed May 27, 2021. https://thenadd.org/idd-mi-diagnosis

21. Matson JL, Mayville EA, Bielecki J, et al. Reliability of the Matson Evaluation of Drug Side Effects Scale (MEDS). Res Dev Disabil. 1998;19:501-506. doi:10.1016/s0891-4222(98)00021-3

22. Fletcher R, Barnhill J, Cooper SA. (2017). Diagnostic Manual-Intellectual Disability: A Textbook of Diagnosis of Mental Disorders in Persons with Intellectual Disability. 2nd ed. National Association for the Dually Diagnosed (NADD); 2017.

23. Marrus N, Hall L. Intellectual disability and language disorder. Child Adolesc Psychiatr Clin N Am. 2017;26:539-554. doi:10.1016/j.chc.2017.03.001

24. Rimmer JH, Yamaki K. Obesity and intellectual disability. Ment Retard Dev Disabil Res Rev. 2006;12;22-7. doi: 10.1002/mrdd.20091

25. Ptomey LT, Saunders RR, Saunders M, et al. Weight management in adults with intellectual and developmental disabilities: a randomized controlled trial of two dietary approaches. J Appl Res Intellect Disabil. 2018;31(suppl 1):82-96. doi:10.1111/jar.12348

26. Marks B, Sisirak J, Magallanes R, et al. Effectiveness of a HealthMessages peer-to-peer program for people with intellectual and developmental disabilities. Intellect Dev Disabil. 2019;57:242-258. doi:10.1352/1934-9556-57.3.242

27. Escudé C. Clinical Pearls in IDD Health care. HRS, Inc; 2020.

28. Kapsal NJ, Dicke T, Morin AJS, et al. Effects of physical activity on the physical and psychosocial health of youth with intellectual disabilities: a systematic review and meta-analysis. J Phys Act Health. 2019;16:1187-1195. doi:10.1123/jpah.2018-0675

29. Physical Activity Guidelines for Americans. 2nd ed. US Department of Health and Human Services; 2018. Accessed May 29, 2021. https://health.gov/sites/default/files/2019-09/Physical_Activity_Guidelines_2nd_edition.pdf

30. National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. Physical activity for people with disability. September 2020. Accessed May 27, 2021. www.cdc.gov/ncbddd/disabilityandhealth/features/physical-activity-for-all.html

31. Introduction to strengthening exercises. National Center on Health, Physical Activity and Disability (NCHPAD). 2020. Accessed May 27, 2021. www.nchpad.org/374/2096/Strengthening~Exercises

References

1. Sullivan WF, Diepstra H, Heng J, et al. Primary care of adults with intellectual and developmental disabilities: 2018 Canadian consensus guidelines. Can Fam Physician. 2018;64:254-279.

2. World Health Organization. International Classification of Impairments, Disabilities, and Handicaps: A Manual of Classification Relating to the Consequences of Disease. May 1980. Accessed May 27, 2021. https://apps.who.int/iris/bitstream/handle/10665/41003/9241541261_eng.pdf?sequence=1&isAllowed=y

3. Berens J, Wozow C, Peacock C. Transition to adult care. Phys Med Rehabil Clin N Am. 2020;31:159-170. doi:10.1016/j.pmr.2019.09.004

4. American Academy of Pediatrics; American Academy of Family Physicians; American College of Physicians; Transitions Clinical Report Authoring Group; Cooley WC, Sagerman PJ. Supporting the health care transition from adolescence to adulthood in the medical home. Pediatrics. 2011;128:182-200. doi:10.1542/peds.2011-0969

5. Dressler PB, Nguyen TK, Moody EJ, et al. Use of transition resources by primary care providers for youth with intellectual and developmental disabilities. Intellect Dev Disabil. 2018;56:56-68. doi:10.1352/1934-9556-56.1.56

6. The National Alliance to Advance Adolescent Health. Six Core Elements of Health Care Transition.™ Got Transition website. Accessed May 27, 2021. www.gottransition.org

7. Schmidt A, Ilango SM, McManus MA, et al. Outcomes of pediatric to adult health care transition interventions: an updated systematic review. J Pediatr Nurs. 2020; 51:92-107. doi: 10.1016/j.pedn.2020.01.002

8. Keith JM, Bennetto L, Rogge RD. The relationship between contact and attitudes: reducing prejudice toward individuals with intellectual and developmental disabilities. Res Dev Disabil. 2015;47:14-26. doi:10.1016/j.ridd.2015.07.032

9. United Spinal Association. Disability Etiquette: Tips on Interacting With People With Disabilities. 2015. Accessed June 9, 2021. www.unitedspinal.org/pdf/DisabilityEtiquette.pdf

10. Nathawad R, Hanks C. Optimizing the office visit for adolescents with special health care needs. Curr Probl Pediatr Adolesc Health Care. 2017;47:182-189. doi:10.1016/j.cppeds.2017.07.002

11. Tyler CV, Baker S. Intellectual Disabilities at Your Fingertips: A Health Care Resource. High Tide Press; 2009.

12. Williamson HJ, Perkins EA. Family caregivers of adults with intellectual and developmental disabilities: outcomes associated with U.S. services and supports. Intellect Dev Disabil. 2014;52:147-159. doi: 10.1352/1934-9556-52.2.147

13. Robertson J, Hatton C, Emerson E, et al. The impact of health checks for people with intellectual disabilities: an updated systematic review of evidence. Res Dev Disabil. 2014;35:2450-2462. doi:10.1016/j.ridd.2014.06.007

14. Perry J, Felce D, Kerr M, et al. Contact with primary care: the experience of people with intellectual disabilities. J Appl Res Intellect Disabil. 2014;27:200-211. doi: 10.1111/jar.12072

15. Recommendation topics. United States Preventive Services Task Force website. 2020. Accessed May 27, 2021. www.uspreventiveservicestaskforce.org

16. Developmental Disabilities Primary Care Initiative. Tools for the Primary Care of People with Developmental Disabilities. 1st ed. MUMS Guideline Clearinghouse; 2011.

17. Jang W, Kim Y, Han E, et al. Chromosomal microarray analysis as a first-tier clinical diagnostic test in patients with developmental delay/intellectual disability, autism spectrum disorders, and multiple congenital anomalies: a prospective multicenter study in Korea. Ann Lab Med. 2019;39:299-310. doi:10.3343/alm.2019.39.3.299

18. Shireman TI, Reichard A, Nazir N, et al. Quality of diabetes care for adults with developmental disabilities. Disabil Health J. 2010;3:179-185. doi:10.1016/j.dhjo.2009.10.004

19. Cyrus AC, Royer J, Carroll DD, et al. Anti-hypertensive medication use and actors related to adherence among adults with intellectual and developmental disabilities. Am J Intellect Dev Disabil. 2019;124:248-262. doi:10.1352/1944-7558-124.3.248

20. IDD/MI diagnosis. National Association for the Dually Diagnosed (NADD) website. 2019. Accessed May 27, 2021. https://thenadd.org/idd-mi-diagnosis

21. Matson JL, Mayville EA, Bielecki J, et al. Reliability of the Matson Evaluation of Drug Side Effects Scale (MEDS). Res Dev Disabil. 1998;19:501-506. doi:10.1016/s0891-4222(98)00021-3

22. Fletcher R, Barnhill J, Cooper SA. (2017). Diagnostic Manual-Intellectual Disability: A Textbook of Diagnosis of Mental Disorders in Persons with Intellectual Disability. 2nd ed. National Association for the Dually Diagnosed (NADD); 2017.

23. Marrus N, Hall L. Intellectual disability and language disorder. Child Adolesc Psychiatr Clin N Am. 2017;26:539-554. doi:10.1016/j.chc.2017.03.001

24. Rimmer JH, Yamaki K. Obesity and intellectual disability. Ment Retard Dev Disabil Res Rev. 2006;12;22-7. doi: 10.1002/mrdd.20091

25. Ptomey LT, Saunders RR, Saunders M, et al. Weight management in adults with intellectual and developmental disabilities: a randomized controlled trial of two dietary approaches. J Appl Res Intellect Disabil. 2018;31(suppl 1):82-96. doi:10.1111/jar.12348

26. Marks B, Sisirak J, Magallanes R, et al. Effectiveness of a HealthMessages peer-to-peer program for people with intellectual and developmental disabilities. Intellect Dev Disabil. 2019;57:242-258. doi:10.1352/1934-9556-57.3.242

27. Escudé C. Clinical Pearls in IDD Health care. HRS, Inc; 2020.

28. Kapsal NJ, Dicke T, Morin AJS, et al. Effects of physical activity on the physical and psychosocial health of youth with intellectual disabilities: a systematic review and meta-analysis. J Phys Act Health. 2019;16:1187-1195. doi:10.1123/jpah.2018-0675

29. Physical Activity Guidelines for Americans. 2nd ed. US Department of Health and Human Services; 2018. Accessed May 29, 2021. https://health.gov/sites/default/files/2019-09/Physical_Activity_Guidelines_2nd_edition.pdf

30. National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. Physical activity for people with disability. September 2020. Accessed May 27, 2021. www.cdc.gov/ncbddd/disabilityandhealth/features/physical-activity-for-all.html

31. Introduction to strengthening exercises. National Center on Health, Physical Activity and Disability (NCHPAD). 2020. Accessed May 27, 2021. www.nchpad.org/374/2096/Strengthening~Exercises

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PRACTICE RECOMMENDATIONS

› Provide young people who have an intellectual or other developmental disability (IDD) with a defined, explicit process for making the transition into the adult health care system. A

› Conduct an annual comprehensive, systematic health assessment for patients who have IDD to improve detection of serious conditions and sensory impairments. A

› Encourage young people and adults with IDD to participate in regular physical activity to reduce psychosocial stressors and counteract metabolic syndromes. A

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A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

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Osteoporosis management: Use a goal-oriented, individualized approach

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Recommendations for care are evolving, with increasingly sophisticated screening and diagnostic tools and a broadening array of treatment options.

 

As the population of older adults rises, primary osteoporosis has become a problem of public health significance, resulting in more than 2 million fractures and $19 billion in related costs annually in the United States.1 Despite the availability of effective primary and secondary preventive measures, many older adults do not receive adequate information on bone health from their primary care provider.2 Initiation of osteoporosis treatment is low even among patients who have had an osteoporotic fracture: Fewer than one-­quarter of older adults with hip fracture have begun taking osteoporosis medication within 12 months of hospital discharge.3

In this overview of osteoporosis care, we provide information on how to evaluate and manage older adults in primary care settings who are at risk of, or have been given a diagnosis of, primary osteoporosis. The guidance that we offer reflects the most recent updates and recommendations by relevant professional societies.1,4-7

The nature and scope of an urgent problem

Osteoporosis is a skeletal disorder characterized by low bone mass and deterioration of bone structure that causes bone fragility and increases the risk of fracture.8 Operationally, it is defined by the World Health Organization as a bone mineral density (BMD) score below 2.5 SD from the mean value for a young White woman (ie, T-score ≤ –2.5).9 Primary osteoporosis is age related and occurs mostly in postmenopausal women and older men, affecting 25% of women and 5% of men ≥ 65 years.10

An osteoporotic fracture is particularly devastating in an older adult because it can cause pain, reduced mobility, depression, and social isolation and can increase the risk of related mortality.1 The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.1 Therefore, it is of paramount importance to identify patients who are at increased risk of fracture and intervene early.

The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.

Clinical manifestations

Osteoporosis does not have a primary presentation; rather, disease manifests clinically when a patient develops complications. Often, a fragility fracture is the first sign in an older person.11

A fracture is the most important complication of osteoporosis and can result from low-trauma injury or a fall from standing height—thus, the term “fragility fracture.” Osteoporotic fractures commonly involve the vertebra, hip, and wrist. Hip and extremity fractures can result in limited or lost mobility and depression. Vertebral fractures can be asymptomatic or result in kyphosis and loss of height. Fractures can give rise to pain.

Age and female sexare risk factors

TABLE 11,6,10 lists risk factors associated with osteoporosis. Age is the most important; prevalence of osteoporosis increases with age. Other nonmodifiable risk factors include female sex (the disease appears earlier in women who enter menopause prematurely), family history of osteoporosis, and race and ethnicity. Twenty percent of Asian and non-Hispanic White women > 50 years have osteoporosis.1 A study showed that Mexican Americans are at higher risk of osteoporosis than non-Hispanic Whites; non-Hispanic Blacks are least affected.10

Risk factors for osteoporosis

Other risk factors include low body weight (< 127 lb) and a history of fractures after age 50. Behavioral risk factors include smoking, excessive alcohol intake (> 3 drinks/d), poor nutrition, and a sedentary lifestyle.1,6

Continue to: Who should be screened?...

 

 

Who should be screened?

Screening is generally performed with a clinical evaluation and a dual-energy x-ray absorptiometry (DXA) scan of BMD. Measurement of BMD is generally recommended for screening all women ≥ 65 years and those < 65 years whose 10-year risk of fracture is equivalent to that of a 65-year-old White woman (see “Assessment of fracture risk” later in the article). For men, the US Preventive Services Task Force recommends screening those with a prior fracture or a secondary risk factor for disease.5 However, the National Osteoporosis Foundation recommends screening all men ≥ 70 years and those 50 to 69 years whose risk profile shows heightened risk.1,4

DXA of the spine and hip is preferred; the distal one-third of the radius (termed “33% radius”) of the nondominant arm can be used when spine and hip BMD cannot be interpreted because of bone changes from the disease process or artifacts, or in certain diseases in which the wrist region shows the earliest change (eg, primary hyperparathyroidism).6,7

Clinical evaluation includes a detailed history, physical examination, laboratory screening, and assessment for risk of fracture.

 History. Explore the presence of risk factors, including fractures in adulthood, falls, medication use, alcohol and tobacco use, family history of osteoporosis, and chronic disease.6,7

Physical exam. Assess height, including any loss (> 1.5 in) since the patient’s second or third decade of life; kyphosis; frailty; and balance and mobility problems.4,6,7

Laboratory and imaging studies. Perform basic laboratory testing when DXA is abnormal, including thyroid function, serum calcium, and renal function.6,12 Radiography of the lateral spine might be necessary, especially when there is kyphosis or loss of height. Assess for vertebral fracture, using lateral spine radiography, when vertebral involvement is suspected.6,7

Assessment of fracture risk. Fracture risk can be assessed with any of a number of tools, including:

  • Simplified Calculated Osteoporosis Risk Estimation (SCORE): www.medicalalgorithms.com/simplified-calculated-osteoporosis-risk-estimation-tool
  • Osteoporosis Risk Assessment Instrument (ORAI): www.physio-pedia.com/The_Osteoporosis_Risk_Assessment_Instrument_(ORAI)
  • Osteoporosis Index of Risk (OSIRIS): https://www.tandfonline.com/doi/abs/10.1080/gye.16.3.245.250?journalCode=igye20
  • Osteoporosis Self-Assessment Tool (OST): www.ncbi.nlm.nih.gov/books/NBK45516/figure/ch10.f2/
  • FRAX tool5: www.sheffield.ac.uk/FRAX.

The FRAX tool is widely used. It assesses a patient’s 10-year risk of fracture.

Diagnosis is based on these criteria

Diagnosis of osteoporosis is based on any 1 or more of the following criteria6:

  • a history of fragility fracture not explained by metabolic bone disease
  • T-score ≤ –2.5 (lumbar, hip, femoral neck, or 33% radius)
  • a nation-specific FRAX score (in the absence of access to DXA).

Secondary disease. Patients in whom secondary osteoporosis is suspected should undergo laboratory investigation to ascertain the cause; treatment of the underlying pathology might then be required. Evaluation for a secondary cause might include a complete blood count, comprehensive metabolic panel, protein electrophoresis and urinary protein electrophoresis (to rule out myeloproliferative and hematologic diseases), and tests of serum 25-hydroxyvitamin D, parathyroid hormone, serum calcium, alkaline phosphatase, 24-hour urinary calcium, sodium, and creatinine.6,7 Specialized testing for biochemical markers of bone turnover—so-called bone-turnover markers—can be considered as part of the initial evaluation and follow-up, although the tests are not recommended by the US Preventive Services Task Force (see “Monitoring the efficacy of treatment,” later in the article, for more information about these markers).6

Although BMD by DXA remains the gold standard in screening for and diagnosing osteoporosis, a high rate of fracture is seen in patients with certain diseases, such as type 2 diabetes and ankylosing spondylitis, who have a nonosteoporotic low T-score. This raises concerns about the usefulness of BMD for diagnosing osteoporosis in patients who have one of these diseases.13-16

Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when risk of fracture is high. Oral bisphosphonates can be used as initial treatment.

❚ Trabecular bone score (TBS), a surrogate bone-quality measure that is calculated based on the spine DXA image, has recently been introduced in clinical practice, and can be used to predict fracture risk in conjunction with BMD assessment by DXA and the FRAX score.17 TBS provides an indirect index of the trabecular microarchitecture using pixel gray-level variation in lumbar spine DXA images.18 Three categories of TBS (≤ 1.200, degraded microarchitecture; 1.200-1.350, partially degraded microarchitecture; and > 1.350, normal microarchitecture) have been reported to correspond with a T-score of, respectively, ≤ −2.5; −2.5 to −1.0; and > −1.0.18 TBS can be used only in patients with a body mass index of 15 to 37.5.19,20

There is no recommendation for monitoring bone quality using TBS after osteoporosis treatment. Such monitoring is at the clinician’s discretion for appropriate patients who might not show a risk of fracture, based on BMD measurement.

 

Continue to: Putting preventive measures into practice...

 

 

Putting preventive measures into practice

Measures to prevent osteoporosis and preserve bone health (TABLE 21,6) are best started in childhood but can be initiated at any age and maintained through the lifespan. Encourage older adults to adopt dietary and behavioral strategies to improve their bone health and prevent fracture. We recommend the following strategies; take each patient’s individual situation into consideration when electing to adopt any of these measures.

Measures to prevent osteoporosis

Vitamin D. Consider checking the serum 25-hydroxyvitamin D level and providing supplementation (800-1000 IU daily, the National Osteoporosis Foundation recommends1) as necessary to maintain the level at 30-50 ng/mL.6

Calcium. Encourage a daily dietary calcium intake of 1000-1200 mg. Supplement calcium if you determine that diet does not provide an adequate amount.

Alcohol. Advise patients to limit consumption to < 3 drinks a day.

Tobacco. Advise smoking cessation.

Activity. Encourage an active lifestyle, including regular weight-bearing and balance exercises and resistance exercises such as Pilates, weightlifting, and tai chi. The regimen should be tailored to the patient’s individual situation.

Medical therapy for concomitant illness. When possible, prescribe medications for chronic comorbidities that can also benefit bone health. For example, long-term use of angiotensin-converting enzyme (ACE) inhibitors and thiazide diuretics for hypertension are associated with a slower decline in BMD in some populations.21-23

Tailor treatment to patient’s circumstances

TABLE 34,6,24 describes indications for pharmacotherapy in osteoporosis. Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when fracture risk is high.24

Indications for pharmacotherapy for osteoporosis in older adults

Generally, you should undertake a discussion with the patient of the relative risks and benefits of treatment, taking into account their values and preferences, to come to a shared decision. Tailoring treatment, based on the patient’s distinctive circumstances, through shared decision-making is key to compliance.25

Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.26 Women with a very high BMD might not need to be retested with DXA any sooner than every 10 to 15 years.

There are 3 main classes of first-line pharmacotherapeutic agents for osteoporosis in older adults (TABLE 44,6,7,26-41): antiresorptives (bisphosphonates and denosumab), anabolics (teriparatide and abaloparatide), and a monoclonal sclerostin antibody (romosozumab). (TABLE 44,6,7,26-41 and the discussion in this section also remark on the selective estrogen-receptor modulator raloxifene, which is used in special clinical circumstances but has been removed from the first line of osteoporosis pharmacotherapy.)

What is the etiology of pediatric hypertension?

Pharmacotherapy for age-related osteoporosis

Pharmacotherapy for age-related osteoporosis


Bisphosphonates. Oral bisphosphonates (alendronate, ibandronate, risedronate) can be used as initial treatment in patients with a high risk of fracture.35 Bisphosphonates have been shown to reduce fracture risk and improve BMD. When an oral bisphosphonate cannot be tolerated, intravenous zoledronate or ibandronate can be used.41

Patients treated with a bisphosphonate should be assessed for their fracture risk after 3 to 5 years of treatment26; when intravenous zoledronate is given as initial therapy, patients should be assessed after 3 years. After assessment, patients who remain at high risk should continue treatment; those whose fracture risk has decreased to low or moderate should have treatment temporarily suspended (bisphosphonate holiday) for as long as 5 years.26 Patients on bisphosphonate holiday should have their fracture risk assessed at 2- to 4-year intervals.26 Restart treatment if there is an increase in fracture risk (eg, a decrease in BMD) or if a fracture occurs. Bisphosphonates have a prolonged effect on BMD—for many years after treatment is discontinued.27,28

Oral bisphosphonates are associated with gastroesophageal reflux disease, difficulty swallowing, and gastritis. Rare adverse effects include osteonecrosis of the jaw and atypical femur fracture.29

Denosumab, a recombinant human antibody, is a relatively newer antiresorptive for initial treatment. Denosumab, 60 mg, is given subcutaneously every 6 months. The drug can be used when bisphosphonates are contraindicated, the patient finds the bisphosphonate dosing regimen difficult to follow, or the patient is unresponsive to bisphosphonates.

Patients taking denosumab are reassessed every 5 to 10 years to determine whether to continue therapy or change to a new drug. Abrupt discontinuation of therapy can lead to rebound bone loss and increased risk of fracture.30-32 As with bisphosphonates, long-term use can be associated with osteonecrosis of the jaw and atypical femur fracture.33

There is no recommendation for a drug holiday for denosumab. An increase in, or no loss of, bone density and no new fractures while being treated are signs of effective treatment. There is no guideline for stopping denosumab, unless the patient develops adverse effects.

Bone anabolics. Patients with a very high risk of fracture (eg, who have sustained multiple vertebral fractures), can begin treatment with teriparatide (20 μg/d subcutaneously) or abaloparatide (80 μg/d subcutaneously) for as long as 2 years, followed by treatment with an antiresorptive, such as a bisphosphonate.4,6 Teriparatide can be used in patients who have not responded to an antiresorptive as first-line treatment.

Both abaloparatide and teriparatide might be associated with a risk of osteosarcoma and are contraindicated in patients who are at increased risk of osteosarcoma.36,39,40

 Romosozumab, a monoclonal sclerostin antibody, can be used in patients with very high risk of fracture or with multiple vertebral fractures. Romosozumab increases bone formation and reduces bone resorption. It is given monthly, 210 mg subcutaneously, for 1 year. The recommendation is that patients who have completed a course of romosozumab continue with antiresorptive treatment.26

Romosozumab is associated with an increase in the risk of cardiovascular disease, including stroke and myocardial infarction.26

Raloxifene, a selective estrogen-­receptor modulator, is no longer a first-line agent for osteoporosis in older adults34 because of its association with an increased risk of deep-vein thrombosis, pulmonary embolism, and lethal stroke. However, raloxifene can be used, at 60 mg/d, when bisphosphonates or denosumab are unsuitable. In addition, raloxifene is particularly useful in women with a high risk of breast cancer and in men who are taking a long-acting gonadotropin-releasing hormone agonist for prostate cancer.37,38

Continue to: Influence of chronic...

 

 

Influence of chronic diseaseon bone health

Chronic diseases—hypertension, type 2 diabetes, hyperthyroidism, rheumatoid arthritis, ankylosing spondylitis, and gastroenterologic disorders such as celiac disease and ulcerative colitis—are known to affect bone loss that can hasten osteoporosis.16,18,21 Furthermore, medications used to treat chronic diseases are known to affect bone health: Some, such as statins, ACE inhibitors, and hydrochlorothiazide, are bone protective; others, such as steroids, pioglitazone, and selective serotonin reuptake inhibitors, accelerate bone loss.1,14,42,43 It is important to be aware of the effect of a patient’s chronic diseases, and treatments for those diseases, on bone health, to help develop an individualized osteoporosis prevention plan.

Monitoring the efficacy of treatment

Treatment of osteoporosis should not be initiated without baseline measurement of BMD of the spine and hip. Subsequent to establishing that baseline, serial measurement of BMD can be used to (1) determine when treatment needs to be initiated for an untreated patient and (2) assess response in a treated patient. There is no consensus on the interval at which DXA should be repeated for the purpose of monitoring treatment response; frequency depends on the individual’s circumstances and the medication used. Notably, many physicians repeat DXA after 2 years of treatment8; however, the American College of Physicians recommends against repeating DXA within the first 5 years of pharmacotherapy in women.24

Patients with suspected vertebral fracture or those with loss of height > 1.5 inches require lateral radiographs of the thoracic and lumbar spine to assess the status of fractures.4,6

 Bone-turnover markers measured in serum can be used to assess treatment efficacy and patient adherence. The formation marker procollagen type I N-terminal propeptide (P1NP) and the resorption marker beta C-terminal cross-linking telopeptide of type 1 collagen (bCTX) are preferred for evaluating bone turnover in the clinical setting. Assessing P1NP and bCTX at baseline and after 3 months of treatment might be effective in monitoring adherence, particularly in patients taking a bisphosphonate.44

Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.

Be sure to address fall prevention

It is important to address falls, and how to prevent them, in patients with osteoporosis. Falls can precipitate fracture in older adults with reduced BMD, and fractures are the most common and debilitating manifestation of osteoporosis. Your discussion of falls with patients should include45:

  • consequences of falls
  • cautions about medications that can cloud mental alertness
  • use of appropriate footwear
  • home safety, such as adequate lighting, removal of floor clutter, and installation of handrails in the bathroom and stairwells and on outside steps.
  • having an annual comprehensive eye exam.

Osteoporosis is avoidable and treatable

Earlier research reported various expressions of number needed to treat for medical management of osteoporosis—making it difficult to follow a single number as a reference for gauging the effectiveness of pharmacotherapy.46,47 However, for older adults of different ethnic and racial backgrounds with multiple comorbidities and polypharmacy, it might be more pragmatic in primary care to establish a model of goal-oriented, individualized care. By focusing on prevention of bone loss, and being mindful that the risk of fracture almost doubles with a decrease of 1 SD in BMD, you can translate numbers to goals of care.48

In the United States, approximately one-half of osteoporosis cases in adults ≥ 50 years are managed by primary care providers. As a chronic disease, osteoporosis requires that you, first, provide regular monitoring and assessment, because risk can vary with comorbidities,49 and, second, discuss and initiate screening and treatment as appropriate, which can be done annually during a well-care visit.

CORRESPONDENCE

Nahid Rianon, MD, DrPH, Department of Family and Community Medicine, UTHealth McGovern Medical School, 6431 Fannin Street #JJL 324C, Houston, TX, 77030; Nahid.J.Rianon@uth.tmc.edu

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  6. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016. Endocr Pract. 2016;22(suppl 4):1-42. doi: 10.4158/EP161435.GL 
  7. Watts NB, Adler RA, Bilezikian JP, et al; Endocrine Society. Osteoporosis in men: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2012;97:1802-1822. doi: 10.1210/jc.2011-3045 
  8. US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2004. Accessed April 28, 2021. www.ncbi.nlm.nih.gov/books/NBK45513/pdf/Bookshelf_NBK45513.pdf 
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  10. Looker AC, Frenk SM. Percentage of adults aged 65 and over with osteoporosis or low bone mass at the femur neck or lumbar spine: United States, 2005--2010. Centers for Disease Control and Prevention, National Center for Health Statistics, Division of Health and Nutrition Examination Surveys. August 2015. Accessed April 28, 2021. www.cdc.gov/nchs/data/hestat/osteoporsis/osteoporosis2005_2010.pdf 
  11. Kerschan-Schindl K. Prevention and rehabilitation of osteoporosis. Wien Med Wochenschr. 2016;166:22-27. doi: 10.1007/s10354-015-0417-y 
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  13. Martineau P, Leslie WD, Johansson H, et al. In which patients does lumbar spine trabecular bone score (TBS) have the largest effect? Bone. 2018;113:161-168. doi: 10.1016/j.bone.2018.05.026 
  14. Rianon NJ, Smith SM, Lee M, et al. Glycemic control and bone turnover in older Mexican Americans with type 2 diabetes. J Osteoporos. 2018;2018:7153021. doi: 10.1155/2018/7153021 
  15. Richards C, Hans D, Leslie WD. Trabecular bone score (TBS) predicts fracture in ankylosing spondylitis: The Manitoba BMD Registry. J Clin Densitom. 2020;23:543-548. doi: 10.1016/j.jocd.2020.01.003 
  16. Xue Y, Baker AL, Nader S, et al. Lumbar spine trabecular bone score (TBS) reflects diminished bone quality in patients with diabetes mellitus and oral glucocorticoid therapy. J Clin Densitom. 2018;21:185-192. doi: 10.1016/j.jocd.2017.09.003 
  17. Silva BC, Broy SB, Boutroy S, et al. Fracture risk prediction by non-BMD DXA measures: the 2015 ISCD Official Positions Part 2: trabecular bone score. J Clin Densitom. 2015;18:309-330. doi: 10.1016/j.jocd.2015.06.008 
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  19. Leslie WD, Aubry-Rozier B, Lamy O, et al; Manitoba Bone Density Program. TBS (trabecular bone score) and diabetes-related fracture risk. J Clin Endocrinol Metab. 2013;98:602-609. 
  20. Looker AC, Sarafrazi Isfahani N, Fan B, et al. Trabecular bone scores and lumbar spine bone mineral density of US adults: comparison of relationships with demographic and body size variables. Osteoporos Int. 2016;27:2467-2475. doi: 10.1007/s00198-016-3550-6 
  21. Rianon N, Ambrose CG, Pervin H, et al. Long-term use of angiotensin-converting enzyme inhibitors protects against bone loss in African-American elderly men. Arch Osteoporos. 2017;12:94. doi: 10.1007/s11657-017-0387-3 
  22. Morton DJ, Barrett-Connor EL, Edelstein SL. Thiazides and bone mineral density in elderly men and women. Am J Epidemiol. 1994;139:1107-1115. doi: 10.1093/oxfordjournals.aje.a116954 
  23. Sigurdsson G, Franzson L. Increased bone mineral density in a population-based group of 70-year-old women on thiazide diuretics, independent of parathyroid hormone levels. J Intern Med. 2001;250:51-56. doi: 10.1046/j.1365-2796.2001.00850.x 
  24. Qaseem A, Forciea MA, McLean RM, et al; Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166:818-839. doi: 10.7326/M15-1361 
  25. des Bordes JKA, Suarez-Almazor ME, Volk RJ, et al. Online educational tool to promote bone health in cancer survivors. J Health Commun. 2017;22:808-817. doi: 10.1080/10810730.2017.1360415 
  26. Shoback D, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J Clin Endocrinol Metab. 2020;105:587-594. doi: 10.1210/clinem/dgaa048 
  27. Black DM, Schwartz AV, Ensrud KE, et al; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938. doi: 10.1001/jama.296.24.2927 
  28. Bone HG, Hosking D, Devogelaer J-P, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199. doi: 10.1056/NEJMoa030897 
  29. Khosla S, Burr D, Cauley J, et al; American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479-1491. doi: 10.1359/jbmr.0707onj 
  30. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96:972-980. doi: 10.1210/jc.2010-1502 
  31. Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM Trial and its extension. J Bone Miner Res. 2018;33:190-198. doi: 10.1002/jbmr.3337 
  32. Symonds C, Kline G. Warning of an increased risk of vertebral fracture after stopping denosumab. CMAJ. 2018;190:E485-E486. doi: 10.1503/cmaj.180115 
  33. Aljohani S, Gaudin R, Weiser J, et al. Osteonecrosis of the jaw in patients treated with denosumab: a multicenter case series. J Craniomaxillofac Surg. 2018;46:1515-1525. doi: 10.1016/j.jcms.2018.05.046 
  34. Barrett-Connor E, Mosca L, Collins P, et al; Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125-137. doi: 10.1056/NEJMoa062462 
  35. Chesnut CH 3rd, Skag A, Christiansen C, et al; Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241-1249. doi: 10.1359/JBMR.040325 
  36. Gilsenban A, Midkiff K, Kellier-Steele N, et al. Teriparatide did not increase adult osteosarcoma incidence in a 15-year US postmarketing surveillance study. J Bone Miner Res. 2021;36:244-252. doi: 10.1002/jbmr.4188 
  37. Cuzick J, Sestak I, Bonanni B, et al; SERM Chemoprevention of Breast Cancer Overview Group. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet. 2013;381:1827-1834. doi: 10.1016/S0140-6736(13)60140-3 
  38. Smith MR, Fallon MA, Lee H, et al. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:3841-3846. doi: 10.1210/jc.2003-032058 
  39. TYMLOS. Prescribing information. Radius Health, Inc.; April 2017. Accessed May 20, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2017/208743lbl.pdf  
  40. FORTEO. Prescribing information. Eli Lilly and Co.; April 2020. Accessed May 20, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2020/021318s053lbl.pdf 
  41. Wooltorton E. Patients receiving intravenous bisphosphonates should avoid invasive dental procedures. Can Med Assoc J. 2003;172:1684. doi: https://doi.org/10.1503/cmaj.050640 
  42. Chiadika SM, Shobayo FO, Naqvi SH, et al. Lower femoral neck bone mineral density (BMD) in elderly women not on statins. Women Health. 2019;59:845-853. doi: 10.1080/03630242.2019.1567646 
  43. Saraykar S, John V, Cao B, et al. Association of selective serotonin reuptake inhibitors and bone mineral density in elderly women. J Clin Densitom. 2018;21:193-199. doi: 10.1016/j.jocd.2017.05.016 
  44. Lorentzon M, Branco J, Brandi ML, et al. Algorithm for the use of biochemical markers of bone turnover in the diagnosis, assessment and follow-up of treatment for osteoporosis. Adv Ther. 2019;36:2811-2824. doi: 10.1007/s12325-019-01063-9 
  45. STEADI--older adult fall prevention. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. 2019. Accessed April 28, 2021. www.cdc.gov/steadi/patient.html 
  46. Cummings SR, San Martin J, McClung MR, et al; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765. doi: 10.1056/NEJMoa0809493 
  47. Zhou Z, Chen C, Zhang J, et al. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol. 2014;7:2113-2122. 
  48. Faulkner KG. Bone matters: are density increases necessary to reduce fracture risk? J Bone Miner Res. 2000;15:183-187. doi: 10.1359/jbmr.2000.15.2.183 
  49. Rianon N, Anand D, Rasu R. Changing trends in osteoporosis care from specialty to primary care physicians. Curr Med Res Opin. 2013;29:881-888. doi: 10.1185/03007995.2013.809335
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Recommendations for care are evolving, with increasingly sophisticated screening and diagnostic tools and a broadening array of treatment options.

Recommendations for care are evolving, with increasingly sophisticated screening and diagnostic tools and a broadening array of treatment options.

 

As the population of older adults rises, primary osteoporosis has become a problem of public health significance, resulting in more than 2 million fractures and $19 billion in related costs annually in the United States.1 Despite the availability of effective primary and secondary preventive measures, many older adults do not receive adequate information on bone health from their primary care provider.2 Initiation of osteoporosis treatment is low even among patients who have had an osteoporotic fracture: Fewer than one-­quarter of older adults with hip fracture have begun taking osteoporosis medication within 12 months of hospital discharge.3

In this overview of osteoporosis care, we provide information on how to evaluate and manage older adults in primary care settings who are at risk of, or have been given a diagnosis of, primary osteoporosis. The guidance that we offer reflects the most recent updates and recommendations by relevant professional societies.1,4-7

The nature and scope of an urgent problem

Osteoporosis is a skeletal disorder characterized by low bone mass and deterioration of bone structure that causes bone fragility and increases the risk of fracture.8 Operationally, it is defined by the World Health Organization as a bone mineral density (BMD) score below 2.5 SD from the mean value for a young White woman (ie, T-score ≤ –2.5).9 Primary osteoporosis is age related and occurs mostly in postmenopausal women and older men, affecting 25% of women and 5% of men ≥ 65 years.10

An osteoporotic fracture is particularly devastating in an older adult because it can cause pain, reduced mobility, depression, and social isolation and can increase the risk of related mortality.1 The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.1 Therefore, it is of paramount importance to identify patients who are at increased risk of fracture and intervene early.

The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.

Clinical manifestations

Osteoporosis does not have a primary presentation; rather, disease manifests clinically when a patient develops complications. Often, a fragility fracture is the first sign in an older person.11

A fracture is the most important complication of osteoporosis and can result from low-trauma injury or a fall from standing height—thus, the term “fragility fracture.” Osteoporotic fractures commonly involve the vertebra, hip, and wrist. Hip and extremity fractures can result in limited or lost mobility and depression. Vertebral fractures can be asymptomatic or result in kyphosis and loss of height. Fractures can give rise to pain.

Age and female sexare risk factors

TABLE 11,6,10 lists risk factors associated with osteoporosis. Age is the most important; prevalence of osteoporosis increases with age. Other nonmodifiable risk factors include female sex (the disease appears earlier in women who enter menopause prematurely), family history of osteoporosis, and race and ethnicity. Twenty percent of Asian and non-Hispanic White women > 50 years have osteoporosis.1 A study showed that Mexican Americans are at higher risk of osteoporosis than non-Hispanic Whites; non-Hispanic Blacks are least affected.10

Risk factors for osteoporosis

Other risk factors include low body weight (< 127 lb) and a history of fractures after age 50. Behavioral risk factors include smoking, excessive alcohol intake (> 3 drinks/d), poor nutrition, and a sedentary lifestyle.1,6

Continue to: Who should be screened?...

 

 

Who should be screened?

Screening is generally performed with a clinical evaluation and a dual-energy x-ray absorptiometry (DXA) scan of BMD. Measurement of BMD is generally recommended for screening all women ≥ 65 years and those < 65 years whose 10-year risk of fracture is equivalent to that of a 65-year-old White woman (see “Assessment of fracture risk” later in the article). For men, the US Preventive Services Task Force recommends screening those with a prior fracture or a secondary risk factor for disease.5 However, the National Osteoporosis Foundation recommends screening all men ≥ 70 years and those 50 to 69 years whose risk profile shows heightened risk.1,4

DXA of the spine and hip is preferred; the distal one-third of the radius (termed “33% radius”) of the nondominant arm can be used when spine and hip BMD cannot be interpreted because of bone changes from the disease process or artifacts, or in certain diseases in which the wrist region shows the earliest change (eg, primary hyperparathyroidism).6,7

Clinical evaluation includes a detailed history, physical examination, laboratory screening, and assessment for risk of fracture.

 History. Explore the presence of risk factors, including fractures in adulthood, falls, medication use, alcohol and tobacco use, family history of osteoporosis, and chronic disease.6,7

Physical exam. Assess height, including any loss (> 1.5 in) since the patient’s second or third decade of life; kyphosis; frailty; and balance and mobility problems.4,6,7

Laboratory and imaging studies. Perform basic laboratory testing when DXA is abnormal, including thyroid function, serum calcium, and renal function.6,12 Radiography of the lateral spine might be necessary, especially when there is kyphosis or loss of height. Assess for vertebral fracture, using lateral spine radiography, when vertebral involvement is suspected.6,7

Assessment of fracture risk. Fracture risk can be assessed with any of a number of tools, including:

  • Simplified Calculated Osteoporosis Risk Estimation (SCORE): www.medicalalgorithms.com/simplified-calculated-osteoporosis-risk-estimation-tool
  • Osteoporosis Risk Assessment Instrument (ORAI): www.physio-pedia.com/The_Osteoporosis_Risk_Assessment_Instrument_(ORAI)
  • Osteoporosis Index of Risk (OSIRIS): https://www.tandfonline.com/doi/abs/10.1080/gye.16.3.245.250?journalCode=igye20
  • Osteoporosis Self-Assessment Tool (OST): www.ncbi.nlm.nih.gov/books/NBK45516/figure/ch10.f2/
  • FRAX tool5: www.sheffield.ac.uk/FRAX.

The FRAX tool is widely used. It assesses a patient’s 10-year risk of fracture.

Diagnosis is based on these criteria

Diagnosis of osteoporosis is based on any 1 or more of the following criteria6:

  • a history of fragility fracture not explained by metabolic bone disease
  • T-score ≤ –2.5 (lumbar, hip, femoral neck, or 33% radius)
  • a nation-specific FRAX score (in the absence of access to DXA).

Secondary disease. Patients in whom secondary osteoporosis is suspected should undergo laboratory investigation to ascertain the cause; treatment of the underlying pathology might then be required. Evaluation for a secondary cause might include a complete blood count, comprehensive metabolic panel, protein electrophoresis and urinary protein electrophoresis (to rule out myeloproliferative and hematologic diseases), and tests of serum 25-hydroxyvitamin D, parathyroid hormone, serum calcium, alkaline phosphatase, 24-hour urinary calcium, sodium, and creatinine.6,7 Specialized testing for biochemical markers of bone turnover—so-called bone-turnover markers—can be considered as part of the initial evaluation and follow-up, although the tests are not recommended by the US Preventive Services Task Force (see “Monitoring the efficacy of treatment,” later in the article, for more information about these markers).6

Although BMD by DXA remains the gold standard in screening for and diagnosing osteoporosis, a high rate of fracture is seen in patients with certain diseases, such as type 2 diabetes and ankylosing spondylitis, who have a nonosteoporotic low T-score. This raises concerns about the usefulness of BMD for diagnosing osteoporosis in patients who have one of these diseases.13-16

Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when risk of fracture is high. Oral bisphosphonates can be used as initial treatment.

❚ Trabecular bone score (TBS), a surrogate bone-quality measure that is calculated based on the spine DXA image, has recently been introduced in clinical practice, and can be used to predict fracture risk in conjunction with BMD assessment by DXA and the FRAX score.17 TBS provides an indirect index of the trabecular microarchitecture using pixel gray-level variation in lumbar spine DXA images.18 Three categories of TBS (≤ 1.200, degraded microarchitecture; 1.200-1.350, partially degraded microarchitecture; and > 1.350, normal microarchitecture) have been reported to correspond with a T-score of, respectively, ≤ −2.5; −2.5 to −1.0; and > −1.0.18 TBS can be used only in patients with a body mass index of 15 to 37.5.19,20

There is no recommendation for monitoring bone quality using TBS after osteoporosis treatment. Such monitoring is at the clinician’s discretion for appropriate patients who might not show a risk of fracture, based on BMD measurement.

 

Continue to: Putting preventive measures into practice...

 

 

Putting preventive measures into practice

Measures to prevent osteoporosis and preserve bone health (TABLE 21,6) are best started in childhood but can be initiated at any age and maintained through the lifespan. Encourage older adults to adopt dietary and behavioral strategies to improve their bone health and prevent fracture. We recommend the following strategies; take each patient’s individual situation into consideration when electing to adopt any of these measures.

Measures to prevent osteoporosis

Vitamin D. Consider checking the serum 25-hydroxyvitamin D level and providing supplementation (800-1000 IU daily, the National Osteoporosis Foundation recommends1) as necessary to maintain the level at 30-50 ng/mL.6

Calcium. Encourage a daily dietary calcium intake of 1000-1200 mg. Supplement calcium if you determine that diet does not provide an adequate amount.

Alcohol. Advise patients to limit consumption to < 3 drinks a day.

Tobacco. Advise smoking cessation.

Activity. Encourage an active lifestyle, including regular weight-bearing and balance exercises and resistance exercises such as Pilates, weightlifting, and tai chi. The regimen should be tailored to the patient’s individual situation.

Medical therapy for concomitant illness. When possible, prescribe medications for chronic comorbidities that can also benefit bone health. For example, long-term use of angiotensin-converting enzyme (ACE) inhibitors and thiazide diuretics for hypertension are associated with a slower decline in BMD in some populations.21-23

Tailor treatment to patient’s circumstances

TABLE 34,6,24 describes indications for pharmacotherapy in osteoporosis. Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when fracture risk is high.24

Indications for pharmacotherapy for osteoporosis in older adults

Generally, you should undertake a discussion with the patient of the relative risks and benefits of treatment, taking into account their values and preferences, to come to a shared decision. Tailoring treatment, based on the patient’s distinctive circumstances, through shared decision-making is key to compliance.25

Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.26 Women with a very high BMD might not need to be retested with DXA any sooner than every 10 to 15 years.

There are 3 main classes of first-line pharmacotherapeutic agents for osteoporosis in older adults (TABLE 44,6,7,26-41): antiresorptives (bisphosphonates and denosumab), anabolics (teriparatide and abaloparatide), and a monoclonal sclerostin antibody (romosozumab). (TABLE 44,6,7,26-41 and the discussion in this section also remark on the selective estrogen-receptor modulator raloxifene, which is used in special clinical circumstances but has been removed from the first line of osteoporosis pharmacotherapy.)

What is the etiology of pediatric hypertension?

Pharmacotherapy for age-related osteoporosis

Pharmacotherapy for age-related osteoporosis


Bisphosphonates. Oral bisphosphonates (alendronate, ibandronate, risedronate) can be used as initial treatment in patients with a high risk of fracture.35 Bisphosphonates have been shown to reduce fracture risk and improve BMD. When an oral bisphosphonate cannot be tolerated, intravenous zoledronate or ibandronate can be used.41

Patients treated with a bisphosphonate should be assessed for their fracture risk after 3 to 5 years of treatment26; when intravenous zoledronate is given as initial therapy, patients should be assessed after 3 years. After assessment, patients who remain at high risk should continue treatment; those whose fracture risk has decreased to low or moderate should have treatment temporarily suspended (bisphosphonate holiday) for as long as 5 years.26 Patients on bisphosphonate holiday should have their fracture risk assessed at 2- to 4-year intervals.26 Restart treatment if there is an increase in fracture risk (eg, a decrease in BMD) or if a fracture occurs. Bisphosphonates have a prolonged effect on BMD—for many years after treatment is discontinued.27,28

Oral bisphosphonates are associated with gastroesophageal reflux disease, difficulty swallowing, and gastritis. Rare adverse effects include osteonecrosis of the jaw and atypical femur fracture.29

Denosumab, a recombinant human antibody, is a relatively newer antiresorptive for initial treatment. Denosumab, 60 mg, is given subcutaneously every 6 months. The drug can be used when bisphosphonates are contraindicated, the patient finds the bisphosphonate dosing regimen difficult to follow, or the patient is unresponsive to bisphosphonates.

Patients taking denosumab are reassessed every 5 to 10 years to determine whether to continue therapy or change to a new drug. Abrupt discontinuation of therapy can lead to rebound bone loss and increased risk of fracture.30-32 As with bisphosphonates, long-term use can be associated with osteonecrosis of the jaw and atypical femur fracture.33

There is no recommendation for a drug holiday for denosumab. An increase in, or no loss of, bone density and no new fractures while being treated are signs of effective treatment. There is no guideline for stopping denosumab, unless the patient develops adverse effects.

Bone anabolics. Patients with a very high risk of fracture (eg, who have sustained multiple vertebral fractures), can begin treatment with teriparatide (20 μg/d subcutaneously) or abaloparatide (80 μg/d subcutaneously) for as long as 2 years, followed by treatment with an antiresorptive, such as a bisphosphonate.4,6 Teriparatide can be used in patients who have not responded to an antiresorptive as first-line treatment.

Both abaloparatide and teriparatide might be associated with a risk of osteosarcoma and are contraindicated in patients who are at increased risk of osteosarcoma.36,39,40

 Romosozumab, a monoclonal sclerostin antibody, can be used in patients with very high risk of fracture or with multiple vertebral fractures. Romosozumab increases bone formation and reduces bone resorption. It is given monthly, 210 mg subcutaneously, for 1 year. The recommendation is that patients who have completed a course of romosozumab continue with antiresorptive treatment.26

Romosozumab is associated with an increase in the risk of cardiovascular disease, including stroke and myocardial infarction.26

Raloxifene, a selective estrogen-­receptor modulator, is no longer a first-line agent for osteoporosis in older adults34 because of its association with an increased risk of deep-vein thrombosis, pulmonary embolism, and lethal stroke. However, raloxifene can be used, at 60 mg/d, when bisphosphonates or denosumab are unsuitable. In addition, raloxifene is particularly useful in women with a high risk of breast cancer and in men who are taking a long-acting gonadotropin-releasing hormone agonist for prostate cancer.37,38

Continue to: Influence of chronic...

 

 

Influence of chronic diseaseon bone health

Chronic diseases—hypertension, type 2 diabetes, hyperthyroidism, rheumatoid arthritis, ankylosing spondylitis, and gastroenterologic disorders such as celiac disease and ulcerative colitis—are known to affect bone loss that can hasten osteoporosis.16,18,21 Furthermore, medications used to treat chronic diseases are known to affect bone health: Some, such as statins, ACE inhibitors, and hydrochlorothiazide, are bone protective; others, such as steroids, pioglitazone, and selective serotonin reuptake inhibitors, accelerate bone loss.1,14,42,43 It is important to be aware of the effect of a patient’s chronic diseases, and treatments for those diseases, on bone health, to help develop an individualized osteoporosis prevention plan.

Monitoring the efficacy of treatment

Treatment of osteoporosis should not be initiated without baseline measurement of BMD of the spine and hip. Subsequent to establishing that baseline, serial measurement of BMD can be used to (1) determine when treatment needs to be initiated for an untreated patient and (2) assess response in a treated patient. There is no consensus on the interval at which DXA should be repeated for the purpose of monitoring treatment response; frequency depends on the individual’s circumstances and the medication used. Notably, many physicians repeat DXA after 2 years of treatment8; however, the American College of Physicians recommends against repeating DXA within the first 5 years of pharmacotherapy in women.24

Patients with suspected vertebral fracture or those with loss of height > 1.5 inches require lateral radiographs of the thoracic and lumbar spine to assess the status of fractures.4,6

 Bone-turnover markers measured in serum can be used to assess treatment efficacy and patient adherence. The formation marker procollagen type I N-terminal propeptide (P1NP) and the resorption marker beta C-terminal cross-linking telopeptide of type 1 collagen (bCTX) are preferred for evaluating bone turnover in the clinical setting. Assessing P1NP and bCTX at baseline and after 3 months of treatment might be effective in monitoring adherence, particularly in patients taking a bisphosphonate.44

Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.

Be sure to address fall prevention

It is important to address falls, and how to prevent them, in patients with osteoporosis. Falls can precipitate fracture in older adults with reduced BMD, and fractures are the most common and debilitating manifestation of osteoporosis. Your discussion of falls with patients should include45:

  • consequences of falls
  • cautions about medications that can cloud mental alertness
  • use of appropriate footwear
  • home safety, such as adequate lighting, removal of floor clutter, and installation of handrails in the bathroom and stairwells and on outside steps.
  • having an annual comprehensive eye exam.

Osteoporosis is avoidable and treatable

Earlier research reported various expressions of number needed to treat for medical management of osteoporosis—making it difficult to follow a single number as a reference for gauging the effectiveness of pharmacotherapy.46,47 However, for older adults of different ethnic and racial backgrounds with multiple comorbidities and polypharmacy, it might be more pragmatic in primary care to establish a model of goal-oriented, individualized care. By focusing on prevention of bone loss, and being mindful that the risk of fracture almost doubles with a decrease of 1 SD in BMD, you can translate numbers to goals of care.48

In the United States, approximately one-half of osteoporosis cases in adults ≥ 50 years are managed by primary care providers. As a chronic disease, osteoporosis requires that you, first, provide regular monitoring and assessment, because risk can vary with comorbidities,49 and, second, discuss and initiate screening and treatment as appropriate, which can be done annually during a well-care visit.

CORRESPONDENCE

Nahid Rianon, MD, DrPH, Department of Family and Community Medicine, UTHealth McGovern Medical School, 6431 Fannin Street #JJL 324C, Houston, TX, 77030; Nahid.J.Rianon@uth.tmc.edu

 

As the population of older adults rises, primary osteoporosis has become a problem of public health significance, resulting in more than 2 million fractures and $19 billion in related costs annually in the United States.1 Despite the availability of effective primary and secondary preventive measures, many older adults do not receive adequate information on bone health from their primary care provider.2 Initiation of osteoporosis treatment is low even among patients who have had an osteoporotic fracture: Fewer than one-­quarter of older adults with hip fracture have begun taking osteoporosis medication within 12 months of hospital discharge.3

In this overview of osteoporosis care, we provide information on how to evaluate and manage older adults in primary care settings who are at risk of, or have been given a diagnosis of, primary osteoporosis. The guidance that we offer reflects the most recent updates and recommendations by relevant professional societies.1,4-7

The nature and scope of an urgent problem

Osteoporosis is a skeletal disorder characterized by low bone mass and deterioration of bone structure that causes bone fragility and increases the risk of fracture.8 Operationally, it is defined by the World Health Organization as a bone mineral density (BMD) score below 2.5 SD from the mean value for a young White woman (ie, T-score ≤ –2.5).9 Primary osteoporosis is age related and occurs mostly in postmenopausal women and older men, affecting 25% of women and 5% of men ≥ 65 years.10

An osteoporotic fracture is particularly devastating in an older adult because it can cause pain, reduced mobility, depression, and social isolation and can increase the risk of related mortality.1 The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.1 Therefore, it is of paramount importance to identify patients who are at increased risk of fracture and intervene early.

The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.

Clinical manifestations

Osteoporosis does not have a primary presentation; rather, disease manifests clinically when a patient develops complications. Often, a fragility fracture is the first sign in an older person.11

A fracture is the most important complication of osteoporosis and can result from low-trauma injury or a fall from standing height—thus, the term “fragility fracture.” Osteoporotic fractures commonly involve the vertebra, hip, and wrist. Hip and extremity fractures can result in limited or lost mobility and depression. Vertebral fractures can be asymptomatic or result in kyphosis and loss of height. Fractures can give rise to pain.

Age and female sexare risk factors

TABLE 11,6,10 lists risk factors associated with osteoporosis. Age is the most important; prevalence of osteoporosis increases with age. Other nonmodifiable risk factors include female sex (the disease appears earlier in women who enter menopause prematurely), family history of osteoporosis, and race and ethnicity. Twenty percent of Asian and non-Hispanic White women > 50 years have osteoporosis.1 A study showed that Mexican Americans are at higher risk of osteoporosis than non-Hispanic Whites; non-Hispanic Blacks are least affected.10

Risk factors for osteoporosis

Other risk factors include low body weight (< 127 lb) and a history of fractures after age 50. Behavioral risk factors include smoking, excessive alcohol intake (> 3 drinks/d), poor nutrition, and a sedentary lifestyle.1,6

Continue to: Who should be screened?...

 

 

Who should be screened?

Screening is generally performed with a clinical evaluation and a dual-energy x-ray absorptiometry (DXA) scan of BMD. Measurement of BMD is generally recommended for screening all women ≥ 65 years and those < 65 years whose 10-year risk of fracture is equivalent to that of a 65-year-old White woman (see “Assessment of fracture risk” later in the article). For men, the US Preventive Services Task Force recommends screening those with a prior fracture or a secondary risk factor for disease.5 However, the National Osteoporosis Foundation recommends screening all men ≥ 70 years and those 50 to 69 years whose risk profile shows heightened risk.1,4

DXA of the spine and hip is preferred; the distal one-third of the radius (termed “33% radius”) of the nondominant arm can be used when spine and hip BMD cannot be interpreted because of bone changes from the disease process or artifacts, or in certain diseases in which the wrist region shows the earliest change (eg, primary hyperparathyroidism).6,7

Clinical evaluation includes a detailed history, physical examination, laboratory screening, and assessment for risk of fracture.

 History. Explore the presence of risk factors, including fractures in adulthood, falls, medication use, alcohol and tobacco use, family history of osteoporosis, and chronic disease.6,7

Physical exam. Assess height, including any loss (> 1.5 in) since the patient’s second or third decade of life; kyphosis; frailty; and balance and mobility problems.4,6,7

Laboratory and imaging studies. Perform basic laboratory testing when DXA is abnormal, including thyroid function, serum calcium, and renal function.6,12 Radiography of the lateral spine might be necessary, especially when there is kyphosis or loss of height. Assess for vertebral fracture, using lateral spine radiography, when vertebral involvement is suspected.6,7

Assessment of fracture risk. Fracture risk can be assessed with any of a number of tools, including:

  • Simplified Calculated Osteoporosis Risk Estimation (SCORE): www.medicalalgorithms.com/simplified-calculated-osteoporosis-risk-estimation-tool
  • Osteoporosis Risk Assessment Instrument (ORAI): www.physio-pedia.com/The_Osteoporosis_Risk_Assessment_Instrument_(ORAI)
  • Osteoporosis Index of Risk (OSIRIS): https://www.tandfonline.com/doi/abs/10.1080/gye.16.3.245.250?journalCode=igye20
  • Osteoporosis Self-Assessment Tool (OST): www.ncbi.nlm.nih.gov/books/NBK45516/figure/ch10.f2/
  • FRAX tool5: www.sheffield.ac.uk/FRAX.

The FRAX tool is widely used. It assesses a patient’s 10-year risk of fracture.

Diagnosis is based on these criteria

Diagnosis of osteoporosis is based on any 1 or more of the following criteria6:

  • a history of fragility fracture not explained by metabolic bone disease
  • T-score ≤ –2.5 (lumbar, hip, femoral neck, or 33% radius)
  • a nation-specific FRAX score (in the absence of access to DXA).

Secondary disease. Patients in whom secondary osteoporosis is suspected should undergo laboratory investigation to ascertain the cause; treatment of the underlying pathology might then be required. Evaluation for a secondary cause might include a complete blood count, comprehensive metabolic panel, protein electrophoresis and urinary protein electrophoresis (to rule out myeloproliferative and hematologic diseases), and tests of serum 25-hydroxyvitamin D, parathyroid hormone, serum calcium, alkaline phosphatase, 24-hour urinary calcium, sodium, and creatinine.6,7 Specialized testing for biochemical markers of bone turnover—so-called bone-turnover markers—can be considered as part of the initial evaluation and follow-up, although the tests are not recommended by the US Preventive Services Task Force (see “Monitoring the efficacy of treatment,” later in the article, for more information about these markers).6

Although BMD by DXA remains the gold standard in screening for and diagnosing osteoporosis, a high rate of fracture is seen in patients with certain diseases, such as type 2 diabetes and ankylosing spondylitis, who have a nonosteoporotic low T-score. This raises concerns about the usefulness of BMD for diagnosing osteoporosis in patients who have one of these diseases.13-16

Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when risk of fracture is high. Oral bisphosphonates can be used as initial treatment.

❚ Trabecular bone score (TBS), a surrogate bone-quality measure that is calculated based on the spine DXA image, has recently been introduced in clinical practice, and can be used to predict fracture risk in conjunction with BMD assessment by DXA and the FRAX score.17 TBS provides an indirect index of the trabecular microarchitecture using pixel gray-level variation in lumbar spine DXA images.18 Three categories of TBS (≤ 1.200, degraded microarchitecture; 1.200-1.350, partially degraded microarchitecture; and > 1.350, normal microarchitecture) have been reported to correspond with a T-score of, respectively, ≤ −2.5; −2.5 to −1.0; and > −1.0.18 TBS can be used only in patients with a body mass index of 15 to 37.5.19,20

There is no recommendation for monitoring bone quality using TBS after osteoporosis treatment. Such monitoring is at the clinician’s discretion for appropriate patients who might not show a risk of fracture, based on BMD measurement.

 

Continue to: Putting preventive measures into practice...

 

 

Putting preventive measures into practice

Measures to prevent osteoporosis and preserve bone health (TABLE 21,6) are best started in childhood but can be initiated at any age and maintained through the lifespan. Encourage older adults to adopt dietary and behavioral strategies to improve their bone health and prevent fracture. We recommend the following strategies; take each patient’s individual situation into consideration when electing to adopt any of these measures.

Measures to prevent osteoporosis

Vitamin D. Consider checking the serum 25-hydroxyvitamin D level and providing supplementation (800-1000 IU daily, the National Osteoporosis Foundation recommends1) as necessary to maintain the level at 30-50 ng/mL.6

Calcium. Encourage a daily dietary calcium intake of 1000-1200 mg. Supplement calcium if you determine that diet does not provide an adequate amount.

Alcohol. Advise patients to limit consumption to < 3 drinks a day.

Tobacco. Advise smoking cessation.

Activity. Encourage an active lifestyle, including regular weight-bearing and balance exercises and resistance exercises such as Pilates, weightlifting, and tai chi. The regimen should be tailored to the patient’s individual situation.

Medical therapy for concomitant illness. When possible, prescribe medications for chronic comorbidities that can also benefit bone health. For example, long-term use of angiotensin-converting enzyme (ACE) inhibitors and thiazide diuretics for hypertension are associated with a slower decline in BMD in some populations.21-23

Tailor treatment to patient’s circumstances

TABLE 34,6,24 describes indications for pharmacotherapy in osteoporosis. Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when fracture risk is high.24

Indications for pharmacotherapy for osteoporosis in older adults

Generally, you should undertake a discussion with the patient of the relative risks and benefits of treatment, taking into account their values and preferences, to come to a shared decision. Tailoring treatment, based on the patient’s distinctive circumstances, through shared decision-making is key to compliance.25

Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.26 Women with a very high BMD might not need to be retested with DXA any sooner than every 10 to 15 years.

There are 3 main classes of first-line pharmacotherapeutic agents for osteoporosis in older adults (TABLE 44,6,7,26-41): antiresorptives (bisphosphonates and denosumab), anabolics (teriparatide and abaloparatide), and a monoclonal sclerostin antibody (romosozumab). (TABLE 44,6,7,26-41 and the discussion in this section also remark on the selective estrogen-receptor modulator raloxifene, which is used in special clinical circumstances but has been removed from the first line of osteoporosis pharmacotherapy.)

What is the etiology of pediatric hypertension?

Pharmacotherapy for age-related osteoporosis

Pharmacotherapy for age-related osteoporosis


Bisphosphonates. Oral bisphosphonates (alendronate, ibandronate, risedronate) can be used as initial treatment in patients with a high risk of fracture.35 Bisphosphonates have been shown to reduce fracture risk and improve BMD. When an oral bisphosphonate cannot be tolerated, intravenous zoledronate or ibandronate can be used.41

Patients treated with a bisphosphonate should be assessed for their fracture risk after 3 to 5 years of treatment26; when intravenous zoledronate is given as initial therapy, patients should be assessed after 3 years. After assessment, patients who remain at high risk should continue treatment; those whose fracture risk has decreased to low or moderate should have treatment temporarily suspended (bisphosphonate holiday) for as long as 5 years.26 Patients on bisphosphonate holiday should have their fracture risk assessed at 2- to 4-year intervals.26 Restart treatment if there is an increase in fracture risk (eg, a decrease in BMD) or if a fracture occurs. Bisphosphonates have a prolonged effect on BMD—for many years after treatment is discontinued.27,28

Oral bisphosphonates are associated with gastroesophageal reflux disease, difficulty swallowing, and gastritis. Rare adverse effects include osteonecrosis of the jaw and atypical femur fracture.29

Denosumab, a recombinant human antibody, is a relatively newer antiresorptive for initial treatment. Denosumab, 60 mg, is given subcutaneously every 6 months. The drug can be used when bisphosphonates are contraindicated, the patient finds the bisphosphonate dosing regimen difficult to follow, or the patient is unresponsive to bisphosphonates.

Patients taking denosumab are reassessed every 5 to 10 years to determine whether to continue therapy or change to a new drug. Abrupt discontinuation of therapy can lead to rebound bone loss and increased risk of fracture.30-32 As with bisphosphonates, long-term use can be associated with osteonecrosis of the jaw and atypical femur fracture.33

There is no recommendation for a drug holiday for denosumab. An increase in, or no loss of, bone density and no new fractures while being treated are signs of effective treatment. There is no guideline for stopping denosumab, unless the patient develops adverse effects.

Bone anabolics. Patients with a very high risk of fracture (eg, who have sustained multiple vertebral fractures), can begin treatment with teriparatide (20 μg/d subcutaneously) or abaloparatide (80 μg/d subcutaneously) for as long as 2 years, followed by treatment with an antiresorptive, such as a bisphosphonate.4,6 Teriparatide can be used in patients who have not responded to an antiresorptive as first-line treatment.

Both abaloparatide and teriparatide might be associated with a risk of osteosarcoma and are contraindicated in patients who are at increased risk of osteosarcoma.36,39,40

 Romosozumab, a monoclonal sclerostin antibody, can be used in patients with very high risk of fracture or with multiple vertebral fractures. Romosozumab increases bone formation and reduces bone resorption. It is given monthly, 210 mg subcutaneously, for 1 year. The recommendation is that patients who have completed a course of romosozumab continue with antiresorptive treatment.26

Romosozumab is associated with an increase in the risk of cardiovascular disease, including stroke and myocardial infarction.26

Raloxifene, a selective estrogen-­receptor modulator, is no longer a first-line agent for osteoporosis in older adults34 because of its association with an increased risk of deep-vein thrombosis, pulmonary embolism, and lethal stroke. However, raloxifene can be used, at 60 mg/d, when bisphosphonates or denosumab are unsuitable. In addition, raloxifene is particularly useful in women with a high risk of breast cancer and in men who are taking a long-acting gonadotropin-releasing hormone agonist for prostate cancer.37,38

Continue to: Influence of chronic...

 

 

Influence of chronic diseaseon bone health

Chronic diseases—hypertension, type 2 diabetes, hyperthyroidism, rheumatoid arthritis, ankylosing spondylitis, and gastroenterologic disorders such as celiac disease and ulcerative colitis—are known to affect bone loss that can hasten osteoporosis.16,18,21 Furthermore, medications used to treat chronic diseases are known to affect bone health: Some, such as statins, ACE inhibitors, and hydrochlorothiazide, are bone protective; others, such as steroids, pioglitazone, and selective serotonin reuptake inhibitors, accelerate bone loss.1,14,42,43 It is important to be aware of the effect of a patient’s chronic diseases, and treatments for those diseases, on bone health, to help develop an individualized osteoporosis prevention plan.

Monitoring the efficacy of treatment

Treatment of osteoporosis should not be initiated without baseline measurement of BMD of the spine and hip. Subsequent to establishing that baseline, serial measurement of BMD can be used to (1) determine when treatment needs to be initiated for an untreated patient and (2) assess response in a treated patient. There is no consensus on the interval at which DXA should be repeated for the purpose of monitoring treatment response; frequency depends on the individual’s circumstances and the medication used. Notably, many physicians repeat DXA after 2 years of treatment8; however, the American College of Physicians recommends against repeating DXA within the first 5 years of pharmacotherapy in women.24

Patients with suspected vertebral fracture or those with loss of height > 1.5 inches require lateral radiographs of the thoracic and lumbar spine to assess the status of fractures.4,6

 Bone-turnover markers measured in serum can be used to assess treatment efficacy and patient adherence. The formation marker procollagen type I N-terminal propeptide (P1NP) and the resorption marker beta C-terminal cross-linking telopeptide of type 1 collagen (bCTX) are preferred for evaluating bone turnover in the clinical setting. Assessing P1NP and bCTX at baseline and after 3 months of treatment might be effective in monitoring adherence, particularly in patients taking a bisphosphonate.44

Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.

Be sure to address fall prevention

It is important to address falls, and how to prevent them, in patients with osteoporosis. Falls can precipitate fracture in older adults with reduced BMD, and fractures are the most common and debilitating manifestation of osteoporosis. Your discussion of falls with patients should include45:

  • consequences of falls
  • cautions about medications that can cloud mental alertness
  • use of appropriate footwear
  • home safety, such as adequate lighting, removal of floor clutter, and installation of handrails in the bathroom and stairwells and on outside steps.
  • having an annual comprehensive eye exam.

Osteoporosis is avoidable and treatable

Earlier research reported various expressions of number needed to treat for medical management of osteoporosis—making it difficult to follow a single number as a reference for gauging the effectiveness of pharmacotherapy.46,47 However, for older adults of different ethnic and racial backgrounds with multiple comorbidities and polypharmacy, it might be more pragmatic in primary care to establish a model of goal-oriented, individualized care. By focusing on prevention of bone loss, and being mindful that the risk of fracture almost doubles with a decrease of 1 SD in BMD, you can translate numbers to goals of care.48

In the United States, approximately one-half of osteoporosis cases in adults ≥ 50 years are managed by primary care providers. As a chronic disease, osteoporosis requires that you, first, provide regular monitoring and assessment, because risk can vary with comorbidities,49 and, second, discuss and initiate screening and treatment as appropriate, which can be done annually during a well-care visit.

CORRESPONDENCE

Nahid Rianon, MD, DrPH, Department of Family and Community Medicine, UTHealth McGovern Medical School, 6431 Fannin Street #JJL 324C, Houston, TX, 77030; Nahid.J.Rianon@uth.tmc.edu

References
  1. What is osteoporosis and what causes it? National Osteoporosis Foundation Website. 2020. Accessed April 28, 2021. www.nof.org/patients/what-is-osteoporosis/ 
  2. des Bordes J, Prasad S, Pratt G, et al. Knowledge, beliefs, and concerns about bone health from a systematic review and metasynthesis of qualitative studies. PLoS One. 2020;15:e0227765. doi: 10.1371/journal.pone.0227765  
  3. Solomon DH, Johnston SS, Boytsov NN, et al. Osteoporosis medication use after hip fracture in U.S. patients between 2002 and 2011. J Bone Miner Res. 2014;29:1929-1937. doi: 10.1002/jbmr.2202 
  4. Cosman F, de Beur SJ, LeBoff MS, et al; National Osteoporosis Foundation. Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25:2359-2381. doi: 10.1007/s00198-014-2794-2 
  5. US Preventive Services Task Force; Curry SJ, Krist AH, Owens DK, et al. Screening for osteoporosis to prevent fractures: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:2521-2531. doi: 10.1001/jama.2018.7498 
  6. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016. Endocr Pract. 2016;22(suppl 4):1-42. doi: 10.4158/EP161435.GL 
  7. Watts NB, Adler RA, Bilezikian JP, et al; Endocrine Society. Osteoporosis in men: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2012;97:1802-1822. doi: 10.1210/jc.2011-3045 
  8. US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2004. Accessed April 28, 2021. www.ncbi.nlm.nih.gov/books/NBK45513/pdf/Bookshelf_NBK45513.pdf 
  9. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser. 1994;843:1-129.  
  10. Looker AC, Frenk SM. Percentage of adults aged 65 and over with osteoporosis or low bone mass at the femur neck or lumbar spine: United States, 2005--2010. Centers for Disease Control and Prevention, National Center for Health Statistics, Division of Health and Nutrition Examination Surveys. August 2015. Accessed April 28, 2021. www.cdc.gov/nchs/data/hestat/osteoporsis/osteoporosis2005_2010.pdf 
  11. Kerschan-Schindl K. Prevention and rehabilitation of osteoporosis. Wien Med Wochenschr. 2016;166:22-27. doi: 10.1007/s10354-015-0417-y 
  12. Tarantino U, Iolascon G, Cianferotti L, et al. Clinical guidelines for the prevention and treatment of osteoporosis: summary statements and recommendations from the Italian Society for Orthopaedics and Traumatology. J Orthop Traumatol. 2017;18(suppl 1):3-36. doi: 10.1007/s10195-017-0474-7 
  13. Martineau P, Leslie WD, Johansson H, et al. In which patients does lumbar spine trabecular bone score (TBS) have the largest effect? Bone. 2018;113:161-168. doi: 10.1016/j.bone.2018.05.026 
  14. Rianon NJ, Smith SM, Lee M, et al. Glycemic control and bone turnover in older Mexican Americans with type 2 diabetes. J Osteoporos. 2018;2018:7153021. doi: 10.1155/2018/7153021 
  15. Richards C, Hans D, Leslie WD. Trabecular bone score (TBS) predicts fracture in ankylosing spondylitis: The Manitoba BMD Registry. J Clin Densitom. 2020;23:543-548. doi: 10.1016/j.jocd.2020.01.003 
  16. Xue Y, Baker AL, Nader S, et al. Lumbar spine trabecular bone score (TBS) reflects diminished bone quality in patients with diabetes mellitus and oral glucocorticoid therapy. J Clin Densitom. 2018;21:185-192. doi: 10.1016/j.jocd.2017.09.003 
  17. Silva BC, Broy SB, Boutroy S, et al. Fracture risk prediction by non-BMD DXA measures: the 2015 ISCD Official Positions Part 2: trabecular bone score. J Clin Densitom. 2015;18:309-330. doi: 10.1016/j.jocd.2015.06.008 
  18. Silva BC, Leslie WD, Resch H, et al. Trabecular bone score: a noninvasive analytical method based upon the DXA image. J Bone Miner Res. 2014;29:518-530. doi: 10.1002/jbmr.2176 
  19. Leslie WD, Aubry-Rozier B, Lamy O, et al; Manitoba Bone Density Program. TBS (trabecular bone score) and diabetes-related fracture risk. J Clin Endocrinol Metab. 2013;98:602-609. 
  20. Looker AC, Sarafrazi Isfahani N, Fan B, et al. Trabecular bone scores and lumbar spine bone mineral density of US adults: comparison of relationships with demographic and body size variables. Osteoporos Int. 2016;27:2467-2475. doi: 10.1007/s00198-016-3550-6 
  21. Rianon N, Ambrose CG, Pervin H, et al. Long-term use of angiotensin-converting enzyme inhibitors protects against bone loss in African-American elderly men. Arch Osteoporos. 2017;12:94. doi: 10.1007/s11657-017-0387-3 
  22. Morton DJ, Barrett-Connor EL, Edelstein SL. Thiazides and bone mineral density in elderly men and women. Am J Epidemiol. 1994;139:1107-1115. doi: 10.1093/oxfordjournals.aje.a116954 
  23. Sigurdsson G, Franzson L. Increased bone mineral density in a population-based group of 70-year-old women on thiazide diuretics, independent of parathyroid hormone levels. J Intern Med. 2001;250:51-56. doi: 10.1046/j.1365-2796.2001.00850.x 
  24. Qaseem A, Forciea MA, McLean RM, et al; Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166:818-839. doi: 10.7326/M15-1361 
  25. des Bordes JKA, Suarez-Almazor ME, Volk RJ, et al. Online educational tool to promote bone health in cancer survivors. J Health Commun. 2017;22:808-817. doi: 10.1080/10810730.2017.1360415 
  26. Shoback D, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J Clin Endocrinol Metab. 2020;105:587-594. doi: 10.1210/clinem/dgaa048 
  27. Black DM, Schwartz AV, Ensrud KE, et al; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938. doi: 10.1001/jama.296.24.2927 
  28. Bone HG, Hosking D, Devogelaer J-P, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199. doi: 10.1056/NEJMoa030897 
  29. Khosla S, Burr D, Cauley J, et al; American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479-1491. doi: 10.1359/jbmr.0707onj 
  30. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96:972-980. doi: 10.1210/jc.2010-1502 
  31. Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM Trial and its extension. J Bone Miner Res. 2018;33:190-198. doi: 10.1002/jbmr.3337 
  32. Symonds C, Kline G. Warning of an increased risk of vertebral fracture after stopping denosumab. CMAJ. 2018;190:E485-E486. doi: 10.1503/cmaj.180115 
  33. Aljohani S, Gaudin R, Weiser J, et al. Osteonecrosis of the jaw in patients treated with denosumab: a multicenter case series. J Craniomaxillofac Surg. 2018;46:1515-1525. doi: 10.1016/j.jcms.2018.05.046 
  34. Barrett-Connor E, Mosca L, Collins P, et al; Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125-137. doi: 10.1056/NEJMoa062462 
  35. Chesnut CH 3rd, Skag A, Christiansen C, et al; Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241-1249. doi: 10.1359/JBMR.040325 
  36. Gilsenban A, Midkiff K, Kellier-Steele N, et al. Teriparatide did not increase adult osteosarcoma incidence in a 15-year US postmarketing surveillance study. J Bone Miner Res. 2021;36:244-252. doi: 10.1002/jbmr.4188 
  37. Cuzick J, Sestak I, Bonanni B, et al; SERM Chemoprevention of Breast Cancer Overview Group. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet. 2013;381:1827-1834. doi: 10.1016/S0140-6736(13)60140-3 
  38. Smith MR, Fallon MA, Lee H, et al. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:3841-3846. doi: 10.1210/jc.2003-032058 
  39. TYMLOS. Prescribing information. Radius Health, Inc.; April 2017. Accessed May 20, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2017/208743lbl.pdf  
  40. FORTEO. Prescribing information. Eli Lilly and Co.; April 2020. Accessed May 20, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2020/021318s053lbl.pdf 
  41. Wooltorton E. Patients receiving intravenous bisphosphonates should avoid invasive dental procedures. Can Med Assoc J. 2003;172:1684. doi: https://doi.org/10.1503/cmaj.050640 
  42. Chiadika SM, Shobayo FO, Naqvi SH, et al. Lower femoral neck bone mineral density (BMD) in elderly women not on statins. Women Health. 2019;59:845-853. doi: 10.1080/03630242.2019.1567646 
  43. Saraykar S, John V, Cao B, et al. Association of selective serotonin reuptake inhibitors and bone mineral density in elderly women. J Clin Densitom. 2018;21:193-199. doi: 10.1016/j.jocd.2017.05.016 
  44. Lorentzon M, Branco J, Brandi ML, et al. Algorithm for the use of biochemical markers of bone turnover in the diagnosis, assessment and follow-up of treatment for osteoporosis. Adv Ther. 2019;36:2811-2824. doi: 10.1007/s12325-019-01063-9 
  45. STEADI--older adult fall prevention. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. 2019. Accessed April 28, 2021. www.cdc.gov/steadi/patient.html 
  46. Cummings SR, San Martin J, McClung MR, et al; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765. doi: 10.1056/NEJMoa0809493 
  47. Zhou Z, Chen C, Zhang J, et al. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol. 2014;7:2113-2122. 
  48. Faulkner KG. Bone matters: are density increases necessary to reduce fracture risk? J Bone Miner Res. 2000;15:183-187. doi: 10.1359/jbmr.2000.15.2.183 
  49. Rianon N, Anand D, Rasu R. Changing trends in osteoporosis care from specialty to primary care physicians. Curr Med Res Opin. 2013;29:881-888. doi: 10.1185/03007995.2013.809335
References
  1. What is osteoporosis and what causes it? National Osteoporosis Foundation Website. 2020. Accessed April 28, 2021. www.nof.org/patients/what-is-osteoporosis/ 
  2. des Bordes J, Prasad S, Pratt G, et al. Knowledge, beliefs, and concerns about bone health from a systematic review and metasynthesis of qualitative studies. PLoS One. 2020;15:e0227765. doi: 10.1371/journal.pone.0227765  
  3. Solomon DH, Johnston SS, Boytsov NN, et al. Osteoporosis medication use after hip fracture in U.S. patients between 2002 and 2011. J Bone Miner Res. 2014;29:1929-1937. doi: 10.1002/jbmr.2202 
  4. Cosman F, de Beur SJ, LeBoff MS, et al; National Osteoporosis Foundation. Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25:2359-2381. doi: 10.1007/s00198-014-2794-2 
  5. US Preventive Services Task Force; Curry SJ, Krist AH, Owens DK, et al. Screening for osteoporosis to prevent fractures: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:2521-2531. doi: 10.1001/jama.2018.7498 
  6. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016. Endocr Pract. 2016;22(suppl 4):1-42. doi: 10.4158/EP161435.GL 
  7. Watts NB, Adler RA, Bilezikian JP, et al; Endocrine Society. Osteoporosis in men: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2012;97:1802-1822. doi: 10.1210/jc.2011-3045 
  8. US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2004. Accessed April 28, 2021. www.ncbi.nlm.nih.gov/books/NBK45513/pdf/Bookshelf_NBK45513.pdf 
  9. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser. 1994;843:1-129.  
  10. Looker AC, Frenk SM. Percentage of adults aged 65 and over with osteoporosis or low bone mass at the femur neck or lumbar spine: United States, 2005--2010. Centers for Disease Control and Prevention, National Center for Health Statistics, Division of Health and Nutrition Examination Surveys. August 2015. Accessed April 28, 2021. www.cdc.gov/nchs/data/hestat/osteoporsis/osteoporosis2005_2010.pdf 
  11. Kerschan-Schindl K. Prevention and rehabilitation of osteoporosis. Wien Med Wochenschr. 2016;166:22-27. doi: 10.1007/s10354-015-0417-y 
  12. Tarantino U, Iolascon G, Cianferotti L, et al. Clinical guidelines for the prevention and treatment of osteoporosis: summary statements and recommendations from the Italian Society for Orthopaedics and Traumatology. J Orthop Traumatol. 2017;18(suppl 1):3-36. doi: 10.1007/s10195-017-0474-7 
  13. Martineau P, Leslie WD, Johansson H, et al. In which patients does lumbar spine trabecular bone score (TBS) have the largest effect? Bone. 2018;113:161-168. doi: 10.1016/j.bone.2018.05.026 
  14. Rianon NJ, Smith SM, Lee M, et al. Glycemic control and bone turnover in older Mexican Americans with type 2 diabetes. J Osteoporos. 2018;2018:7153021. doi: 10.1155/2018/7153021 
  15. Richards C, Hans D, Leslie WD. Trabecular bone score (TBS) predicts fracture in ankylosing spondylitis: The Manitoba BMD Registry. J Clin Densitom. 2020;23:543-548. doi: 10.1016/j.jocd.2020.01.003 
  16. Xue Y, Baker AL, Nader S, et al. Lumbar spine trabecular bone score (TBS) reflects diminished bone quality in patients with diabetes mellitus and oral glucocorticoid therapy. J Clin Densitom. 2018;21:185-192. doi: 10.1016/j.jocd.2017.09.003 
  17. Silva BC, Broy SB, Boutroy S, et al. Fracture risk prediction by non-BMD DXA measures: the 2015 ISCD Official Positions Part 2: trabecular bone score. J Clin Densitom. 2015;18:309-330. doi: 10.1016/j.jocd.2015.06.008 
  18. Silva BC, Leslie WD, Resch H, et al. Trabecular bone score: a noninvasive analytical method based upon the DXA image. J Bone Miner Res. 2014;29:518-530. doi: 10.1002/jbmr.2176 
  19. Leslie WD, Aubry-Rozier B, Lamy O, et al; Manitoba Bone Density Program. TBS (trabecular bone score) and diabetes-related fracture risk. J Clin Endocrinol Metab. 2013;98:602-609. 
  20. Looker AC, Sarafrazi Isfahani N, Fan B, et al. Trabecular bone scores and lumbar spine bone mineral density of US adults: comparison of relationships with demographic and body size variables. Osteoporos Int. 2016;27:2467-2475. doi: 10.1007/s00198-016-3550-6 
  21. Rianon N, Ambrose CG, Pervin H, et al. Long-term use of angiotensin-converting enzyme inhibitors protects against bone loss in African-American elderly men. Arch Osteoporos. 2017;12:94. doi: 10.1007/s11657-017-0387-3 
  22. Morton DJ, Barrett-Connor EL, Edelstein SL. Thiazides and bone mineral density in elderly men and women. Am J Epidemiol. 1994;139:1107-1115. doi: 10.1093/oxfordjournals.aje.a116954 
  23. Sigurdsson G, Franzson L. Increased bone mineral density in a population-based group of 70-year-old women on thiazide diuretics, independent of parathyroid hormone levels. J Intern Med. 2001;250:51-56. doi: 10.1046/j.1365-2796.2001.00850.x 
  24. Qaseem A, Forciea MA, McLean RM, et al; Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166:818-839. doi: 10.7326/M15-1361 
  25. des Bordes JKA, Suarez-Almazor ME, Volk RJ, et al. Online educational tool to promote bone health in cancer survivors. J Health Commun. 2017;22:808-817. doi: 10.1080/10810730.2017.1360415 
  26. Shoback D, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J Clin Endocrinol Metab. 2020;105:587-594. doi: 10.1210/clinem/dgaa048 
  27. Black DM, Schwartz AV, Ensrud KE, et al; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938. doi: 10.1001/jama.296.24.2927 
  28. Bone HG, Hosking D, Devogelaer J-P, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199. doi: 10.1056/NEJMoa030897 
  29. Khosla S, Burr D, Cauley J, et al; American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479-1491. doi: 10.1359/jbmr.0707onj 
  30. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96:972-980. doi: 10.1210/jc.2010-1502 
  31. Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM Trial and its extension. J Bone Miner Res. 2018;33:190-198. doi: 10.1002/jbmr.3337 
  32. Symonds C, Kline G. Warning of an increased risk of vertebral fracture after stopping denosumab. CMAJ. 2018;190:E485-E486. doi: 10.1503/cmaj.180115 
  33. Aljohani S, Gaudin R, Weiser J, et al. Osteonecrosis of the jaw in patients treated with denosumab: a multicenter case series. J Craniomaxillofac Surg. 2018;46:1515-1525. doi: 10.1016/j.jcms.2018.05.046 
  34. Barrett-Connor E, Mosca L, Collins P, et al; Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125-137. doi: 10.1056/NEJMoa062462 
  35. Chesnut CH 3rd, Skag A, Christiansen C, et al; Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241-1249. doi: 10.1359/JBMR.040325 
  36. Gilsenban A, Midkiff K, Kellier-Steele N, et al. Teriparatide did not increase adult osteosarcoma incidence in a 15-year US postmarketing surveillance study. J Bone Miner Res. 2021;36:244-252. doi: 10.1002/jbmr.4188 
  37. Cuzick J, Sestak I, Bonanni B, et al; SERM Chemoprevention of Breast Cancer Overview Group. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet. 2013;381:1827-1834. doi: 10.1016/S0140-6736(13)60140-3 
  38. Smith MR, Fallon MA, Lee H, et al. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:3841-3846. doi: 10.1210/jc.2003-032058 
  39. TYMLOS. Prescribing information. Radius Health, Inc.; April 2017. Accessed May 20, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2017/208743lbl.pdf  
  40. FORTEO. Prescribing information. Eli Lilly and Co.; April 2020. Accessed May 20, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2020/021318s053lbl.pdf 
  41. Wooltorton E. Patients receiving intravenous bisphosphonates should avoid invasive dental procedures. Can Med Assoc J. 2003;172:1684. doi: https://doi.org/10.1503/cmaj.050640 
  42. Chiadika SM, Shobayo FO, Naqvi SH, et al. Lower femoral neck bone mineral density (BMD) in elderly women not on statins. Women Health. 2019;59:845-853. doi: 10.1080/03630242.2019.1567646 
  43. Saraykar S, John V, Cao B, et al. Association of selective serotonin reuptake inhibitors and bone mineral density in elderly women. J Clin Densitom. 2018;21:193-199. doi: 10.1016/j.jocd.2017.05.016 
  44. Lorentzon M, Branco J, Brandi ML, et al. Algorithm for the use of biochemical markers of bone turnover in the diagnosis, assessment and follow-up of treatment for osteoporosis. Adv Ther. 2019;36:2811-2824. doi: 10.1007/s12325-019-01063-9 
  45. STEADI--older adult fall prevention. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. 2019. Accessed April 28, 2021. www.cdc.gov/steadi/patient.html 
  46. Cummings SR, San Martin J, McClung MR, et al; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765. doi: 10.1056/NEJMoa0809493 
  47. Zhou Z, Chen C, Zhang J, et al. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol. 2014;7:2113-2122. 
  48. Faulkner KG. Bone matters: are density increases necessary to reduce fracture risk? J Bone Miner Res. 2000;15:183-187. doi: 10.1359/jbmr.2000.15.2.183 
  49. Rianon N, Anand D, Rasu R. Changing trends in osteoporosis care from specialty to primary care physicians. Curr Med Res Opin. 2013;29:881-888. doi: 10.1185/03007995.2013.809335
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PRACTICE RECOMMENDATIONS

❯ Consider screening for osteoporosis, using bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), in all postmenopausal women ≥ 65 years and in women < 65 years at high risk of osteoporosis.

❯ Consider screening in men ≥ 70 years and in younger men at high risk of fracture.

❯ Use the trabecular bone score with DXA BMD to screen patients at high risk of fracture who have a normal BMD—eg, patients with type 2 diabetes or ankylosing spondylitis.

❯ Offer individualized pharmacotherapy to older patients with a diagnosis of osteoporosis and to those at high risk of fracture.

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Getting hypertension under control in the youngest of patients

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Getting hypertension under control in the youngest of patients

Hypertension and elevated blood pressure (BP) in children and adolescents correlate to hypertension in adults, insofar as complications and medical therapy increase with age.1,2 Untreated, hypertension in children and adolescents can result in multiple harmful physiologic changes, including left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, arterial stiffening, endothelial dysfunction, and neurocognitive deficits.3-5

In 2017, the American Academy of Pediatrics (AAP) published clinical practice guidelines for the diagnosis and management of elevated BP and hypertension in children and adolescentsa (TABLE 16). Applying the definition of elevated BP set out in these guidelines yielded a 13% prevalence of hypertension in a cohort of subjects 10 to 18 years of age with comorbid obesity and diabetes mellitus (DM). AAP guideline definitions also improved the sensitivity for identifying hypertensive end-organ damage.7

Classification of normal and elevated BP and hypertension in children

The American Academy of Pediatrics recommends measuring BP annually in all children ≥ 3 years of age and at every encounter in patients with specific comorbid conditions and in those taking a medication known to increase BP

As the prevalence of hypertension increases, screening for and accurate diagnosis of this condition in children are becoming more important. Recognition and management remain a vital part of primary care. In this article, we review the updated guidance on diagnosis and treatment, including lifestyle modification and pharmacotherapy.

 

First step: Identifying hypertension

Risk factors

Risk factors for pediatric hypertension are similar to those in adults. These include obesity (body mass index ≥ 95th percentile for age), types 1 and 2 DM, elevated sodium intake, sleep-disordered breathing, and chronic kidney disease (CKD). Some risk factors, such as premature birth and coarctation of the aorta, are specific to the pediatric population.8-14 Pediatric obesity strongly correlates with both pediatric and adult hypertension, and accelerated weight gain might increase the risk of elevated BP in adulthood.15,16

Child with blood pressure cuff

Intervening early to mitigate or eliminate some of these modifiable risk factors can prevent or treat hypertension.17 Alternatively, having been breastfed as an infant has been reliably shown to reduce the risk of elevated BP in children.13

Recommendations for screening and measuring BP

The optimal age to start measuring BP is not clearly defined. AAP recommends measurement:

  • annually in all children ≥ 3 years of age
  • at every encounter in patients who have a specific comorbid condition, including obesity, DM, renal disease, and aortic-arch abnormalities (obstruction and coarctation) and in those who are taking medication known to increase BP.6

Protocol. Measure BP in the right arm for consistency and comparison with reference values. The width of the cuff bladder should be at least 40%, and the length, 80% to 100%, of arm circumference. Position the cuff bladder midway between the olecranon and acromion. Obtain the measurement in a quiet and comfortable environment after the patient has rested for 3 to 5 minutes. The patient should be seated, preferably with feet on the floor; elbows should be supported at the level of the heart.

Continue to: When an initial reading...

 

 

When an initial reading is elevated, whether by oscillometric or auscultatory measurement, 2 more auscultatory BP measurements should be taken during the same visit; these measurements are averaged to determine the BP category.18

TABLE 16 defines BP categories based on age, sex, and height. We recommend using the free resource MD Calc (www.mdcalc.com/aap-pediatric-hypertension-guidelines) to assist in calculating the BP category.

TABLE 26 describes the timing of follow-up based on the initial BP reading and diagnosis.

Ambulatory BP monitoring (ABPM) is a validated device that measures BP every 20 to 30 minutes throughout the day and night. ABPM should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity (TABLE 26). Note: Insurance coverage of ABPM is limited.

Initial measurement of BP determines the timing and elements of follow-up

Children older than 10 years who have been given a diagnosis of hypertension should be asked about smoking, alcohol, and other substance use.

ABPM is also used to diagnose so-called white-coat hypertension, defined as BP ≥ 95th percentile for age, sex, and height in the clinic setting but < 95th percentile during ABPM. This phenomenon can be challenging to diagnose.

Continue to: Home monitoring

 

 

Home monitoring. Do not use home BP monitoring to establish a diagnosis of hypertension, although one of these devices can be used as an adjunct to office and ambulatory BP monitoring after the diagnosis has been made.6

Evaluating hypertension in children and adolescents

Once a diagnosis of hypertension has been made, undertake a thorough history, physical examination, and diagnostic testing to evaluate for possible causes, comorbidities, and any evidence of end-organ damage.

Comprehensive history. Pertinent aspects include perinatal, nutritional, physical activity, psychosocial, family, medication—and of course, medical—histories.6

Maternal elevated BP or hypertension is related to an offspring’s elevated BP in childhood and adolescence.19 Other pertinent aspects of the perinatal history include complications of pregnancy, gestational age, birth weight, and neonatal complications.6

Nutritional and physical activity histories can highlight contributing factors in the development of hypertension and can be a guide to recommending lifestyle modifications.6 Sodium intake, which influences BP, should be part of the nutritional history.20

Continue to: Important aspects...

 

 

Important aspects of the psychosocial history include feelings of depression or anxiety, bullying, and body perception. Children older than 10 years should be asked about smoking, alcohol, and other substance use.

The family history should include notation of first- and second-degree relatives with hypertension.6

Inquire about medications that can raise BP, including oral contraceptives, which are commonly prescribed in this population.21,22

The physical exam should include measured height and weight, with calculation of the body mass index percentile for age; of note, obesity is strongly associated with hypertension, and poor growth might signal underlying chronic disease. Once elevated BP has been confirmed, the exam should include measurement of BP in both arms and in a leg (TABLE 26). BP that is lower in the leg than in the arms (in any given patient, BP readings in the legs are usually higher than in the arms), or weak or absent femoral pulses, suggest coarctation of the aorta.6

Focus the balance of the physical exam on physical findings that suggest secondary causes of hypertension or evidence of end-organ damage.

Continue to: Testing

 

 

Testing. TABLE 36,23 summarizes the diagnostic testing recommended for all children and for specific populations; TABLE 26 indicates when to obtain diagnostic testing. Patients 6 years and older who are overweight or obese and have a family history of hypertension likely have primary hypertension; they do not require an extensive work-up for secondary hypertension unless findings of the comprehensive history and physical examination lead in that direction.6,23

Diagnostic testing in children with hypertension

TABLE 42,12,13,24 outlines the basis of primary and of secondary hypertension and common historical and physical findings that suggest a secondary cause.

What is the etiology of pediatric hypertension?

Mapping out the treatment plan

Pediatric hypertension should be treated in patients with stage 1 or higher hypertension.6 This threshold for therapy is based on evidence that reducing BP below a goal of (1) the 90th percentile (calculated based on age, sex, and height) in children up to 12 years of age or (2) of < 130/80 mm Hg for children ≥ 13 years reduces short- and long-term morbidity and mortality.5,6,25

Ambulatory BP monitoring should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity.

Choice of initial treatment depends on the severity of BP elevation and the presence of comorbidities (FIGURE6,20,25-28). The initial, fundamental treatment recommendation is lifestyle modification,6,29 including regular physical exercise, a change in nutritional habits, weight loss (because obesity is a common comorbid condition), elimination of tobacco and substance use, and stress reduction.25,26 Medications can be used as well, along with other treatments for specific causes of secondary hypertension.

Management of confirmed pediatric hypertension

Referral to a specialist can be considered if consultation for assistance with treatment is preferred (TABLE 26) or if the patient has:

  • treatment-resistant hypertension
  • stage 2 hypertension that is not quickly responsive to initial treatment
  • an identified secondary cause of ­hypertension.

Continue to: Lifestyle modification can make a big difference

 

 

Lifestyle modification can make a big difference

Exercise. “Regular” physical exercise for children to reduce BP is defined as ≥ 30 to 60 minutes of active play daily.6,29 Studies have shown significant improvement not only in BP but also in other cardiovascular disease risk parameters with regular physical exercise.27 A study found that the reduction in systolic BP is, on average, approximately 6 mm Hg with physical activity alone.30

Nutrition. DASH—Dietary Approaches to Stop Hypertension—is an evidence-based program to reduce BP. This nutritional guideline focuses on a diet rich in natural foods, including fruits, vegetables, minimally processed carbohydrates and whole grains, and low-fat dairy and meats. It also emphasizes the importance of avoiding foods high in processed sugars and reducing sodium intake.31 Higher-than-recommended sodium intake, based on age and sex (and established as part of dietary recommendations for children on the US Department of Health and Human Services’ website health.gov) directly correlates with the risk of prehypertension and hypertension—especially in overweight and obese children.20,32 DASH has been shown to reliably reduce the incidence of hypertension in children; other studies have supported increased intake of fruits, vegetables, and legumes as strategies to reduce BP.33,34

The family history should include notation of first- and second-degree relatives with hypertension. Inquire about medications that can raise BP, including oral contraceptives.

Other interventions. Techniques to improve adherence to exercise and nutritional modifications for children include motivational interviewing, community programs and education, and family counseling.27,35 A recent study showed that a community-based lifestyle modification program that is focused on weight loss in obese children resulted in a significant reduction in BP values at higher stages of obesity.36 There is evidence that techniques such as controlled breathing and meditation can reduce BP.37 Last, screening and counseling to encourage tobacco and substance use discontinuation are recommended for children and adolescents to improve health outcomes.25

 

Proceed with pharmacotherapy when these criteria are met

Medical therapy is recommended when certain criteria are met, although this decision should be individualized and made in agreement by the treating physician, patient, and family. These criteria (FIGURE6,20,25-28) are6,29:

  • once a diagnosis of stage 1 hypertension has been established, failure to meet a BP goal after 3 to 6 months of attempting lifestyle modifications
  • stage 2 hypertension without a modifiable risk factor, such as obesity
  • any stage of hypertension with comorbid CKD, DM, or proteinuria
  • target-organ damage, such as left ventricular hypertrophy
  • symptomatic hypertension.6,29

There are circumstances in which one or another specific antihypertensive agent is recommended for children; however, for most patients with primary hypertension, the following classes are recommended for first-line use6,22:

  • angiotensin-converting enzyme (ACE) inhibitors
  • angiotensin receptor blockers (ARBs)
  • calcium-channel blockers (CCBs)
  • thiazide diuretics.

Continue to: For a child with known CKD...

 

 

For a child with known CKD, DM, or proteinuria, an ACE inhibitor or ARB is beneficial as first-line therapy.38 Because ACE inhibitors and ARBs have teratogenic effects, however, a thorough review of fertility status is recommended for female patients before any of these agents are started. CCBs and thiazides are typically recommended as first-line agents for Black patients.6,28 Beta-blockers are typically avoided in the first line because of their adverse effect profile.

Most antihypertensive medications can be titrated every 1 or 2 weeks; the patient’s BP can be monitored with a home BP cuff to track the effect of titration. In general, the patient should be seen for follow-up every 4 to 6 weeks for a BP recheck and review of medication tolerance and adverse effects. Once the treatment goal is achieved, it is reasonable to have the patient return every 3 to 6 months to reassess the treatment plan.

The initial, fundamental treatment recommendation is lifestyle modification, including regular physical exercise, a change in nutritional habits, and weight loss.

If the BP goal is difficult to achieve despite titration of medication and lifestyle changes, consider repeat ABPM assessment, a specialty referral, or both. It is reasonable for children who have been started on medication and have adhered to lifestyle modifications to practice a “step-down” approach to discontinuing medication; this approach can also be considered once any secondary cause has been corrected. Any target-organ abnormalities identified at diagnosis (eg, proteinuria, CKD, left ventricular hypertrophy) need to be reexamined at follow-up.6

 

Restrict activities—or not?

There is evidence that a child with stage 1 or well-controlled stage 2 hypertension without evidence of end-organ damage should not have restrictions on sports or activity. However, in uncontrolled stage 2 hypertension or when evidence of target end-organ damage is present, you should advise against participation in highly competitive sports and highly static sports (eg, weightlifting, wrestling), based on expert opinion6,25 (FIGURE6,20,25-28).

aAAP guidelines on the management of pediatric hypertension vary from those of the US Preventive Services Task Force. See the Practice Alert, “A review of the latest USPSTF recommendations,” in the May 2021 issue.

CORRESPONDENCE
Dustin K. Smith, MD, Family Medicine Department, 2080 Child Street, Jacksonville, FL, 32214; dustinksmith@yahoo.com

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2. Lurbe E, Agabiti-Rosei E, Cruickshank JK, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens. 2016;34:1887-1920. doi: 10.1097/HJH.0000000000001039

3. Weaver DJ, Mitsnefes MM. Effects of systemic hypertension on the cardiovascular system. Prog Pediatr Cardiol. 2016;41:59-65. https://doi.org/10.1016/j.ppedcard.2015.11.005

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13. Martin RM, Ness AR, Gunnell D, et al; ALSPAC Study Team. Does breast-feeding in infancy lower blood pressure in childhood? The Avon Longitudinal Study of Parents and Children (ALSPAC). Circulation. 2004;109:1259-1266. doi: 10.1161/01.CIR.0000118468.76447.CE

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28. Li JS, Baker-Smith CM, Smith PB, et al. Racial differences in blood pressure response to angiotensin-converting enzyme inhibitors in children: a meta-analysis. Clin Pharmacol Ther. 2008;84:315-319. doi: 10.1038/clpt.2008.113

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Author and Disclosure Information

Jacksonville Family Medicine Residency Program, Naval Hospital Jacksonville, FL (Drs. Smith and Martin); Mayo Clinic Florida, Jacksonville (Dr. McMullan); Uniformed Services University of Health Sciences, Bethesda, MD (Dr. Smith)
dustinksmith@yahoo.com

The authors reported no potential conflict of interest relevant to this article.

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the US Department of the Navy, US Department of Defense, or the government of the United States.

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dustinksmith@yahoo.com

The authors reported no potential conflict of interest relevant to this article.

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the US Department of the Navy, US Department of Defense, or the government of the United States.

Author and Disclosure Information

Jacksonville Family Medicine Residency Program, Naval Hospital Jacksonville, FL (Drs. Smith and Martin); Mayo Clinic Florida, Jacksonville (Dr. McMullan); Uniformed Services University of Health Sciences, Bethesda, MD (Dr. Smith)
dustinksmith@yahoo.com

The authors reported no potential conflict of interest relevant to this article.

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the US Department of the Navy, US Department of Defense, or the government of the United States.

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Hypertension and elevated blood pressure (BP) in children and adolescents correlate to hypertension in adults, insofar as complications and medical therapy increase with age.1,2 Untreated, hypertension in children and adolescents can result in multiple harmful physiologic changes, including left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, arterial stiffening, endothelial dysfunction, and neurocognitive deficits.3-5

In 2017, the American Academy of Pediatrics (AAP) published clinical practice guidelines for the diagnosis and management of elevated BP and hypertension in children and adolescentsa (TABLE 16). Applying the definition of elevated BP set out in these guidelines yielded a 13% prevalence of hypertension in a cohort of subjects 10 to 18 years of age with comorbid obesity and diabetes mellitus (DM). AAP guideline definitions also improved the sensitivity for identifying hypertensive end-organ damage.7

Classification of normal and elevated BP and hypertension in children

The American Academy of Pediatrics recommends measuring BP annually in all children ≥ 3 years of age and at every encounter in patients with specific comorbid conditions and in those taking a medication known to increase BP

As the prevalence of hypertension increases, screening for and accurate diagnosis of this condition in children are becoming more important. Recognition and management remain a vital part of primary care. In this article, we review the updated guidance on diagnosis and treatment, including lifestyle modification and pharmacotherapy.

 

First step: Identifying hypertension

Risk factors

Risk factors for pediatric hypertension are similar to those in adults. These include obesity (body mass index ≥ 95th percentile for age), types 1 and 2 DM, elevated sodium intake, sleep-disordered breathing, and chronic kidney disease (CKD). Some risk factors, such as premature birth and coarctation of the aorta, are specific to the pediatric population.8-14 Pediatric obesity strongly correlates with both pediatric and adult hypertension, and accelerated weight gain might increase the risk of elevated BP in adulthood.15,16

Child with blood pressure cuff

Intervening early to mitigate or eliminate some of these modifiable risk factors can prevent or treat hypertension.17 Alternatively, having been breastfed as an infant has been reliably shown to reduce the risk of elevated BP in children.13

Recommendations for screening and measuring BP

The optimal age to start measuring BP is not clearly defined. AAP recommends measurement:

  • annually in all children ≥ 3 years of age
  • at every encounter in patients who have a specific comorbid condition, including obesity, DM, renal disease, and aortic-arch abnormalities (obstruction and coarctation) and in those who are taking medication known to increase BP.6

Protocol. Measure BP in the right arm for consistency and comparison with reference values. The width of the cuff bladder should be at least 40%, and the length, 80% to 100%, of arm circumference. Position the cuff bladder midway between the olecranon and acromion. Obtain the measurement in a quiet and comfortable environment after the patient has rested for 3 to 5 minutes. The patient should be seated, preferably with feet on the floor; elbows should be supported at the level of the heart.

Continue to: When an initial reading...

 

 

When an initial reading is elevated, whether by oscillometric or auscultatory measurement, 2 more auscultatory BP measurements should be taken during the same visit; these measurements are averaged to determine the BP category.18

TABLE 16 defines BP categories based on age, sex, and height. We recommend using the free resource MD Calc (www.mdcalc.com/aap-pediatric-hypertension-guidelines) to assist in calculating the BP category.

TABLE 26 describes the timing of follow-up based on the initial BP reading and diagnosis.

Ambulatory BP monitoring (ABPM) is a validated device that measures BP every 20 to 30 minutes throughout the day and night. ABPM should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity (TABLE 26). Note: Insurance coverage of ABPM is limited.

Initial measurement of BP determines the timing and elements of follow-up

Children older than 10 years who have been given a diagnosis of hypertension should be asked about smoking, alcohol, and other substance use.

ABPM is also used to diagnose so-called white-coat hypertension, defined as BP ≥ 95th percentile for age, sex, and height in the clinic setting but < 95th percentile during ABPM. This phenomenon can be challenging to diagnose.

Continue to: Home monitoring

 

 

Home monitoring. Do not use home BP monitoring to establish a diagnosis of hypertension, although one of these devices can be used as an adjunct to office and ambulatory BP monitoring after the diagnosis has been made.6

Evaluating hypertension in children and adolescents

Once a diagnosis of hypertension has been made, undertake a thorough history, physical examination, and diagnostic testing to evaluate for possible causes, comorbidities, and any evidence of end-organ damage.

Comprehensive history. Pertinent aspects include perinatal, nutritional, physical activity, psychosocial, family, medication—and of course, medical—histories.6

Maternal elevated BP or hypertension is related to an offspring’s elevated BP in childhood and adolescence.19 Other pertinent aspects of the perinatal history include complications of pregnancy, gestational age, birth weight, and neonatal complications.6

Nutritional and physical activity histories can highlight contributing factors in the development of hypertension and can be a guide to recommending lifestyle modifications.6 Sodium intake, which influences BP, should be part of the nutritional history.20

Continue to: Important aspects...

 

 

Important aspects of the psychosocial history include feelings of depression or anxiety, bullying, and body perception. Children older than 10 years should be asked about smoking, alcohol, and other substance use.

The family history should include notation of first- and second-degree relatives with hypertension.6

Inquire about medications that can raise BP, including oral contraceptives, which are commonly prescribed in this population.21,22

The physical exam should include measured height and weight, with calculation of the body mass index percentile for age; of note, obesity is strongly associated with hypertension, and poor growth might signal underlying chronic disease. Once elevated BP has been confirmed, the exam should include measurement of BP in both arms and in a leg (TABLE 26). BP that is lower in the leg than in the arms (in any given patient, BP readings in the legs are usually higher than in the arms), or weak or absent femoral pulses, suggest coarctation of the aorta.6

Focus the balance of the physical exam on physical findings that suggest secondary causes of hypertension or evidence of end-organ damage.

Continue to: Testing

 

 

Testing. TABLE 36,23 summarizes the diagnostic testing recommended for all children and for specific populations; TABLE 26 indicates when to obtain diagnostic testing. Patients 6 years and older who are overweight or obese and have a family history of hypertension likely have primary hypertension; they do not require an extensive work-up for secondary hypertension unless findings of the comprehensive history and physical examination lead in that direction.6,23

Diagnostic testing in children with hypertension

TABLE 42,12,13,24 outlines the basis of primary and of secondary hypertension and common historical and physical findings that suggest a secondary cause.

What is the etiology of pediatric hypertension?

Mapping out the treatment plan

Pediatric hypertension should be treated in patients with stage 1 or higher hypertension.6 This threshold for therapy is based on evidence that reducing BP below a goal of (1) the 90th percentile (calculated based on age, sex, and height) in children up to 12 years of age or (2) of < 130/80 mm Hg for children ≥ 13 years reduces short- and long-term morbidity and mortality.5,6,25

Ambulatory BP monitoring should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity.

Choice of initial treatment depends on the severity of BP elevation and the presence of comorbidities (FIGURE6,20,25-28). The initial, fundamental treatment recommendation is lifestyle modification,6,29 including regular physical exercise, a change in nutritional habits, weight loss (because obesity is a common comorbid condition), elimination of tobacco and substance use, and stress reduction.25,26 Medications can be used as well, along with other treatments for specific causes of secondary hypertension.

Management of confirmed pediatric hypertension

Referral to a specialist can be considered if consultation for assistance with treatment is preferred (TABLE 26) or if the patient has:

  • treatment-resistant hypertension
  • stage 2 hypertension that is not quickly responsive to initial treatment
  • an identified secondary cause of ­hypertension.

Continue to: Lifestyle modification can make a big difference

 

 

Lifestyle modification can make a big difference

Exercise. “Regular” physical exercise for children to reduce BP is defined as ≥ 30 to 60 minutes of active play daily.6,29 Studies have shown significant improvement not only in BP but also in other cardiovascular disease risk parameters with regular physical exercise.27 A study found that the reduction in systolic BP is, on average, approximately 6 mm Hg with physical activity alone.30

Nutrition. DASH—Dietary Approaches to Stop Hypertension—is an evidence-based program to reduce BP. This nutritional guideline focuses on a diet rich in natural foods, including fruits, vegetables, minimally processed carbohydrates and whole grains, and low-fat dairy and meats. It also emphasizes the importance of avoiding foods high in processed sugars and reducing sodium intake.31 Higher-than-recommended sodium intake, based on age and sex (and established as part of dietary recommendations for children on the US Department of Health and Human Services’ website health.gov) directly correlates with the risk of prehypertension and hypertension—especially in overweight and obese children.20,32 DASH has been shown to reliably reduce the incidence of hypertension in children; other studies have supported increased intake of fruits, vegetables, and legumes as strategies to reduce BP.33,34

The family history should include notation of first- and second-degree relatives with hypertension. Inquire about medications that can raise BP, including oral contraceptives.

Other interventions. Techniques to improve adherence to exercise and nutritional modifications for children include motivational interviewing, community programs and education, and family counseling.27,35 A recent study showed that a community-based lifestyle modification program that is focused on weight loss in obese children resulted in a significant reduction in BP values at higher stages of obesity.36 There is evidence that techniques such as controlled breathing and meditation can reduce BP.37 Last, screening and counseling to encourage tobacco and substance use discontinuation are recommended for children and adolescents to improve health outcomes.25

 

Proceed with pharmacotherapy when these criteria are met

Medical therapy is recommended when certain criteria are met, although this decision should be individualized and made in agreement by the treating physician, patient, and family. These criteria (FIGURE6,20,25-28) are6,29:

  • once a diagnosis of stage 1 hypertension has been established, failure to meet a BP goal after 3 to 6 months of attempting lifestyle modifications
  • stage 2 hypertension without a modifiable risk factor, such as obesity
  • any stage of hypertension with comorbid CKD, DM, or proteinuria
  • target-organ damage, such as left ventricular hypertrophy
  • symptomatic hypertension.6,29

There are circumstances in which one or another specific antihypertensive agent is recommended for children; however, for most patients with primary hypertension, the following classes are recommended for first-line use6,22:

  • angiotensin-converting enzyme (ACE) inhibitors
  • angiotensin receptor blockers (ARBs)
  • calcium-channel blockers (CCBs)
  • thiazide diuretics.

Continue to: For a child with known CKD...

 

 

For a child with known CKD, DM, or proteinuria, an ACE inhibitor or ARB is beneficial as first-line therapy.38 Because ACE inhibitors and ARBs have teratogenic effects, however, a thorough review of fertility status is recommended for female patients before any of these agents are started. CCBs and thiazides are typically recommended as first-line agents for Black patients.6,28 Beta-blockers are typically avoided in the first line because of their adverse effect profile.

Most antihypertensive medications can be titrated every 1 or 2 weeks; the patient’s BP can be monitored with a home BP cuff to track the effect of titration. In general, the patient should be seen for follow-up every 4 to 6 weeks for a BP recheck and review of medication tolerance and adverse effects. Once the treatment goal is achieved, it is reasonable to have the patient return every 3 to 6 months to reassess the treatment plan.

The initial, fundamental treatment recommendation is lifestyle modification, including regular physical exercise, a change in nutritional habits, and weight loss.

If the BP goal is difficult to achieve despite titration of medication and lifestyle changes, consider repeat ABPM assessment, a specialty referral, or both. It is reasonable for children who have been started on medication and have adhered to lifestyle modifications to practice a “step-down” approach to discontinuing medication; this approach can also be considered once any secondary cause has been corrected. Any target-organ abnormalities identified at diagnosis (eg, proteinuria, CKD, left ventricular hypertrophy) need to be reexamined at follow-up.6

 

Restrict activities—or not?

There is evidence that a child with stage 1 or well-controlled stage 2 hypertension without evidence of end-organ damage should not have restrictions on sports or activity. However, in uncontrolled stage 2 hypertension or when evidence of target end-organ damage is present, you should advise against participation in highly competitive sports and highly static sports (eg, weightlifting, wrestling), based on expert opinion6,25 (FIGURE6,20,25-28).

aAAP guidelines on the management of pediatric hypertension vary from those of the US Preventive Services Task Force. See the Practice Alert, “A review of the latest USPSTF recommendations,” in the May 2021 issue.

CORRESPONDENCE
Dustin K. Smith, MD, Family Medicine Department, 2080 Child Street, Jacksonville, FL, 32214; dustinksmith@yahoo.com

Hypertension and elevated blood pressure (BP) in children and adolescents correlate to hypertension in adults, insofar as complications and medical therapy increase with age.1,2 Untreated, hypertension in children and adolescents can result in multiple harmful physiologic changes, including left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, arterial stiffening, endothelial dysfunction, and neurocognitive deficits.3-5

In 2017, the American Academy of Pediatrics (AAP) published clinical practice guidelines for the diagnosis and management of elevated BP and hypertension in children and adolescentsa (TABLE 16). Applying the definition of elevated BP set out in these guidelines yielded a 13% prevalence of hypertension in a cohort of subjects 10 to 18 years of age with comorbid obesity and diabetes mellitus (DM). AAP guideline definitions also improved the sensitivity for identifying hypertensive end-organ damage.7

Classification of normal and elevated BP and hypertension in children

The American Academy of Pediatrics recommends measuring BP annually in all children ≥ 3 years of age and at every encounter in patients with specific comorbid conditions and in those taking a medication known to increase BP

As the prevalence of hypertension increases, screening for and accurate diagnosis of this condition in children are becoming more important. Recognition and management remain a vital part of primary care. In this article, we review the updated guidance on diagnosis and treatment, including lifestyle modification and pharmacotherapy.

 

First step: Identifying hypertension

Risk factors

Risk factors for pediatric hypertension are similar to those in adults. These include obesity (body mass index ≥ 95th percentile for age), types 1 and 2 DM, elevated sodium intake, sleep-disordered breathing, and chronic kidney disease (CKD). Some risk factors, such as premature birth and coarctation of the aorta, are specific to the pediatric population.8-14 Pediatric obesity strongly correlates with both pediatric and adult hypertension, and accelerated weight gain might increase the risk of elevated BP in adulthood.15,16

Child with blood pressure cuff

Intervening early to mitigate or eliminate some of these modifiable risk factors can prevent or treat hypertension.17 Alternatively, having been breastfed as an infant has been reliably shown to reduce the risk of elevated BP in children.13

Recommendations for screening and measuring BP

The optimal age to start measuring BP is not clearly defined. AAP recommends measurement:

  • annually in all children ≥ 3 years of age
  • at every encounter in patients who have a specific comorbid condition, including obesity, DM, renal disease, and aortic-arch abnormalities (obstruction and coarctation) and in those who are taking medication known to increase BP.6

Protocol. Measure BP in the right arm for consistency and comparison with reference values. The width of the cuff bladder should be at least 40%, and the length, 80% to 100%, of arm circumference. Position the cuff bladder midway between the olecranon and acromion. Obtain the measurement in a quiet and comfortable environment after the patient has rested for 3 to 5 minutes. The patient should be seated, preferably with feet on the floor; elbows should be supported at the level of the heart.

Continue to: When an initial reading...

 

 

When an initial reading is elevated, whether by oscillometric or auscultatory measurement, 2 more auscultatory BP measurements should be taken during the same visit; these measurements are averaged to determine the BP category.18

TABLE 16 defines BP categories based on age, sex, and height. We recommend using the free resource MD Calc (www.mdcalc.com/aap-pediatric-hypertension-guidelines) to assist in calculating the BP category.

TABLE 26 describes the timing of follow-up based on the initial BP reading and diagnosis.

Ambulatory BP monitoring (ABPM) is a validated device that measures BP every 20 to 30 minutes throughout the day and night. ABPM should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity (TABLE 26). Note: Insurance coverage of ABPM is limited.

Initial measurement of BP determines the timing and elements of follow-up

Children older than 10 years who have been given a diagnosis of hypertension should be asked about smoking, alcohol, and other substance use.

ABPM is also used to diagnose so-called white-coat hypertension, defined as BP ≥ 95th percentile for age, sex, and height in the clinic setting but < 95th percentile during ABPM. This phenomenon can be challenging to diagnose.

Continue to: Home monitoring

 

 

Home monitoring. Do not use home BP monitoring to establish a diagnosis of hypertension, although one of these devices can be used as an adjunct to office and ambulatory BP monitoring after the diagnosis has been made.6

Evaluating hypertension in children and adolescents

Once a diagnosis of hypertension has been made, undertake a thorough history, physical examination, and diagnostic testing to evaluate for possible causes, comorbidities, and any evidence of end-organ damage.

Comprehensive history. Pertinent aspects include perinatal, nutritional, physical activity, psychosocial, family, medication—and of course, medical—histories.6

Maternal elevated BP or hypertension is related to an offspring’s elevated BP in childhood and adolescence.19 Other pertinent aspects of the perinatal history include complications of pregnancy, gestational age, birth weight, and neonatal complications.6

Nutritional and physical activity histories can highlight contributing factors in the development of hypertension and can be a guide to recommending lifestyle modifications.6 Sodium intake, which influences BP, should be part of the nutritional history.20

Continue to: Important aspects...

 

 

Important aspects of the psychosocial history include feelings of depression or anxiety, bullying, and body perception. Children older than 10 years should be asked about smoking, alcohol, and other substance use.

The family history should include notation of first- and second-degree relatives with hypertension.6

Inquire about medications that can raise BP, including oral contraceptives, which are commonly prescribed in this population.21,22

The physical exam should include measured height and weight, with calculation of the body mass index percentile for age; of note, obesity is strongly associated with hypertension, and poor growth might signal underlying chronic disease. Once elevated BP has been confirmed, the exam should include measurement of BP in both arms and in a leg (TABLE 26). BP that is lower in the leg than in the arms (in any given patient, BP readings in the legs are usually higher than in the arms), or weak or absent femoral pulses, suggest coarctation of the aorta.6

Focus the balance of the physical exam on physical findings that suggest secondary causes of hypertension or evidence of end-organ damage.

Continue to: Testing

 

 

Testing. TABLE 36,23 summarizes the diagnostic testing recommended for all children and for specific populations; TABLE 26 indicates when to obtain diagnostic testing. Patients 6 years and older who are overweight or obese and have a family history of hypertension likely have primary hypertension; they do not require an extensive work-up for secondary hypertension unless findings of the comprehensive history and physical examination lead in that direction.6,23

Diagnostic testing in children with hypertension

TABLE 42,12,13,24 outlines the basis of primary and of secondary hypertension and common historical and physical findings that suggest a secondary cause.

What is the etiology of pediatric hypertension?

Mapping out the treatment plan

Pediatric hypertension should be treated in patients with stage 1 or higher hypertension.6 This threshold for therapy is based on evidence that reducing BP below a goal of (1) the 90th percentile (calculated based on age, sex, and height) in children up to 12 years of age or (2) of < 130/80 mm Hg for children ≥ 13 years reduces short- and long-term morbidity and mortality.5,6,25

Ambulatory BP monitoring should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity.

Choice of initial treatment depends on the severity of BP elevation and the presence of comorbidities (FIGURE6,20,25-28). The initial, fundamental treatment recommendation is lifestyle modification,6,29 including regular physical exercise, a change in nutritional habits, weight loss (because obesity is a common comorbid condition), elimination of tobacco and substance use, and stress reduction.25,26 Medications can be used as well, along with other treatments for specific causes of secondary hypertension.

Management of confirmed pediatric hypertension

Referral to a specialist can be considered if consultation for assistance with treatment is preferred (TABLE 26) or if the patient has:

  • treatment-resistant hypertension
  • stage 2 hypertension that is not quickly responsive to initial treatment
  • an identified secondary cause of ­hypertension.

Continue to: Lifestyle modification can make a big difference

 

 

Lifestyle modification can make a big difference

Exercise. “Regular” physical exercise for children to reduce BP is defined as ≥ 30 to 60 minutes of active play daily.6,29 Studies have shown significant improvement not only in BP but also in other cardiovascular disease risk parameters with regular physical exercise.27 A study found that the reduction in systolic BP is, on average, approximately 6 mm Hg with physical activity alone.30

Nutrition. DASH—Dietary Approaches to Stop Hypertension—is an evidence-based program to reduce BP. This nutritional guideline focuses on a diet rich in natural foods, including fruits, vegetables, minimally processed carbohydrates and whole grains, and low-fat dairy and meats. It also emphasizes the importance of avoiding foods high in processed sugars and reducing sodium intake.31 Higher-than-recommended sodium intake, based on age and sex (and established as part of dietary recommendations for children on the US Department of Health and Human Services’ website health.gov) directly correlates with the risk of prehypertension and hypertension—especially in overweight and obese children.20,32 DASH has been shown to reliably reduce the incidence of hypertension in children; other studies have supported increased intake of fruits, vegetables, and legumes as strategies to reduce BP.33,34

The family history should include notation of first- and second-degree relatives with hypertension. Inquire about medications that can raise BP, including oral contraceptives.

Other interventions. Techniques to improve adherence to exercise and nutritional modifications for children include motivational interviewing, community programs and education, and family counseling.27,35 A recent study showed that a community-based lifestyle modification program that is focused on weight loss in obese children resulted in a significant reduction in BP values at higher stages of obesity.36 There is evidence that techniques such as controlled breathing and meditation can reduce BP.37 Last, screening and counseling to encourage tobacco and substance use discontinuation are recommended for children and adolescents to improve health outcomes.25

 

Proceed with pharmacotherapy when these criteria are met

Medical therapy is recommended when certain criteria are met, although this decision should be individualized and made in agreement by the treating physician, patient, and family. These criteria (FIGURE6,20,25-28) are6,29:

  • once a diagnosis of stage 1 hypertension has been established, failure to meet a BP goal after 3 to 6 months of attempting lifestyle modifications
  • stage 2 hypertension without a modifiable risk factor, such as obesity
  • any stage of hypertension with comorbid CKD, DM, or proteinuria
  • target-organ damage, such as left ventricular hypertrophy
  • symptomatic hypertension.6,29

There are circumstances in which one or another specific antihypertensive agent is recommended for children; however, for most patients with primary hypertension, the following classes are recommended for first-line use6,22:

  • angiotensin-converting enzyme (ACE) inhibitors
  • angiotensin receptor blockers (ARBs)
  • calcium-channel blockers (CCBs)
  • thiazide diuretics.

Continue to: For a child with known CKD...

 

 

For a child with known CKD, DM, or proteinuria, an ACE inhibitor or ARB is beneficial as first-line therapy.38 Because ACE inhibitors and ARBs have teratogenic effects, however, a thorough review of fertility status is recommended for female patients before any of these agents are started. CCBs and thiazides are typically recommended as first-line agents for Black patients.6,28 Beta-blockers are typically avoided in the first line because of their adverse effect profile.

Most antihypertensive medications can be titrated every 1 or 2 weeks; the patient’s BP can be monitored with a home BP cuff to track the effect of titration. In general, the patient should be seen for follow-up every 4 to 6 weeks for a BP recheck and review of medication tolerance and adverse effects. Once the treatment goal is achieved, it is reasonable to have the patient return every 3 to 6 months to reassess the treatment plan.

The initial, fundamental treatment recommendation is lifestyle modification, including regular physical exercise, a change in nutritional habits, and weight loss.

If the BP goal is difficult to achieve despite titration of medication and lifestyle changes, consider repeat ABPM assessment, a specialty referral, or both. It is reasonable for children who have been started on medication and have adhered to lifestyle modifications to practice a “step-down” approach to discontinuing medication; this approach can also be considered once any secondary cause has been corrected. Any target-organ abnormalities identified at diagnosis (eg, proteinuria, CKD, left ventricular hypertrophy) need to be reexamined at follow-up.6

 

Restrict activities—or not?

There is evidence that a child with stage 1 or well-controlled stage 2 hypertension without evidence of end-organ damage should not have restrictions on sports or activity. However, in uncontrolled stage 2 hypertension or when evidence of target end-organ damage is present, you should advise against participation in highly competitive sports and highly static sports (eg, weightlifting, wrestling), based on expert opinion6,25 (FIGURE6,20,25-28).

aAAP guidelines on the management of pediatric hypertension vary from those of the US Preventive Services Task Force. See the Practice Alert, “A review of the latest USPSTF recommendations,” in the May 2021 issue.

CORRESPONDENCE
Dustin K. Smith, MD, Family Medicine Department, 2080 Child Street, Jacksonville, FL, 32214; dustinksmith@yahoo.com

References

1. Theodore RF, Broadbent J, Nagin D, et al. Childhood to early-midlife systolic blood pressure trajectories: early-life predictors, effect modifiers, and adult cardiovascular outcomes. Hypertension. 2015;66:1108-1115. doi: 10.1161/HYPERTENSIONAHA.115.05831

2. Lurbe E, Agabiti-Rosei E, Cruickshank JK, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens. 2016;34:1887-1920. doi: 10.1097/HJH.0000000000001039

3. Weaver DJ, Mitsnefes MM. Effects of systemic hypertension on the cardiovascular system. Prog Pediatr Cardiol. 2016;41:59-65. https://doi.org/10.1016/j.ppedcard.2015.11.005

4. Ippisch HM, Daniels SR. Hypertension in overweight and obese children. Prog Pediatr Cardiol. 2008;25:177-182. doi: org/10.1016/j.ppedcard.2008.05.002

5. Urbina EM, Lande MB, Hooper SR, et al. Target organ abnormalities in pediatric hypertension. J Pediatr. 2018;202:14-22. doi: 10.1016/j.jpeds.2018.07.026

6. Flynn JT, Kaelber DC, Baker-Smith CM, et al; Subcommittee on Screening and Management of High Blood Pressure in Children. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017;140:e20171904. doi: 10.1542/peds.2017-1904

7. Khoury M, Khoury PR, Dolan LM, et al. Clinical implications of the revised AAP pediatric hypertension guidelines. Pediatrics. 2018;142:e20180245. doi: 10.1542/peds.2018-0245

8. Falkner B, Gidding SS, Ramirez-Garnica G, et al. The relationship of body mass index and blood pressure in primary care pediatric patients. J Pediatr. 2006;148:195-200. doi: 10.1016/j.jpeds.2005.10.030

9. Rodriguez BL, Dabelea D, Liese AD, et al; SEARCH Study Group. Prevalence and correlates of elevated blood pressure in youth with diabetes mellitus: the SEARCH for diabetes in youth study. J Pediatr. 2010;157:245-251.e1. doi: 10.1016/j.jpeds.2010.02.021

10. Shay CM, Ning H, Daniels SR, et al. Status of cardiovascular health in US adolescents: prevalence estimates from the National Health and Nutrition Examination Surveys (NHANES) 2005-2010. Circulation. 2013;127:1369-1376. doi: 10.1161/CIRCULATIONAHA.113.001559

11. Archbold KH, Vasquez MM, Goodwin JL, et al. Effects of sleep patterns and obesity on increases in blood pressure in a 5-year period: report from the Tucson Children’s Assessment of Sleep Apnea Study. J Pediatr. 2012;161:26-30. doi: 10.1016/j.jpeds.2011.12.034

12. Flynn JT, Mitsnefes M, Pierce C, et al; Chronic Kidney Disease in Children Study Group. Blood pressure in children with chronic kidney disease: a report from the Chronic Kidney Disease in Children study. Hypertension. 2008;52:631-637. doi: 10.1161/HYPERTENSIONAHA.108.110635

13. Martin RM, Ness AR, Gunnell D, et al; ALSPAC Study Team. Does breast-feeding in infancy lower blood pressure in childhood? The Avon Longitudinal Study of Parents and Children (ALSPAC). Circulation. 2004;109:1259-1266. doi: 10.1161/01.CIR.0000118468.76447.CE

14. Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults. N Engl J Med. 2000;342:256-263. doi: 10.1056/NEJM200001273420407

15. Chen X, Wang Y. Tracking of blood pressure from childhood to adulthood: a systematic review and meta-regression analysis. Circulation. 2008;117:3171-3180. doi: 10.1161/CIRCULATIONAHA.107.730366

16. Sun SS, Grave GD, Siervogel RM, et al. Systolic blood pressure in childhood predicts hypertension and metabolic syndrome later in life. Pediatrics. 2007;119:237-246. doi: 10.1542/peds.2006-2543

17. Parker ED, Sinaiko AR, Kharbanda EO, et al. Change in weight status and development of hypertension. Pediatrics. 2016; 137:e20151662. doi: 10.1542/peds.2015-1662

18. Pickering TG, Hall JE, Appel LJ, et al; Subcommittee of ­Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005;45:142-161. doi: 10.1161/01.HYP.0000150859.47929.8e

19. Staley JR, Bradley J, Silverwood RJ, et al. Associations of blood pressure in pregnancy with offspring blood pressure trajectories during childhood and adolescence: findings from a prospective study. J Am Heart Assoc. 2015;4:e001422. doi: 10.1161/JAHA.114.001422

20. Yang Q, Zhang Z, Zuklina EV, et al. Sodium intake and blood pressure among US children and adolescents. Pediatrics. 2012;130:611-619. doi: 10.1542/peds.2011-3870

21. Le-Ha C, Beilin LJ, Burrows S, et al. Oral contraceptive use in girls and alcohol consumption in boys are associated with increased blood pressure in late adolescence. Eur J Prev Cardiol. 2013;20:947-955. doi: 10.1177/2047487312452966

22. Samuels JA, Franco K, Wan F, Sorof JM. Effect of stimulants on 24-h ambulatory blood pressure in children with ADHD: a double-blind, randomized, cross-over trial. Pediatr Nephrol. 2006;21:92-95. doi: 10.1007/s00467-005-2051-1

23. Wiesen J, Adkins M, Fortune S, et al. Evaluation of pediatric patients with mild-to-moderate hypertension: yield of diagnostic testing. Pediatrics. 2008;122:e988-993. doi: 10.1542/peds.2008-0365

24. Kapur G, Ahmed M, Pan C, et al. Secondary hypertension in overweight and stage 1 hypertensive children: a Midwest Pediatric Nephrology Consortium report. J Clin Hypertens (Greenwich). 2010;12:34-39. doi: 10.1111/j.1751-7176.2009.00195.x

25. Anyaegbu EI, Dharnidharka VR. Hypertension in the teenager. Pediatr Clin North Am. 2014;61:131-151. doi: 10.1016/j.pcl.2013.09.011

26. Gandhi B, Cheek S, Campo JV. Anxiety in the pediatric medical setting. Child Adolesc Psychiatr Clin N Am. 2012;21:643-653. doi: 10.1016/j.chc.2012.05.013

27. Farpour-Lambert NJ, Aggoun Y, Marchand LM, et al. Physical activity reduces systemic blood pressure and improves early markers of atherosclerosis in pre-pubertal obese children. J Am Coll Cardiol. 2009;54:2396-2406. doi: 10.1016/j.jacc.2009.08.030

28. Li JS, Baker-Smith CM, Smith PB, et al. Racial differences in blood pressure response to angiotensin-converting enzyme inhibitors in children: a meta-analysis. Clin Pharmacol Ther. 2008;84:315-319. doi: 10.1038/clpt.2008.113

29. Singer PS. Updates on hypertension and new guidelines. Adv Pediatr. 2019;66:177-187. doi: 10.1016/j.yapd.2019.03.009

30. Torrance B, McGuire KA, Lewanczuk R, et al. Overweight, physical activity and high blood pressure in children: a review of the literature. Vasc Health Risk Manag. 2007;3:139-149.

31. DASH eating plan. National Heart, Lung, and Blood Institute. Accessed April 26, 2021. www.nhlbi.nih.gov/health-topics/dash-eating-plan

32. Nutritional goals for age-sex groups based on dietary reference intakes and dietary guidelines recommendations (Appendix 7). In: US Department of Agriculture. Dietary guidelines for Americans, 2015-2020. 8th ed. December 2015;97-98. Accessed April 26, 2021. https://health.gov/sites/default/files/2019-09/2015-2020_Dietary_Guidelines.pdf

33. Asghari G, Yuzbashian E, Mirmiran P, et al. Dietary Approaches to Stop Hypertension (DASH) dietary pattern is associated with reduced incidence of metabolic syndrome in children and adolescents. J Pediatr. 2016;174:178-184.e1. doi: 10.1016/j.jpeds.2016.03.077

34. Damasceno MMC, de Araújo MFM, de Freitas RWJF, et al. The association between blood pressure in adolescents and the consumption of fruits, vegetables and fruit juice–an exploratory study. J Clin Nurs. 2011;20:1553-1560. doi: 10.1111/j.1365-2702.2010.03608.x

35. Anderson KL. A review of the prevention and medical management of childhood obesity. Child Adolesc Psychiatr Clin N Am. 2018;27:63-76. doi: 10.1016/j.chc.2017.08.003

36. Kumar S, King EC, Christison, et al; POWER Work Group. Health outcomes of youth in clinical pediatric weight management programs in POWER. J Pediatr. 2019;208:57-65.e4. doi: 10.1016/j.jpeds.2018.12.049

37. Gregoski MJ, Barnes VA, Tingen MS, et al. Breathing awareness meditation and LifeSkills® Training programs influence upon ambulatory blood pressure and sodium excretion among African American adolescents. J Adolesc Health. 2011;48:59-64. doi: 10.1016/j.jadohealth.2010.05.019

38. Escape Trial Group; Wühl E, Trivelli A, Picca S, et al. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009;361:1639-1650. doi: 10.1056/NEJMoa0902066

References

1. Theodore RF, Broadbent J, Nagin D, et al. Childhood to early-midlife systolic blood pressure trajectories: early-life predictors, effect modifiers, and adult cardiovascular outcomes. Hypertension. 2015;66:1108-1115. doi: 10.1161/HYPERTENSIONAHA.115.05831

2. Lurbe E, Agabiti-Rosei E, Cruickshank JK, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens. 2016;34:1887-1920. doi: 10.1097/HJH.0000000000001039

3. Weaver DJ, Mitsnefes MM. Effects of systemic hypertension on the cardiovascular system. Prog Pediatr Cardiol. 2016;41:59-65. https://doi.org/10.1016/j.ppedcard.2015.11.005

4. Ippisch HM, Daniels SR. Hypertension in overweight and obese children. Prog Pediatr Cardiol. 2008;25:177-182. doi: org/10.1016/j.ppedcard.2008.05.002

5. Urbina EM, Lande MB, Hooper SR, et al. Target organ abnormalities in pediatric hypertension. J Pediatr. 2018;202:14-22. doi: 10.1016/j.jpeds.2018.07.026

6. Flynn JT, Kaelber DC, Baker-Smith CM, et al; Subcommittee on Screening and Management of High Blood Pressure in Children. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017;140:e20171904. doi: 10.1542/peds.2017-1904

7. Khoury M, Khoury PR, Dolan LM, et al. Clinical implications of the revised AAP pediatric hypertension guidelines. Pediatrics. 2018;142:e20180245. doi: 10.1542/peds.2018-0245

8. Falkner B, Gidding SS, Ramirez-Garnica G, et al. The relationship of body mass index and blood pressure in primary care pediatric patients. J Pediatr. 2006;148:195-200. doi: 10.1016/j.jpeds.2005.10.030

9. Rodriguez BL, Dabelea D, Liese AD, et al; SEARCH Study Group. Prevalence and correlates of elevated blood pressure in youth with diabetes mellitus: the SEARCH for diabetes in youth study. J Pediatr. 2010;157:245-251.e1. doi: 10.1016/j.jpeds.2010.02.021

10. Shay CM, Ning H, Daniels SR, et al. Status of cardiovascular health in US adolescents: prevalence estimates from the National Health and Nutrition Examination Surveys (NHANES) 2005-2010. Circulation. 2013;127:1369-1376. doi: 10.1161/CIRCULATIONAHA.113.001559

11. Archbold KH, Vasquez MM, Goodwin JL, et al. Effects of sleep patterns and obesity on increases in blood pressure in a 5-year period: report from the Tucson Children’s Assessment of Sleep Apnea Study. J Pediatr. 2012;161:26-30. doi: 10.1016/j.jpeds.2011.12.034

12. Flynn JT, Mitsnefes M, Pierce C, et al; Chronic Kidney Disease in Children Study Group. Blood pressure in children with chronic kidney disease: a report from the Chronic Kidney Disease in Children study. Hypertension. 2008;52:631-637. doi: 10.1161/HYPERTENSIONAHA.108.110635

13. Martin RM, Ness AR, Gunnell D, et al; ALSPAC Study Team. Does breast-feeding in infancy lower blood pressure in childhood? The Avon Longitudinal Study of Parents and Children (ALSPAC). Circulation. 2004;109:1259-1266. doi: 10.1161/01.CIR.0000118468.76447.CE

14. Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults. N Engl J Med. 2000;342:256-263. doi: 10.1056/NEJM200001273420407

15. Chen X, Wang Y. Tracking of blood pressure from childhood to adulthood: a systematic review and meta-regression analysis. Circulation. 2008;117:3171-3180. doi: 10.1161/CIRCULATIONAHA.107.730366

16. Sun SS, Grave GD, Siervogel RM, et al. Systolic blood pressure in childhood predicts hypertension and metabolic syndrome later in life. Pediatrics. 2007;119:237-246. doi: 10.1542/peds.2006-2543

17. Parker ED, Sinaiko AR, Kharbanda EO, et al. Change in weight status and development of hypertension. Pediatrics. 2016; 137:e20151662. doi: 10.1542/peds.2015-1662

18. Pickering TG, Hall JE, Appel LJ, et al; Subcommittee of ­Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005;45:142-161. doi: 10.1161/01.HYP.0000150859.47929.8e

19. Staley JR, Bradley J, Silverwood RJ, et al. Associations of blood pressure in pregnancy with offspring blood pressure trajectories during childhood and adolescence: findings from a prospective study. J Am Heart Assoc. 2015;4:e001422. doi: 10.1161/JAHA.114.001422

20. Yang Q, Zhang Z, Zuklina EV, et al. Sodium intake and blood pressure among US children and adolescents. Pediatrics. 2012;130:611-619. doi: 10.1542/peds.2011-3870

21. Le-Ha C, Beilin LJ, Burrows S, et al. Oral contraceptive use in girls and alcohol consumption in boys are associated with increased blood pressure in late adolescence. Eur J Prev Cardiol. 2013;20:947-955. doi: 10.1177/2047487312452966

22. Samuels JA, Franco K, Wan F, Sorof JM. Effect of stimulants on 24-h ambulatory blood pressure in children with ADHD: a double-blind, randomized, cross-over trial. Pediatr Nephrol. 2006;21:92-95. doi: 10.1007/s00467-005-2051-1

23. Wiesen J, Adkins M, Fortune S, et al. Evaluation of pediatric patients with mild-to-moderate hypertension: yield of diagnostic testing. Pediatrics. 2008;122:e988-993. doi: 10.1542/peds.2008-0365

24. Kapur G, Ahmed M, Pan C, et al. Secondary hypertension in overweight and stage 1 hypertensive children: a Midwest Pediatric Nephrology Consortium report. J Clin Hypertens (Greenwich). 2010;12:34-39. doi: 10.1111/j.1751-7176.2009.00195.x

25. Anyaegbu EI, Dharnidharka VR. Hypertension in the teenager. Pediatr Clin North Am. 2014;61:131-151. doi: 10.1016/j.pcl.2013.09.011

26. Gandhi B, Cheek S, Campo JV. Anxiety in the pediatric medical setting. Child Adolesc Psychiatr Clin N Am. 2012;21:643-653. doi: 10.1016/j.chc.2012.05.013

27. Farpour-Lambert NJ, Aggoun Y, Marchand LM, et al. Physical activity reduces systemic blood pressure and improves early markers of atherosclerosis in pre-pubertal obese children. J Am Coll Cardiol. 2009;54:2396-2406. doi: 10.1016/j.jacc.2009.08.030

28. Li JS, Baker-Smith CM, Smith PB, et al. Racial differences in blood pressure response to angiotensin-converting enzyme inhibitors in children: a meta-analysis. Clin Pharmacol Ther. 2008;84:315-319. doi: 10.1038/clpt.2008.113

29. Singer PS. Updates on hypertension and new guidelines. Adv Pediatr. 2019;66:177-187. doi: 10.1016/j.yapd.2019.03.009

30. Torrance B, McGuire KA, Lewanczuk R, et al. Overweight, physical activity and high blood pressure in children: a review of the literature. Vasc Health Risk Manag. 2007;3:139-149.

31. DASH eating plan. National Heart, Lung, and Blood Institute. Accessed April 26, 2021. www.nhlbi.nih.gov/health-topics/dash-eating-plan

32. Nutritional goals for age-sex groups based on dietary reference intakes and dietary guidelines recommendations (Appendix 7). In: US Department of Agriculture. Dietary guidelines for Americans, 2015-2020. 8th ed. December 2015;97-98. Accessed April 26, 2021. https://health.gov/sites/default/files/2019-09/2015-2020_Dietary_Guidelines.pdf

33. Asghari G, Yuzbashian E, Mirmiran P, et al. Dietary Approaches to Stop Hypertension (DASH) dietary pattern is associated with reduced incidence of metabolic syndrome in children and adolescents. J Pediatr. 2016;174:178-184.e1. doi: 10.1016/j.jpeds.2016.03.077

34. Damasceno MMC, de Araújo MFM, de Freitas RWJF, et al. The association between blood pressure in adolescents and the consumption of fruits, vegetables and fruit juice–an exploratory study. J Clin Nurs. 2011;20:1553-1560. doi: 10.1111/j.1365-2702.2010.03608.x

35. Anderson KL. A review of the prevention and medical management of childhood obesity. Child Adolesc Psychiatr Clin N Am. 2018;27:63-76. doi: 10.1016/j.chc.2017.08.003

36. Kumar S, King EC, Christison, et al; POWER Work Group. Health outcomes of youth in clinical pediatric weight management programs in POWER. J Pediatr. 2019;208:57-65.e4. doi: 10.1016/j.jpeds.2018.12.049

37. Gregoski MJ, Barnes VA, Tingen MS, et al. Breathing awareness meditation and LifeSkills® Training programs influence upon ambulatory blood pressure and sodium excretion among African American adolescents. J Adolesc Health. 2011;48:59-64. doi: 10.1016/j.jadohealth.2010.05.019

38. Escape Trial Group; Wühl E, Trivelli A, Picca S, et al. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009;361:1639-1650. doi: 10.1056/NEJMoa0902066

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PRACTICE RECOMMENDATIONS

› Measure the blood pressure (BP) of all children 3 years and older annually; those who have a specific comorbid condition (eg, obesity, diabetes, renal disease, or an aortic-arch abnormality) or who are taking medication known to elevate BP should have their BP checked at every health care visit. C

› Encourage lifestyle modification as the initial treatment for elevated BP or hypertension in children. A

› Utilize pharmacotherapy for (1) children with stage 1 hypertension who have failed to meet BP goals after 3 to 6 months of lifestyle modification and (2) children with stage 2 hypertension who do not have a modifiable risk factor, such as obesity. C

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

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Numerous large nodules on scalp

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Numerous large nodules on scalp

A 31-year-old Hispanic man presented for evaluation of numerous disfiguring growths on his scalp. They first appeared when he was 19 years old. A review of his family history revealed that his father had 2 “cysts” on his body.

The patient had 10 nodules on his scalp and upper back (Figures 1A and 1B). The ones on his scalp lacked puncta and appeared in a “turban tumor” configuration. The lesions were pink, smooth, and semisoft, and ranged in size from 1 to 6 cm.

Large nodules on the front and back of the patient’s scalp

Six years earlier, the patient had been seen for evaluation of 20 protuberant nodules. At the time, he had been referred to plastic surgery, where 15 lesions were excised. No other treatment was reported by the patient during the 6-year gap between exams.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Pilar cysts

Pilar cysts (PC), also known as trichilemma cysts, wen, or isthmus-catagen cysts, are benign cysts that manifest as smooth, firm, well-­circumscribed, pink nodules. PCs originate from the follicular isthmus of the hair’s external root sheath1 and are found in 5% to 10% of the US population.2 Possible sites of appearance include the face, neck, trunk, and extremities, although 90% of PCs develop on the scalp.1 They tend to have an autosomal dominant pattern of inheritance with linkages to the short arm of chromosome 3.3 PCs can occasionally become inflamed following infection or trauma.

Characteristic histology of PCs demonstrates semisolid, keratin-filled, subepidermal cysts lined by stratified epithelium without a granular layer (trichilemmal keratinization). Lesions excised from this patient’s scalp showed 2 subtypes of PCs: nonproliferating (FIGURE 2A) and proliferating (FIGURE 2B). Subtypes appear similar on exam but can be differentiated on histology.

Nonproliferating and proliferating cysts excised from patient’s scalp

With gradual growth, proliferating PCs can reach up to 25 cm in diameter.1 Rapid growth, size > 5 cm, infiltration, or a non-scalp location may indicate malignancy.4

 

Differential diagnosis includes lipomas

The differential diagnosis for a lesion such as this includes epidermal inclusion cysts, dermoid cysts, and lipomas. Epidermal inclusion cysts have a punctum, whereas PCs do not. Dermoid cysts are single congenital lesions that manifest much earlier than PCs. Lipomas are easily movable rubbery bulges that appear more frequently in lipid-dense areas of the body.

For this patient, the striking turban ­tumor–like presentation, with numerous large cysts on the scalp, initially inspired a differential diagnosis including several genetic tumor syndromes. However, unlike the association between Gardner syndrome and numerous epidermoid cysts or Brooke-Spiegler syndrome and spiradenomas, no syndromes have been linked to numerous trichilemmal cysts.

Continue to: Excision is effective

 

 

Excision is effective

Excision is the treatment of choice for both proliferating and nonproliferating PCs.5 The local recurrence rate of proliferating PCs is 3.7% with a rare likelihood of transformation to trichilemmal carcinoma.6

Our patient continues to be followed in clinic for monitoring and periodic excision of bothersome cysts.

References

1. Ramaswamy AS, Manjunatha HK, Sunilkumar B, et al. Morphological spectrum of pilar cysts. N Am J Med Sci. 2013;5:124-128. http://doi.org/10.4103/1947-2714.107532

2. Ibrahim AE, Barikian A, Janom H, et al. Numerous recurrent trichilemmal cysts of the scalp: differential diagnosis and surgical management. J Craniofac Surg. 2012;23:e164-168. http://doi.org/10.1097/SCS.0b013e31824cdbd2

3. Adya KA, Inamadar AC, Palit A. Multiple firm mobile swellings over the scalp. Int J Trichology. 2012;4:98-99. http://doi.org/10.4103/0974-7753.96906

4. Folpe AL, Reisenauer AK, Mentzel T, et al. Proliferating trichilemmal tumors: clinicopathologic evaluation is a guide to biologic behavior. J Cutan Pathol. 2003;30:492-498. http://doi.org/10.1034/j.1600-0560.2003.00041.x

5. Leppard BJ, Sanderson KV. The natural history of trichilemmal cysts. Br J Dermatol. 1976;94:379-390. http://doi.org/10.1111/j.1365-2133.1976.tb06115.x

6. Kim UG, Kook DB, Kim TH, et al. Trichilemmal carcinoma from proliferating trichilemmal cyst on the posterior neck. Arch Craniofac Surg. 2017;18:50-53. http://doi.org/10.7181/acfs.2017.18.1.50

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gladed@uthscsa.edu

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The authors reported no potential conflict of interest relevant to this article.

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Richard P. Usatine, MD

University of Texas Health at San Antonio

The authors reported no potential conflict of interest relevant to this article.

Author and Disclosure Information

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University of Texas Health at San Antonio

The authors reported no potential conflict of interest relevant to this article.

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A 31-year-old Hispanic man presented for evaluation of numerous disfiguring growths on his scalp. They first appeared when he was 19 years old. A review of his family history revealed that his father had 2 “cysts” on his body.

The patient had 10 nodules on his scalp and upper back (Figures 1A and 1B). The ones on his scalp lacked puncta and appeared in a “turban tumor” configuration. The lesions were pink, smooth, and semisoft, and ranged in size from 1 to 6 cm.

Large nodules on the front and back of the patient’s scalp

Six years earlier, the patient had been seen for evaluation of 20 protuberant nodules. At the time, he had been referred to plastic surgery, where 15 lesions were excised. No other treatment was reported by the patient during the 6-year gap between exams.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Pilar cysts

Pilar cysts (PC), also known as trichilemma cysts, wen, or isthmus-catagen cysts, are benign cysts that manifest as smooth, firm, well-­circumscribed, pink nodules. PCs originate from the follicular isthmus of the hair’s external root sheath1 and are found in 5% to 10% of the US population.2 Possible sites of appearance include the face, neck, trunk, and extremities, although 90% of PCs develop on the scalp.1 They tend to have an autosomal dominant pattern of inheritance with linkages to the short arm of chromosome 3.3 PCs can occasionally become inflamed following infection or trauma.

Characteristic histology of PCs demonstrates semisolid, keratin-filled, subepidermal cysts lined by stratified epithelium without a granular layer (trichilemmal keratinization). Lesions excised from this patient’s scalp showed 2 subtypes of PCs: nonproliferating (FIGURE 2A) and proliferating (FIGURE 2B). Subtypes appear similar on exam but can be differentiated on histology.

Nonproliferating and proliferating cysts excised from patient’s scalp

With gradual growth, proliferating PCs can reach up to 25 cm in diameter.1 Rapid growth, size > 5 cm, infiltration, or a non-scalp location may indicate malignancy.4

 

Differential diagnosis includes lipomas

The differential diagnosis for a lesion such as this includes epidermal inclusion cysts, dermoid cysts, and lipomas. Epidermal inclusion cysts have a punctum, whereas PCs do not. Dermoid cysts are single congenital lesions that manifest much earlier than PCs. Lipomas are easily movable rubbery bulges that appear more frequently in lipid-dense areas of the body.

For this patient, the striking turban ­tumor–like presentation, with numerous large cysts on the scalp, initially inspired a differential diagnosis including several genetic tumor syndromes. However, unlike the association between Gardner syndrome and numerous epidermoid cysts or Brooke-Spiegler syndrome and spiradenomas, no syndromes have been linked to numerous trichilemmal cysts.

Continue to: Excision is effective

 

 

Excision is effective

Excision is the treatment of choice for both proliferating and nonproliferating PCs.5 The local recurrence rate of proliferating PCs is 3.7% with a rare likelihood of transformation to trichilemmal carcinoma.6

Our patient continues to be followed in clinic for monitoring and periodic excision of bothersome cysts.

A 31-year-old Hispanic man presented for evaluation of numerous disfiguring growths on his scalp. They first appeared when he was 19 years old. A review of his family history revealed that his father had 2 “cysts” on his body.

The patient had 10 nodules on his scalp and upper back (Figures 1A and 1B). The ones on his scalp lacked puncta and appeared in a “turban tumor” configuration. The lesions were pink, smooth, and semisoft, and ranged in size from 1 to 6 cm.

Large nodules on the front and back of the patient’s scalp

Six years earlier, the patient had been seen for evaluation of 20 protuberant nodules. At the time, he had been referred to plastic surgery, where 15 lesions were excised. No other treatment was reported by the patient during the 6-year gap between exams.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Pilar cysts

Pilar cysts (PC), also known as trichilemma cysts, wen, or isthmus-catagen cysts, are benign cysts that manifest as smooth, firm, well-­circumscribed, pink nodules. PCs originate from the follicular isthmus of the hair’s external root sheath1 and are found in 5% to 10% of the US population.2 Possible sites of appearance include the face, neck, trunk, and extremities, although 90% of PCs develop on the scalp.1 They tend to have an autosomal dominant pattern of inheritance with linkages to the short arm of chromosome 3.3 PCs can occasionally become inflamed following infection or trauma.

Characteristic histology of PCs demonstrates semisolid, keratin-filled, subepidermal cysts lined by stratified epithelium without a granular layer (trichilemmal keratinization). Lesions excised from this patient’s scalp showed 2 subtypes of PCs: nonproliferating (FIGURE 2A) and proliferating (FIGURE 2B). Subtypes appear similar on exam but can be differentiated on histology.

Nonproliferating and proliferating cysts excised from patient’s scalp

With gradual growth, proliferating PCs can reach up to 25 cm in diameter.1 Rapid growth, size > 5 cm, infiltration, or a non-scalp location may indicate malignancy.4

 

Differential diagnosis includes lipomas

The differential diagnosis for a lesion such as this includes epidermal inclusion cysts, dermoid cysts, and lipomas. Epidermal inclusion cysts have a punctum, whereas PCs do not. Dermoid cysts are single congenital lesions that manifest much earlier than PCs. Lipomas are easily movable rubbery bulges that appear more frequently in lipid-dense areas of the body.

For this patient, the striking turban ­tumor–like presentation, with numerous large cysts on the scalp, initially inspired a differential diagnosis including several genetic tumor syndromes. However, unlike the association between Gardner syndrome and numerous epidermoid cysts or Brooke-Spiegler syndrome and spiradenomas, no syndromes have been linked to numerous trichilemmal cysts.

Continue to: Excision is effective

 

 

Excision is effective

Excision is the treatment of choice for both proliferating and nonproliferating PCs.5 The local recurrence rate of proliferating PCs is 3.7% with a rare likelihood of transformation to trichilemmal carcinoma.6

Our patient continues to be followed in clinic for monitoring and periodic excision of bothersome cysts.

References

1. Ramaswamy AS, Manjunatha HK, Sunilkumar B, et al. Morphological spectrum of pilar cysts. N Am J Med Sci. 2013;5:124-128. http://doi.org/10.4103/1947-2714.107532

2. Ibrahim AE, Barikian A, Janom H, et al. Numerous recurrent trichilemmal cysts of the scalp: differential diagnosis and surgical management. J Craniofac Surg. 2012;23:e164-168. http://doi.org/10.1097/SCS.0b013e31824cdbd2

3. Adya KA, Inamadar AC, Palit A. Multiple firm mobile swellings over the scalp. Int J Trichology. 2012;4:98-99. http://doi.org/10.4103/0974-7753.96906

4. Folpe AL, Reisenauer AK, Mentzel T, et al. Proliferating trichilemmal tumors: clinicopathologic evaluation is a guide to biologic behavior. J Cutan Pathol. 2003;30:492-498. http://doi.org/10.1034/j.1600-0560.2003.00041.x

5. Leppard BJ, Sanderson KV. The natural history of trichilemmal cysts. Br J Dermatol. 1976;94:379-390. http://doi.org/10.1111/j.1365-2133.1976.tb06115.x

6. Kim UG, Kook DB, Kim TH, et al. Trichilemmal carcinoma from proliferating trichilemmal cyst on the posterior neck. Arch Craniofac Surg. 2017;18:50-53. http://doi.org/10.7181/acfs.2017.18.1.50

References

1. Ramaswamy AS, Manjunatha HK, Sunilkumar B, et al. Morphological spectrum of pilar cysts. N Am J Med Sci. 2013;5:124-128. http://doi.org/10.4103/1947-2714.107532

2. Ibrahim AE, Barikian A, Janom H, et al. Numerous recurrent trichilemmal cysts of the scalp: differential diagnosis and surgical management. J Craniofac Surg. 2012;23:e164-168. http://doi.org/10.1097/SCS.0b013e31824cdbd2

3. Adya KA, Inamadar AC, Palit A. Multiple firm mobile swellings over the scalp. Int J Trichology. 2012;4:98-99. http://doi.org/10.4103/0974-7753.96906

4. Folpe AL, Reisenauer AK, Mentzel T, et al. Proliferating trichilemmal tumors: clinicopathologic evaluation is a guide to biologic behavior. J Cutan Pathol. 2003;30:492-498. http://doi.org/10.1034/j.1600-0560.2003.00041.x

5. Leppard BJ, Sanderson KV. The natural history of trichilemmal cysts. Br J Dermatol. 1976;94:379-390. http://doi.org/10.1111/j.1365-2133.1976.tb06115.x

6. Kim UG, Kook DB, Kim TH, et al. Trichilemmal carcinoma from proliferating trichilemmal cyst on the posterior neck. Arch Craniofac Surg. 2017;18:50-53. http://doi.org/10.7181/acfs.2017.18.1.50

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The Journal of Family Practice - 70(4)
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The Journal of Family Practice - 70(4)
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201-203
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New-onset hirsutism

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Display Headline
New-onset hirsutism

A 74-year-old woman presented to the dermatology clinic for follow-up 3 months after the surgical excision of a basal cell carcinoma on her left jawline. During this postop period, the patient developed new-onset hirsutism. She appeared to be in otherwise good health.

Family and personal medical history were unremarkable. Her medication regimen included aspirin 81 mg/d and a daily multivitamin. The patient was postmenopausal and had a body mass index of 28 and a history of acid reflux and osteoarthritis.

Physical examination of the patient’s scalp showed male-pattern alopecia (FIGURE 1A). She also had coarse terminal hairs on her forearms and back, as well as on her chin (FIGURE 1B).

Virilization with male-pattern balding and coarse terminal hairs of the chin

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Dx: Androgen-secreting ovarian tumor

Based on the distribution of terminal hairs and marked change over 3 months, as well as the male-pattern alopecia, a diagnosis of androgen excess was suspected. Laboratory work-up, including thyroid-stimulating hormone, dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating hormone, luteinizing hormone, prolactin, complete blood count, and complete metabolic panel, was within normal limits. Pelvic ultrasound of the ovaries and abdominal computed tomography (CT) of the adrenal glands were also normal.

Further testing showed an elevated testosterone level of 464 ng/dL (reference range: 2-45 ng/dL) and an elevated free testosterone level of 66.8 ng/dL (reference range: 0.2-3.7 ng/dL). These levels pointed to an androgen-secreting ovarian tumor; the androgen excess was likely the cause of her hirsutism.

Hirsutism or hypertrichosis?

Hirsutism, a common disorder affecting up to 8% of women, is defined by excess terminal hairs that appear in a male pattern in women due to production of excess androgens.1 This should be distinguished from hypertrichosis, which is generalized excessive hair growth not caused by androgen excess.

Hirsutism is more often associated with adrenal or ovarian tumors in postmenopausal patients.

Testosterone and DHEAS—produced in the ovaries and adrenal glands, respectively—contribute to the development of hirsutism.1 Hirsutism is more often associated with adrenal or ovarian tumors in postmenopausal patients.2 Generalized hypertrichosis can be associated with porphyria cutanea tarda, severe anorexia nervosa, and rarely, malignancies; it also can be secondary to certain agents, such as cyclosporin, phenytoin, and minoxidil.

While hirsutism is associated with hyperandrogenemia, its degree correlates poorly with serum levels. Notably, about half of women with hirsutism have been found to have normal levels of circulating androgens.1 Severe signs of hyperandrogenemia include rapid onset of symptoms, signs of virilization, and a palpable abdominal or pelvic mass.3

Continue to: Is the patient pre- or postmenopausal?

 

 

Is the patient pre- or postmenopausal? Polycystic ovary syndrome (PCOS) accounts for up to three-fourths of premenopausal hirsutism.3 The likelihood of hirsutism is actually decreased in postmenopausal women because estrogen levels can drop abruptly after menopause. That said, conditions linked to hirsutism in postmenopausal women include adrenal hyperplasia, thyroid dysfunction, Cushing syndrome, and least frequently, androgen-secreting tumors (seen in this patient). (Hirsutism can also be idiopathic or iatrogenic [medications].)

Methods for detection

Research suggests that when a female patient is given a diagnosis of hirsutism, it’s important to explore possible underlying ovarian and/or adrenal tumors and adult-onset adrenal hyperplasia.1 The following tests and procedure can be helpful:

Serum testosterone and DHEAS. Levels of total testosterone > 200 ng/dL and/or DHEAS > 700 ng/dL are strongly indicative of androgen-secreting tumors.1

Imaging—including ultrasound, CT, or magnetic resonance imaging—can be used for evaluation of the adrenal glands and ovaries. However, imaging is often unable to identify these small tumors.4

Selective venous catheterization can be useful in the localization and lateralization of an androgen-secreting tumor, although a nondiagnostic result with this technique is not uncommon.4

Continue to: Dynamic hormonal testing

 

 

Dynamic hormonal testing may assist in determining the pathology of disease but not laterality.2 For example, testing for gonadotropin-releasing hormone agonists can be helpful because the constant administration of such agonists can lead to ovarian suppression without affecting adrenal androgen secretion.5

Testing with oral dexamethasone may induce adrenal hormonal depression of androgens and subsequent estradiol through aromatase conversion, which can help rule out an ovarian source.6 Exogenous administration of follicle-stimulating hormone or luteinizing hormone can further differentiate the source from ovarian theca or granulosa cell production.4

Treatment varies

The specific etiology of a patient’s hirsutism dictates the most appropriate treatment. For example, medication-induced hirsutism often requires discontinuation of the offending agent, whereas PCOS would necessitate appropriate nonpharmacologic and pharmacologic interventions.

For our patient, the elevated testosterone and free testosterone levels with normal DHEAS strongly suggested the presence of an androgen-secreting ovarian tumor. These findings led to a referral for bilateral salpingo-oophorectomy. The surgical gross appearance of the patient’s ovaries was unremarkable, but gross dissection and pathology of the ovaries (which were not postoperatively identified to determine laterality) showed one was larger (2.7 × 1.5 × 0.8 cm vs 3.2 × 1.4 × 1.2 cm).

The larger ovary contained an area of brown induration measuring 2.3 × 1.1 × 1.1 cm. This area corresponded to abundant eosinophilic cytoplasm with nuclear, rich, round-cell proliferation, consistent with the diagnosis of a benign ovarian Leydig cell tumor (FIGURE 2). Thus, the bilateral salpingo-oophorectomy was both diagnostic and therapeutic.

Pathology of the patient’s ovarian Leydig cell tumor

Six weeks after the surgery, blood work showed normalization of testosterone and free testosterone levels. The patient’s hirsutism completely resolved over the course of the next several months.

References

1. Hunter M, Carek PJ. Evaluation and treatment of women with hirsutism. Am Fam Physician. 2003;67:2565-2572.

2. Alpañés M, González-Casbas JM, Sánchez J, et al. Management of postmenopausal virilization. J Clin Endocrinol Metab. 2012;97:2584-2588.

3. Bode D, Seehusen DA, Baird D. Hirsutism in women. Am Fam Physician. 2012;85:373-380.

4. Cohen I, Nabriski D, Fishman A. Noninvasive test for the diagnosis of ovarian hormone-secreting-neopolasm in postmenopausal women. Gynecol Oncol Rep. 2016;15:12-15.

5. Gandrapu B, Sundar P, Phillips B. Hyperandrogenism in a postmenaupsal woman secondary to testosterone secreting ovarian stromal tumor with acoustic schwannoma. Case Rep Endocrinol. 2018;2018:8154513.

6. Curran DR, Moore C, Huber T. What is the best approach to the evaluation of hirsutism? J Fam Pract. 2005;54:458-473.

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Maine-Dartmouth Family Medicine Residency, Augusta
joshua.sparling@mainegeneral.org

DEPARTMENT EDITOR
Richard P. Usatine, MD

University of Texas Health at San Antonio

The authors reported no potential conflict of interest relevant to this article.

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joshua.sparling@mainegeneral.org

DEPARTMENT EDITOR
Richard P. Usatine, MD

University of Texas Health at San Antonio

The authors reported no potential conflict of interest relevant to this article.

Author and Disclosure Information

Maine-Dartmouth Family Medicine Residency, Augusta
joshua.sparling@mainegeneral.org

DEPARTMENT EDITOR
Richard P. Usatine, MD

University of Texas Health at San Antonio

The authors reported no potential conflict of interest relevant to this article.

Article PDF
Article PDF

A 74-year-old woman presented to the dermatology clinic for follow-up 3 months after the surgical excision of a basal cell carcinoma on her left jawline. During this postop period, the patient developed new-onset hirsutism. She appeared to be in otherwise good health.

Family and personal medical history were unremarkable. Her medication regimen included aspirin 81 mg/d and a daily multivitamin. The patient was postmenopausal and had a body mass index of 28 and a history of acid reflux and osteoarthritis.

Physical examination of the patient’s scalp showed male-pattern alopecia (FIGURE 1A). She also had coarse terminal hairs on her forearms and back, as well as on her chin (FIGURE 1B).

Virilization with male-pattern balding and coarse terminal hairs of the chin

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Dx: Androgen-secreting ovarian tumor

Based on the distribution of terminal hairs and marked change over 3 months, as well as the male-pattern alopecia, a diagnosis of androgen excess was suspected. Laboratory work-up, including thyroid-stimulating hormone, dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating hormone, luteinizing hormone, prolactin, complete blood count, and complete metabolic panel, was within normal limits. Pelvic ultrasound of the ovaries and abdominal computed tomography (CT) of the adrenal glands were also normal.

Further testing showed an elevated testosterone level of 464 ng/dL (reference range: 2-45 ng/dL) and an elevated free testosterone level of 66.8 ng/dL (reference range: 0.2-3.7 ng/dL). These levels pointed to an androgen-secreting ovarian tumor; the androgen excess was likely the cause of her hirsutism.

Hirsutism or hypertrichosis?

Hirsutism, a common disorder affecting up to 8% of women, is defined by excess terminal hairs that appear in a male pattern in women due to production of excess androgens.1 This should be distinguished from hypertrichosis, which is generalized excessive hair growth not caused by androgen excess.

Hirsutism is more often associated with adrenal or ovarian tumors in postmenopausal patients.

Testosterone and DHEAS—produced in the ovaries and adrenal glands, respectively—contribute to the development of hirsutism.1 Hirsutism is more often associated with adrenal or ovarian tumors in postmenopausal patients.2 Generalized hypertrichosis can be associated with porphyria cutanea tarda, severe anorexia nervosa, and rarely, malignancies; it also can be secondary to certain agents, such as cyclosporin, phenytoin, and minoxidil.

While hirsutism is associated with hyperandrogenemia, its degree correlates poorly with serum levels. Notably, about half of women with hirsutism have been found to have normal levels of circulating androgens.1 Severe signs of hyperandrogenemia include rapid onset of symptoms, signs of virilization, and a palpable abdominal or pelvic mass.3

Continue to: Is the patient pre- or postmenopausal?

 

 

Is the patient pre- or postmenopausal? Polycystic ovary syndrome (PCOS) accounts for up to three-fourths of premenopausal hirsutism.3 The likelihood of hirsutism is actually decreased in postmenopausal women because estrogen levels can drop abruptly after menopause. That said, conditions linked to hirsutism in postmenopausal women include adrenal hyperplasia, thyroid dysfunction, Cushing syndrome, and least frequently, androgen-secreting tumors (seen in this patient). (Hirsutism can also be idiopathic or iatrogenic [medications].)

Methods for detection

Research suggests that when a female patient is given a diagnosis of hirsutism, it’s important to explore possible underlying ovarian and/or adrenal tumors and adult-onset adrenal hyperplasia.1 The following tests and procedure can be helpful:

Serum testosterone and DHEAS. Levels of total testosterone > 200 ng/dL and/or DHEAS > 700 ng/dL are strongly indicative of androgen-secreting tumors.1

Imaging—including ultrasound, CT, or magnetic resonance imaging—can be used for evaluation of the adrenal glands and ovaries. However, imaging is often unable to identify these small tumors.4

Selective venous catheterization can be useful in the localization and lateralization of an androgen-secreting tumor, although a nondiagnostic result with this technique is not uncommon.4

Continue to: Dynamic hormonal testing

 

 

Dynamic hormonal testing may assist in determining the pathology of disease but not laterality.2 For example, testing for gonadotropin-releasing hormone agonists can be helpful because the constant administration of such agonists can lead to ovarian suppression without affecting adrenal androgen secretion.5

Testing with oral dexamethasone may induce adrenal hormonal depression of androgens and subsequent estradiol through aromatase conversion, which can help rule out an ovarian source.6 Exogenous administration of follicle-stimulating hormone or luteinizing hormone can further differentiate the source from ovarian theca or granulosa cell production.4

Treatment varies

The specific etiology of a patient’s hirsutism dictates the most appropriate treatment. For example, medication-induced hirsutism often requires discontinuation of the offending agent, whereas PCOS would necessitate appropriate nonpharmacologic and pharmacologic interventions.

For our patient, the elevated testosterone and free testosterone levels with normal DHEAS strongly suggested the presence of an androgen-secreting ovarian tumor. These findings led to a referral for bilateral salpingo-oophorectomy. The surgical gross appearance of the patient’s ovaries was unremarkable, but gross dissection and pathology of the ovaries (which were not postoperatively identified to determine laterality) showed one was larger (2.7 × 1.5 × 0.8 cm vs 3.2 × 1.4 × 1.2 cm).

The larger ovary contained an area of brown induration measuring 2.3 × 1.1 × 1.1 cm. This area corresponded to abundant eosinophilic cytoplasm with nuclear, rich, round-cell proliferation, consistent with the diagnosis of a benign ovarian Leydig cell tumor (FIGURE 2). Thus, the bilateral salpingo-oophorectomy was both diagnostic and therapeutic.

Pathology of the patient’s ovarian Leydig cell tumor

Six weeks after the surgery, blood work showed normalization of testosterone and free testosterone levels. The patient’s hirsutism completely resolved over the course of the next several months.

A 74-year-old woman presented to the dermatology clinic for follow-up 3 months after the surgical excision of a basal cell carcinoma on her left jawline. During this postop period, the patient developed new-onset hirsutism. She appeared to be in otherwise good health.

Family and personal medical history were unremarkable. Her medication regimen included aspirin 81 mg/d and a daily multivitamin. The patient was postmenopausal and had a body mass index of 28 and a history of acid reflux and osteoarthritis.

Physical examination of the patient’s scalp showed male-pattern alopecia (FIGURE 1A). She also had coarse terminal hairs on her forearms and back, as well as on her chin (FIGURE 1B).

Virilization with male-pattern balding and coarse terminal hairs of the chin

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Dx: Androgen-secreting ovarian tumor

Based on the distribution of terminal hairs and marked change over 3 months, as well as the male-pattern alopecia, a diagnosis of androgen excess was suspected. Laboratory work-up, including thyroid-stimulating hormone, dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating hormone, luteinizing hormone, prolactin, complete blood count, and complete metabolic panel, was within normal limits. Pelvic ultrasound of the ovaries and abdominal computed tomography (CT) of the adrenal glands were also normal.

Further testing showed an elevated testosterone level of 464 ng/dL (reference range: 2-45 ng/dL) and an elevated free testosterone level of 66.8 ng/dL (reference range: 0.2-3.7 ng/dL). These levels pointed to an androgen-secreting ovarian tumor; the androgen excess was likely the cause of her hirsutism.

Hirsutism or hypertrichosis?

Hirsutism, a common disorder affecting up to 8% of women, is defined by excess terminal hairs that appear in a male pattern in women due to production of excess androgens.1 This should be distinguished from hypertrichosis, which is generalized excessive hair growth not caused by androgen excess.

Hirsutism is more often associated with adrenal or ovarian tumors in postmenopausal patients.

Testosterone and DHEAS—produced in the ovaries and adrenal glands, respectively—contribute to the development of hirsutism.1 Hirsutism is more often associated with adrenal or ovarian tumors in postmenopausal patients.2 Generalized hypertrichosis can be associated with porphyria cutanea tarda, severe anorexia nervosa, and rarely, malignancies; it also can be secondary to certain agents, such as cyclosporin, phenytoin, and minoxidil.

While hirsutism is associated with hyperandrogenemia, its degree correlates poorly with serum levels. Notably, about half of women with hirsutism have been found to have normal levels of circulating androgens.1 Severe signs of hyperandrogenemia include rapid onset of symptoms, signs of virilization, and a palpable abdominal or pelvic mass.3

Continue to: Is the patient pre- or postmenopausal?

 

 

Is the patient pre- or postmenopausal? Polycystic ovary syndrome (PCOS) accounts for up to three-fourths of premenopausal hirsutism.3 The likelihood of hirsutism is actually decreased in postmenopausal women because estrogen levels can drop abruptly after menopause. That said, conditions linked to hirsutism in postmenopausal women include adrenal hyperplasia, thyroid dysfunction, Cushing syndrome, and least frequently, androgen-secreting tumors (seen in this patient). (Hirsutism can also be idiopathic or iatrogenic [medications].)

Methods for detection

Research suggests that when a female patient is given a diagnosis of hirsutism, it’s important to explore possible underlying ovarian and/or adrenal tumors and adult-onset adrenal hyperplasia.1 The following tests and procedure can be helpful:

Serum testosterone and DHEAS. Levels of total testosterone > 200 ng/dL and/or DHEAS > 700 ng/dL are strongly indicative of androgen-secreting tumors.1

Imaging—including ultrasound, CT, or magnetic resonance imaging—can be used for evaluation of the adrenal glands and ovaries. However, imaging is often unable to identify these small tumors.4

Selective venous catheterization can be useful in the localization and lateralization of an androgen-secreting tumor, although a nondiagnostic result with this technique is not uncommon.4

Continue to: Dynamic hormonal testing

 

 

Dynamic hormonal testing may assist in determining the pathology of disease but not laterality.2 For example, testing for gonadotropin-releasing hormone agonists can be helpful because the constant administration of such agonists can lead to ovarian suppression without affecting adrenal androgen secretion.5

Testing with oral dexamethasone may induce adrenal hormonal depression of androgens and subsequent estradiol through aromatase conversion, which can help rule out an ovarian source.6 Exogenous administration of follicle-stimulating hormone or luteinizing hormone can further differentiate the source from ovarian theca or granulosa cell production.4

Treatment varies

The specific etiology of a patient’s hirsutism dictates the most appropriate treatment. For example, medication-induced hirsutism often requires discontinuation of the offending agent, whereas PCOS would necessitate appropriate nonpharmacologic and pharmacologic interventions.

For our patient, the elevated testosterone and free testosterone levels with normal DHEAS strongly suggested the presence of an androgen-secreting ovarian tumor. These findings led to a referral for bilateral salpingo-oophorectomy. The surgical gross appearance of the patient’s ovaries was unremarkable, but gross dissection and pathology of the ovaries (which were not postoperatively identified to determine laterality) showed one was larger (2.7 × 1.5 × 0.8 cm vs 3.2 × 1.4 × 1.2 cm).

The larger ovary contained an area of brown induration measuring 2.3 × 1.1 × 1.1 cm. This area corresponded to abundant eosinophilic cytoplasm with nuclear, rich, round-cell proliferation, consistent with the diagnosis of a benign ovarian Leydig cell tumor (FIGURE 2). Thus, the bilateral salpingo-oophorectomy was both diagnostic and therapeutic.

Pathology of the patient’s ovarian Leydig cell tumor

Six weeks after the surgery, blood work showed normalization of testosterone and free testosterone levels. The patient’s hirsutism completely resolved over the course of the next several months.

References

1. Hunter M, Carek PJ. Evaluation and treatment of women with hirsutism. Am Fam Physician. 2003;67:2565-2572.

2. Alpañés M, González-Casbas JM, Sánchez J, et al. Management of postmenopausal virilization. J Clin Endocrinol Metab. 2012;97:2584-2588.

3. Bode D, Seehusen DA, Baird D. Hirsutism in women. Am Fam Physician. 2012;85:373-380.

4. Cohen I, Nabriski D, Fishman A. Noninvasive test for the diagnosis of ovarian hormone-secreting-neopolasm in postmenopausal women. Gynecol Oncol Rep. 2016;15:12-15.

5. Gandrapu B, Sundar P, Phillips B. Hyperandrogenism in a postmenaupsal woman secondary to testosterone secreting ovarian stromal tumor with acoustic schwannoma. Case Rep Endocrinol. 2018;2018:8154513.

6. Curran DR, Moore C, Huber T. What is the best approach to the evaluation of hirsutism? J Fam Pract. 2005;54:458-473.

References

1. Hunter M, Carek PJ. Evaluation and treatment of women with hirsutism. Am Fam Physician. 2003;67:2565-2572.

2. Alpañés M, González-Casbas JM, Sánchez J, et al. Management of postmenopausal virilization. J Clin Endocrinol Metab. 2012;97:2584-2588.

3. Bode D, Seehusen DA, Baird D. Hirsutism in women. Am Fam Physician. 2012;85:373-380.

4. Cohen I, Nabriski D, Fishman A. Noninvasive test for the diagnosis of ovarian hormone-secreting-neopolasm in postmenopausal women. Gynecol Oncol Rep. 2016;15:12-15.

5. Gandrapu B, Sundar P, Phillips B. Hyperandrogenism in a postmenaupsal woman secondary to testosterone secreting ovarian stromal tumor with acoustic schwannoma. Case Rep Endocrinol. 2018;2018:8154513.

6. Curran DR, Moore C, Huber T. What is the best approach to the evaluation of hirsutism? J Fam Pract. 2005;54:458-473.

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Theory of Planned Behavior Provides A Theoretical Explanation For Enhanced Behavior Change With Genetic-Based Lifestyle Interventions

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Theory of Planned Behavior Provides A Theoretical Explanation For Enhanced Behavior Change With Genetic-Based Lifestyle Interventions

Study Overview

Objective. To determine the impact of providing genetically tailored and population-based lifestyle advice for weight management on key constructs of the Theory of Planned Behavior (TPB), a widely accepted theory used to help predict human lifestyle-related behaviors.

Design. Pragmatic, cluster, randomized controlled trial.

Settings and participants. This study took place at the East Elgin Family Health Team, a primary care clinic in Aylmer, Ontario, Canada. Recruitment occurred between April 2017 and September 2018, with staggered intervention cohorts occurring from May 2017 to September 2019. Participants enrolled in a weight management program at the clinic were invited to participate in the study if they met the following inclusion criteria: body mass index (BMI) ≥25 kg/m2, >18 years of age, English-speaking, willing to undergo genetic testing, having access to a computer with internet at least 1 day per week, and not seeing another health care provider for weight loss advice outside of the study. Exclusion criteria included pregnancy and lactation. All participants provided written informed consent.

Interventions. At baseline, weight management program cohorts (average cohort size was 14 participants) were randomized (1:1) to receive either the standard population-based intervention (Group Lifestyle Balance, or GLB) or a modified GLB intervention, which included the provision of lifestyle genomics (LGx) information and advice (GLB+LGx). Both interventions aimed to assist participants with weight management and healthy lifestyle change, with particular focus on nutrition and physical activity (PA). Interventions were 12 months long, consisting of 23 group-based sessions and 3 one-on-one sessions with a registered dietitian after 3, 6, and 12 months (all sessions were face-to-face). To improve intervention adherence, participants were given reminder calls for their one-on-one appointments and for the start of their program. A sample size was calculated based on the primary outcome indicating that a total of 74 participants were needed (n = 37 per group) for this trial. By September 2019, this sample size was exceeded with 10 randomized groups (n = 140).

The 5 randomized standard GLB groups followed the established GLB program curriculum comprising population-based information and advice while focusing on following a calorie-controlled, moderate-fat (25% of calories) nutrition plan with at least 150 minutes of weekly moderate-intensity PA. Participants were also provided with a 1-page summary report of their nutrition and PA guidelines at the first group meeting outlining population-based targets, including acceptable macronutrient distribution ranges for protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, sodium, calories, snacking, and PA.

The 5 randomized modified GLB+LGx groups followed a modified GLB program curriculum in which participants were given genetic-based information and advice, which differed from the advice given to the standard GLB group, while focusing on following a calorie-controlled nutrition plan. The nutrition and PA targets were personalized based on their individual genetic variation. For example, participants with the AA variant of FTO (rs9939609) were advised to engage in at least 30 to 60 minutes of PA daily 6 days per week, with muscle-strengthening activities at least 2 days per week, rather than receiving the standard population-based advice to aim for 150 minutes weekly of PA with at least 2 days per week of muscle-strengthening activity. Participants were also provided with a 1-page summary report of their nutrition and PA guidelines at the first group meeting, which outlined genetic-based information and advice related to protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, sodium, calories, snacking, and PA.

Measures and analysis. Change in the TPB components (attitudes, subjective norms and perceived behavioral control) were measured via a TPB questionnaire at 5 time points: baseline (2-week run-in period), immediately after the first group session (where participants received a summary report of either population-based or genetic-based recommendations depending on group assignment), and after 3-, 6- and 12-month follow-ups. Attitudes, subjective norms, and perceived behavioral control were measured on a Likert scale from 1 through 7. Self-reported measures of actual behavioral control (including annual household income, perceptions about events arising in one’s day-to-day life that suddenly take up one’s free time, perceptions about the frequency of feeling ill or tired, and highest achieved level of education) were collected via survey questions and assessed on a Likert scale of 1 through 7. Stage of change was also measured, based on the Transtheoretical Model, using a Likert scale of 1 through 6.

Linear mixed models were used to conduct within- and between-group analyses using SPSS version 26.0, while controlling for measures of actual behavioral control. All analyses were intention-to-treat by originally assigned groups, with mean value imputation conducted for missing data. A Bonferroni correction for multiple testing was used. For all statistical analyses, the level of significance was set at P < 0.05 and trending towards significance at P = 0.05–0.06.

Main results. Participants consisted of primarily middle-age, middle-income, Caucasian females. Baseline attitudes towards the effectiveness of nutrition and PA for weight management were generally positive, and participants perceived that undergoing genetic testing would assist with weight management. Participants had overall neutral subjective norms related to friends and family consuming a healthy diet and engaging in PA, but perceived that their friends, family, and health care team (HCT) believed it was important for them to achieve their nutrition and PA recommendations. Participants overall also perceived that their HCT believed genetic testing could assist with weight management. Baseline measures of perceived behavioral control were overall neutral, with baseline stage of change between “motivation” and “action” (short-term; <3 months).

In within-group analyses, significant improvements (P < 0.05) in attitudes towards the effectiveness of nutrition and PA recommendations for weight management, subjective norms related to both friends and family consuming a healthy diet, and perceived behavioral control in changing PA/dietary intake and managing weight tended to be short-term in the GLB group and long-term for the GLB+LGx group. In all cases of between-group differences for changes in TPB components, the GLB group exhibited reductions in scores, whereas the GLB+LGx group exhibited increases or improvements. Between-group differences (short-term and long-term) in several measures of subjective norms were observed. For example, after 3 months, significant between-group differences were observed in changes in perception that friends believed LGx would help with weight management (P = 0.024). After 12 months, between-group differences trending towards significance were also observed in changes in perception that family members believed genetic testing would help with weight management (P = 0.05). Significant between-group differences and differences trending towards significance were also observed at 12 months for changes in perception that family believed it was important for the participant to achieve the PA recommendations (P = 0.049) and nutrition recommendations (P = 0.05). Between-group differences trending towards significance were also observed at 3 months in attitudes towards the effectiveness of LGx for weight management (P = 0.06). There were no significant between-group differences observed in changes in perceived behavioral control.

Conclusion. Results from this study support the hypothesis that the TPB can help provide a theoretical explanation for why genetically tailored lifestyle information and advice can lead to improvements in lifestyle behavior change.

 

 

Commentary

Because health behaviors are critical in areas such as prevention, treatment, and rehabilitation, it is important to describe and understand what drives these behaviors.1 Theories are important tools in this effort as they aim to explain and predict health behavior and are used in the design and evaluation of interventions.1 The TPB is one of the most widely accepted behavior change theories and posits that attitudes, subjective norms (or social pressures and behaviors), and perceived behavioral control are significant predictors of an individual’s intention to engage in behaviors.2 TPB has been highlighted in the literature as a validated theory for predicting nutrition and PA intentions and resulting behaviors.3,4

Motivating lifestyle behavior change in clinical practice can be challenging, but some studies have demonstrated how providing genetic information and advice (or lifestyle genomics) can help motivate changes in nutrition and PA among patients.5-7 Because this has yet to be explained using the TPB, this study is an important contribution to the literature as it aimed to determine the impact of providing genetically tailored and population-based lifestyle advice for weight management on key constructs of the TPB. Briefly, results from within-group analyses in this study demonstrated that the provision of genetically tailored lifestyle information and advice (via the GLB+LGx intervention) tended to impact antecedents of behavior change, more so over the long-term, while population-based advice (via the standard GLB intervention) tended to impact antecedents of behavior change over the short-term (eg, attitudes towards dietary fat intake, perceptions that friends and family consume a healthy diet, and perceptions about the impact of genetic-based advice for weight management). In addition, between-group differences in subjective norms observed at 12 months suggested that social pressures and norms may be influencing long-term changes in lifestyle habits.

While key strengths of this study include its pragmatic cluster randomized controlled trial design, 12-month intervention duration, and intent-to-treat analyses, there are some study limitations, which are acknowledged by the authors. Generalizability is limited to the demographic characteristics of the study population (ie, middle-aged, middle-income, Caucasian females enrolled in a lifestyle change weight management program). Thus, replication of the study is needed in more diverse study populations and with health-related outcomes beyond weight management. In addition, as the authors indicate, future research should ensure the inclusion of theory-based questionnaires in genetic-based intervention studies assessing lifestyle behavior change to elucidate theory-based mechanisms of change.

Applications for Clinical Practice

Population-based research has consistently indicated that nutrition interventions typically impact short-term dietary changes. Confronting the challenge of long-term adherence to nutrition and PA recommendations requires an understanding of factors impacting long-term motivation and behavior change. With increased attention on and research into genetically tailored lifestyle advice (or lifestyle genomics), it is important for clinical practitioners to be familiar with the evidence supporting these approaches. In addition, this research highlights the need to consider individual factors (attitudes, subjective norms, and perceived behavioral control) that may predict successful change in lifestyle habits when providing nutrition and PA recommendations, whether population-based or genetically tailored.

—Katrina F. Mateo, PhD, MPH

References

1. Lippke S, Ziegelmann JP. Theory-based health behavior change: Developing, testing, and applying theories for evidence-based interventions. Appl Psychol. 2008;57:698-716.

2. Ajzen I. The Theory of planned behaviour: reactions and reflections. Psychol Health. 2011;26:1113-1127.

3. McDermott MS, Oliver M, Simnadis T, et al. The Theory of Planned Behaviour and dietary patterns: A systematic review and meta-analysis. Prev Med (Baltim). 2015;81:150-156.

4. McEachan RRC, Conner M, Taylor NJ, Lawton RJ. Prospective prediction of health-related behaviours with the theory of planned behaviour: A meta-analysis. Health Psychol Rev. 2011;5:97-144.

5. Hietaranta-Luoma H-L, Tahvonen R, Iso-Touru T, et al A. An intervention study of individual, APOE genotype-based dietary and physical-activity advice: impact on health behavior. J Nutrigenet Nutrigenomics. 2014;7:161-174.

6. Nielsen DE, El-Sohemy A. Disclosure of genetic information and change in dietary intake: a randomized controlled trial. DeAngelis MM, ed. PLoS One. 2014;9(11):e112665.

7. Egglestone C, Morris A, O’Brien A. Effect of direct‐to‐consumer genetic tests on health behaviour and anxiety: a survey of consumers and potential consumers. J Genet Couns. 2013;22:565-575.

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Study Overview

Objective. To determine the impact of providing genetically tailored and population-based lifestyle advice for weight management on key constructs of the Theory of Planned Behavior (TPB), a widely accepted theory used to help predict human lifestyle-related behaviors.

Design. Pragmatic, cluster, randomized controlled trial.

Settings and participants. This study took place at the East Elgin Family Health Team, a primary care clinic in Aylmer, Ontario, Canada. Recruitment occurred between April 2017 and September 2018, with staggered intervention cohorts occurring from May 2017 to September 2019. Participants enrolled in a weight management program at the clinic were invited to participate in the study if they met the following inclusion criteria: body mass index (BMI) ≥25 kg/m2, >18 years of age, English-speaking, willing to undergo genetic testing, having access to a computer with internet at least 1 day per week, and not seeing another health care provider for weight loss advice outside of the study. Exclusion criteria included pregnancy and lactation. All participants provided written informed consent.

Interventions. At baseline, weight management program cohorts (average cohort size was 14 participants) were randomized (1:1) to receive either the standard population-based intervention (Group Lifestyle Balance, or GLB) or a modified GLB intervention, which included the provision of lifestyle genomics (LGx) information and advice (GLB+LGx). Both interventions aimed to assist participants with weight management and healthy lifestyle change, with particular focus on nutrition and physical activity (PA). Interventions were 12 months long, consisting of 23 group-based sessions and 3 one-on-one sessions with a registered dietitian after 3, 6, and 12 months (all sessions were face-to-face). To improve intervention adherence, participants were given reminder calls for their one-on-one appointments and for the start of their program. A sample size was calculated based on the primary outcome indicating that a total of 74 participants were needed (n = 37 per group) for this trial. By September 2019, this sample size was exceeded with 10 randomized groups (n = 140).

The 5 randomized standard GLB groups followed the established GLB program curriculum comprising population-based information and advice while focusing on following a calorie-controlled, moderate-fat (25% of calories) nutrition plan with at least 150 minutes of weekly moderate-intensity PA. Participants were also provided with a 1-page summary report of their nutrition and PA guidelines at the first group meeting outlining population-based targets, including acceptable macronutrient distribution ranges for protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, sodium, calories, snacking, and PA.

The 5 randomized modified GLB+LGx groups followed a modified GLB program curriculum in which participants were given genetic-based information and advice, which differed from the advice given to the standard GLB group, while focusing on following a calorie-controlled nutrition plan. The nutrition and PA targets were personalized based on their individual genetic variation. For example, participants with the AA variant of FTO (rs9939609) were advised to engage in at least 30 to 60 minutes of PA daily 6 days per week, with muscle-strengthening activities at least 2 days per week, rather than receiving the standard population-based advice to aim for 150 minutes weekly of PA with at least 2 days per week of muscle-strengthening activity. Participants were also provided with a 1-page summary report of their nutrition and PA guidelines at the first group meeting, which outlined genetic-based information and advice related to protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, sodium, calories, snacking, and PA.

Measures and analysis. Change in the TPB components (attitudes, subjective norms and perceived behavioral control) were measured via a TPB questionnaire at 5 time points: baseline (2-week run-in period), immediately after the first group session (where participants received a summary report of either population-based or genetic-based recommendations depending on group assignment), and after 3-, 6- and 12-month follow-ups. Attitudes, subjective norms, and perceived behavioral control were measured on a Likert scale from 1 through 7. Self-reported measures of actual behavioral control (including annual household income, perceptions about events arising in one’s day-to-day life that suddenly take up one’s free time, perceptions about the frequency of feeling ill or tired, and highest achieved level of education) were collected via survey questions and assessed on a Likert scale of 1 through 7. Stage of change was also measured, based on the Transtheoretical Model, using a Likert scale of 1 through 6.

Linear mixed models were used to conduct within- and between-group analyses using SPSS version 26.0, while controlling for measures of actual behavioral control. All analyses were intention-to-treat by originally assigned groups, with mean value imputation conducted for missing data. A Bonferroni correction for multiple testing was used. For all statistical analyses, the level of significance was set at P < 0.05 and trending towards significance at P = 0.05–0.06.

Main results. Participants consisted of primarily middle-age, middle-income, Caucasian females. Baseline attitudes towards the effectiveness of nutrition and PA for weight management were generally positive, and participants perceived that undergoing genetic testing would assist with weight management. Participants had overall neutral subjective norms related to friends and family consuming a healthy diet and engaging in PA, but perceived that their friends, family, and health care team (HCT) believed it was important for them to achieve their nutrition and PA recommendations. Participants overall also perceived that their HCT believed genetic testing could assist with weight management. Baseline measures of perceived behavioral control were overall neutral, with baseline stage of change between “motivation” and “action” (short-term; <3 months).

In within-group analyses, significant improvements (P < 0.05) in attitudes towards the effectiveness of nutrition and PA recommendations for weight management, subjective norms related to both friends and family consuming a healthy diet, and perceived behavioral control in changing PA/dietary intake and managing weight tended to be short-term in the GLB group and long-term for the GLB+LGx group. In all cases of between-group differences for changes in TPB components, the GLB group exhibited reductions in scores, whereas the GLB+LGx group exhibited increases or improvements. Between-group differences (short-term and long-term) in several measures of subjective norms were observed. For example, after 3 months, significant between-group differences were observed in changes in perception that friends believed LGx would help with weight management (P = 0.024). After 12 months, between-group differences trending towards significance were also observed in changes in perception that family members believed genetic testing would help with weight management (P = 0.05). Significant between-group differences and differences trending towards significance were also observed at 12 months for changes in perception that family believed it was important for the participant to achieve the PA recommendations (P = 0.049) and nutrition recommendations (P = 0.05). Between-group differences trending towards significance were also observed at 3 months in attitudes towards the effectiveness of LGx for weight management (P = 0.06). There were no significant between-group differences observed in changes in perceived behavioral control.

Conclusion. Results from this study support the hypothesis that the TPB can help provide a theoretical explanation for why genetically tailored lifestyle information and advice can lead to improvements in lifestyle behavior change.

 

 

Commentary

Because health behaviors are critical in areas such as prevention, treatment, and rehabilitation, it is important to describe and understand what drives these behaviors.1 Theories are important tools in this effort as they aim to explain and predict health behavior and are used in the design and evaluation of interventions.1 The TPB is one of the most widely accepted behavior change theories and posits that attitudes, subjective norms (or social pressures and behaviors), and perceived behavioral control are significant predictors of an individual’s intention to engage in behaviors.2 TPB has been highlighted in the literature as a validated theory for predicting nutrition and PA intentions and resulting behaviors.3,4

Motivating lifestyle behavior change in clinical practice can be challenging, but some studies have demonstrated how providing genetic information and advice (or lifestyle genomics) can help motivate changes in nutrition and PA among patients.5-7 Because this has yet to be explained using the TPB, this study is an important contribution to the literature as it aimed to determine the impact of providing genetically tailored and population-based lifestyle advice for weight management on key constructs of the TPB. Briefly, results from within-group analyses in this study demonstrated that the provision of genetically tailored lifestyle information and advice (via the GLB+LGx intervention) tended to impact antecedents of behavior change, more so over the long-term, while population-based advice (via the standard GLB intervention) tended to impact antecedents of behavior change over the short-term (eg, attitudes towards dietary fat intake, perceptions that friends and family consume a healthy diet, and perceptions about the impact of genetic-based advice for weight management). In addition, between-group differences in subjective norms observed at 12 months suggested that social pressures and norms may be influencing long-term changes in lifestyle habits.

While key strengths of this study include its pragmatic cluster randomized controlled trial design, 12-month intervention duration, and intent-to-treat analyses, there are some study limitations, which are acknowledged by the authors. Generalizability is limited to the demographic characteristics of the study population (ie, middle-aged, middle-income, Caucasian females enrolled in a lifestyle change weight management program). Thus, replication of the study is needed in more diverse study populations and with health-related outcomes beyond weight management. In addition, as the authors indicate, future research should ensure the inclusion of theory-based questionnaires in genetic-based intervention studies assessing lifestyle behavior change to elucidate theory-based mechanisms of change.

Applications for Clinical Practice

Population-based research has consistently indicated that nutrition interventions typically impact short-term dietary changes. Confronting the challenge of long-term adherence to nutrition and PA recommendations requires an understanding of factors impacting long-term motivation and behavior change. With increased attention on and research into genetically tailored lifestyle advice (or lifestyle genomics), it is important for clinical practitioners to be familiar with the evidence supporting these approaches. In addition, this research highlights the need to consider individual factors (attitudes, subjective norms, and perceived behavioral control) that may predict successful change in lifestyle habits when providing nutrition and PA recommendations, whether population-based or genetically tailored.

—Katrina F. Mateo, PhD, MPH

Study Overview

Objective. To determine the impact of providing genetically tailored and population-based lifestyle advice for weight management on key constructs of the Theory of Planned Behavior (TPB), a widely accepted theory used to help predict human lifestyle-related behaviors.

Design. Pragmatic, cluster, randomized controlled trial.

Settings and participants. This study took place at the East Elgin Family Health Team, a primary care clinic in Aylmer, Ontario, Canada. Recruitment occurred between April 2017 and September 2018, with staggered intervention cohorts occurring from May 2017 to September 2019. Participants enrolled in a weight management program at the clinic were invited to participate in the study if they met the following inclusion criteria: body mass index (BMI) ≥25 kg/m2, >18 years of age, English-speaking, willing to undergo genetic testing, having access to a computer with internet at least 1 day per week, and not seeing another health care provider for weight loss advice outside of the study. Exclusion criteria included pregnancy and lactation. All participants provided written informed consent.

Interventions. At baseline, weight management program cohorts (average cohort size was 14 participants) were randomized (1:1) to receive either the standard population-based intervention (Group Lifestyle Balance, or GLB) or a modified GLB intervention, which included the provision of lifestyle genomics (LGx) information and advice (GLB+LGx). Both interventions aimed to assist participants with weight management and healthy lifestyle change, with particular focus on nutrition and physical activity (PA). Interventions were 12 months long, consisting of 23 group-based sessions and 3 one-on-one sessions with a registered dietitian after 3, 6, and 12 months (all sessions were face-to-face). To improve intervention adherence, participants were given reminder calls for their one-on-one appointments and for the start of their program. A sample size was calculated based on the primary outcome indicating that a total of 74 participants were needed (n = 37 per group) for this trial. By September 2019, this sample size was exceeded with 10 randomized groups (n = 140).

The 5 randomized standard GLB groups followed the established GLB program curriculum comprising population-based information and advice while focusing on following a calorie-controlled, moderate-fat (25% of calories) nutrition plan with at least 150 minutes of weekly moderate-intensity PA. Participants were also provided with a 1-page summary report of their nutrition and PA guidelines at the first group meeting outlining population-based targets, including acceptable macronutrient distribution ranges for protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, sodium, calories, snacking, and PA.

The 5 randomized modified GLB+LGx groups followed a modified GLB program curriculum in which participants were given genetic-based information and advice, which differed from the advice given to the standard GLB group, while focusing on following a calorie-controlled nutrition plan. The nutrition and PA targets were personalized based on their individual genetic variation. For example, participants with the AA variant of FTO (rs9939609) were advised to engage in at least 30 to 60 minutes of PA daily 6 days per week, with muscle-strengthening activities at least 2 days per week, rather than receiving the standard population-based advice to aim for 150 minutes weekly of PA with at least 2 days per week of muscle-strengthening activity. Participants were also provided with a 1-page summary report of their nutrition and PA guidelines at the first group meeting, which outlined genetic-based information and advice related to protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, sodium, calories, snacking, and PA.

Measures and analysis. Change in the TPB components (attitudes, subjective norms and perceived behavioral control) were measured via a TPB questionnaire at 5 time points: baseline (2-week run-in period), immediately after the first group session (where participants received a summary report of either population-based or genetic-based recommendations depending on group assignment), and after 3-, 6- and 12-month follow-ups. Attitudes, subjective norms, and perceived behavioral control were measured on a Likert scale from 1 through 7. Self-reported measures of actual behavioral control (including annual household income, perceptions about events arising in one’s day-to-day life that suddenly take up one’s free time, perceptions about the frequency of feeling ill or tired, and highest achieved level of education) were collected via survey questions and assessed on a Likert scale of 1 through 7. Stage of change was also measured, based on the Transtheoretical Model, using a Likert scale of 1 through 6.

Linear mixed models were used to conduct within- and between-group analyses using SPSS version 26.0, while controlling for measures of actual behavioral control. All analyses were intention-to-treat by originally assigned groups, with mean value imputation conducted for missing data. A Bonferroni correction for multiple testing was used. For all statistical analyses, the level of significance was set at P < 0.05 and trending towards significance at P = 0.05–0.06.

Main results. Participants consisted of primarily middle-age, middle-income, Caucasian females. Baseline attitudes towards the effectiveness of nutrition and PA for weight management were generally positive, and participants perceived that undergoing genetic testing would assist with weight management. Participants had overall neutral subjective norms related to friends and family consuming a healthy diet and engaging in PA, but perceived that their friends, family, and health care team (HCT) believed it was important for them to achieve their nutrition and PA recommendations. Participants overall also perceived that their HCT believed genetic testing could assist with weight management. Baseline measures of perceived behavioral control were overall neutral, with baseline stage of change between “motivation” and “action” (short-term; <3 months).

In within-group analyses, significant improvements (P < 0.05) in attitudes towards the effectiveness of nutrition and PA recommendations for weight management, subjective norms related to both friends and family consuming a healthy diet, and perceived behavioral control in changing PA/dietary intake and managing weight tended to be short-term in the GLB group and long-term for the GLB+LGx group. In all cases of between-group differences for changes in TPB components, the GLB group exhibited reductions in scores, whereas the GLB+LGx group exhibited increases or improvements. Between-group differences (short-term and long-term) in several measures of subjective norms were observed. For example, after 3 months, significant between-group differences were observed in changes in perception that friends believed LGx would help with weight management (P = 0.024). After 12 months, between-group differences trending towards significance were also observed in changes in perception that family members believed genetic testing would help with weight management (P = 0.05). Significant between-group differences and differences trending towards significance were also observed at 12 months for changes in perception that family believed it was important for the participant to achieve the PA recommendations (P = 0.049) and nutrition recommendations (P = 0.05). Between-group differences trending towards significance were also observed at 3 months in attitudes towards the effectiveness of LGx for weight management (P = 0.06). There were no significant between-group differences observed in changes in perceived behavioral control.

Conclusion. Results from this study support the hypothesis that the TPB can help provide a theoretical explanation for why genetically tailored lifestyle information and advice can lead to improvements in lifestyle behavior change.

 

 

Commentary

Because health behaviors are critical in areas such as prevention, treatment, and rehabilitation, it is important to describe and understand what drives these behaviors.1 Theories are important tools in this effort as they aim to explain and predict health behavior and are used in the design and evaluation of interventions.1 The TPB is one of the most widely accepted behavior change theories and posits that attitudes, subjective norms (or social pressures and behaviors), and perceived behavioral control are significant predictors of an individual’s intention to engage in behaviors.2 TPB has been highlighted in the literature as a validated theory for predicting nutrition and PA intentions and resulting behaviors.3,4

Motivating lifestyle behavior change in clinical practice can be challenging, but some studies have demonstrated how providing genetic information and advice (or lifestyle genomics) can help motivate changes in nutrition and PA among patients.5-7 Because this has yet to be explained using the TPB, this study is an important contribution to the literature as it aimed to determine the impact of providing genetically tailored and population-based lifestyle advice for weight management on key constructs of the TPB. Briefly, results from within-group analyses in this study demonstrated that the provision of genetically tailored lifestyle information and advice (via the GLB+LGx intervention) tended to impact antecedents of behavior change, more so over the long-term, while population-based advice (via the standard GLB intervention) tended to impact antecedents of behavior change over the short-term (eg, attitudes towards dietary fat intake, perceptions that friends and family consume a healthy diet, and perceptions about the impact of genetic-based advice for weight management). In addition, between-group differences in subjective norms observed at 12 months suggested that social pressures and norms may be influencing long-term changes in lifestyle habits.

While key strengths of this study include its pragmatic cluster randomized controlled trial design, 12-month intervention duration, and intent-to-treat analyses, there are some study limitations, which are acknowledged by the authors. Generalizability is limited to the demographic characteristics of the study population (ie, middle-aged, middle-income, Caucasian females enrolled in a lifestyle change weight management program). Thus, replication of the study is needed in more diverse study populations and with health-related outcomes beyond weight management. In addition, as the authors indicate, future research should ensure the inclusion of theory-based questionnaires in genetic-based intervention studies assessing lifestyle behavior change to elucidate theory-based mechanisms of change.

Applications for Clinical Practice

Population-based research has consistently indicated that nutrition interventions typically impact short-term dietary changes. Confronting the challenge of long-term adherence to nutrition and PA recommendations requires an understanding of factors impacting long-term motivation and behavior change. With increased attention on and research into genetically tailored lifestyle advice (or lifestyle genomics), it is important for clinical practitioners to be familiar with the evidence supporting these approaches. In addition, this research highlights the need to consider individual factors (attitudes, subjective norms, and perceived behavioral control) that may predict successful change in lifestyle habits when providing nutrition and PA recommendations, whether population-based or genetically tailored.

—Katrina F. Mateo, PhD, MPH

References

1. Lippke S, Ziegelmann JP. Theory-based health behavior change: Developing, testing, and applying theories for evidence-based interventions. Appl Psychol. 2008;57:698-716.

2. Ajzen I. The Theory of planned behaviour: reactions and reflections. Psychol Health. 2011;26:1113-1127.

3. McDermott MS, Oliver M, Simnadis T, et al. The Theory of Planned Behaviour and dietary patterns: A systematic review and meta-analysis. Prev Med (Baltim). 2015;81:150-156.

4. McEachan RRC, Conner M, Taylor NJ, Lawton RJ. Prospective prediction of health-related behaviours with the theory of planned behaviour: A meta-analysis. Health Psychol Rev. 2011;5:97-144.

5. Hietaranta-Luoma H-L, Tahvonen R, Iso-Touru T, et al A. An intervention study of individual, APOE genotype-based dietary and physical-activity advice: impact on health behavior. J Nutrigenet Nutrigenomics. 2014;7:161-174.

6. Nielsen DE, El-Sohemy A. Disclosure of genetic information and change in dietary intake: a randomized controlled trial. DeAngelis MM, ed. PLoS One. 2014;9(11):e112665.

7. Egglestone C, Morris A, O’Brien A. Effect of direct‐to‐consumer genetic tests on health behaviour and anxiety: a survey of consumers and potential consumers. J Genet Couns. 2013;22:565-575.

References

1. Lippke S, Ziegelmann JP. Theory-based health behavior change: Developing, testing, and applying theories for evidence-based interventions. Appl Psychol. 2008;57:698-716.

2. Ajzen I. The Theory of planned behaviour: reactions and reflections. Psychol Health. 2011;26:1113-1127.

3. McDermott MS, Oliver M, Simnadis T, et al. The Theory of Planned Behaviour and dietary patterns: A systematic review and meta-analysis. Prev Med (Baltim). 2015;81:150-156.

4. McEachan RRC, Conner M, Taylor NJ, Lawton RJ. Prospective prediction of health-related behaviours with the theory of planned behaviour: A meta-analysis. Health Psychol Rev. 2011;5:97-144.

5. Hietaranta-Luoma H-L, Tahvonen R, Iso-Touru T, et al A. An intervention study of individual, APOE genotype-based dietary and physical-activity advice: impact on health behavior. J Nutrigenet Nutrigenomics. 2014;7:161-174.

6. Nielsen DE, El-Sohemy A. Disclosure of genetic information and change in dietary intake: a randomized controlled trial. DeAngelis MM, ed. PLoS One. 2014;9(11):e112665.

7. Egglestone C, Morris A, O’Brien A. Effect of direct‐to‐consumer genetic tests on health behaviour and anxiety: a survey of consumers and potential consumers. J Genet Couns. 2013;22:565-575.

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Breaking the cycle of medication overuse headache

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Breaking the cycle of medication overuse headache

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.1

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.2

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

Pills over man holding head in pain
IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.3 An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability4; psychiatric comorbidity5; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs8; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.9

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,10 accounting for about 4% of primary care visits11 and approximately 20% of outpatient neurology consultations.12 Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.13 According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.10 Headache is the second leading cause of disability among people 15 to 49 years of age.10

Continue to: The prevalence of MOH...

 

 

The prevalence of MOH in the general population is 2%.7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year16; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.6

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),17 which lists diagnostic criteria for recognized headache disorders.

Diagnostic criteria for medication overuse headache

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 217) because the frequency of analgesic use required to develop MOH differs by agent.

Medication overuse headache subcategories by offending abortive agent

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 35,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Risk factors for increasing headache frequency

Continue to: Pathophysiology

 

 

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.23 Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.24

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache25—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

 

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

 

 

First and best strategy: Avoid onset of MOH

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.6 A similar effect has been seen with triptans.16 Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).26

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.27

Prospective cohort studies6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.28

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

 

 

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.2

A subsequent, long-term follow-up study29 of patients from the Norway trial2 who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies23 recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

 

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.30 There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

 

 

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.31

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.32

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.33 Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.2

Continue to: The research evidence for preventives

 

 

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

  • Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.24
  • Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.27 A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.34
  • Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.35 However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.36
  • Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month37; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.23 Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.38

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

  • A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms39; however, oral prednisolone has been shown to have no benefit.40
  • Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.41
  • Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.42

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.38

Continue to: Cognitive behavioral therapy...

 

 

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.43

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.44 Looking at the correlation between type of medication overused and relapse rate, the research indicates that

  • triptans have the lowest risk of relapse,44
  • simple analgesics have a higher risk of relapse than triptans,22,44 and
  • opioids have the highest risk of relapse.22

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.22 In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.22

 

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

 

 

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology45 and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes23); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; Allison.Crain@dignityhealth.org.

References

1. Zeeberg P, Olesen J, Jensen R. Discontinuation of medication overuse in headache patients: recovery of therapeutic responsiveness. Cephalalgia. 2006;26:1192-1198.

2. Kristoffersen ES, Straand J, Vetvik KG, et al. Brief intervention for medication-overuse headache in primary care. The BIMOH study: a double-blind pragmatic cluster randomised parallel controlled trial. J Neurol Neurosurg Psychiatry. 2015;86:505-512.

3. Bahra A, Walsh M, Menon S, et al. Does chronic daily headache arise de novo in association with regular use of analgesics? Headache. 2003;43:179-190.

4. Blumenfeld AM, Varon SF, Wilcox TK, et al. Disability, HRQoL and resource use among chronic and episodic migraineurs: results from the International Burden of Migraine Study (IBMS) Cephalalgia. 2011;31:301-315.

5. Chu H-T, Liang C-S, Lee J-T, et al. Associations between depression/anxiety and headache frequency in migraineurs: a cross-sectional study. Headache. 2018;58:407-415.

6. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;71:1821-1828.

7. Colás R, Muñoz P, Temprano R, et al. Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life. Neurology. 2004;62:1338-1342.

8. Linde M, Gustavsson A, Stovner LJ, et al. The cost of headache disorders in Europe: the Eurolight project. Eur J Neurol. 2012;19:703-711.

9. Shah AM, Bendtsen L, Zeeberg P, et al. Reduction of medication costs after detoxification for medication-overuse headache. Headache. 2013;53:665-672.

10. GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17:954-976.

11. Kernick D, Stapley S, Goadsby PJ, et al. What happens to new-onset headache presenting to primary care? A case–cohort study using electronic primary care records. Cephalalgia. 2008;28:1188-1195.

12. Stone J, Carson A, Duncan R, et al. Who is referred to neurology clinics?—the diagnoses made in 3781 new patients. Clin Neurol Neurosurg. 2010;112:747-751.

13. Munoz-Ceron J, Marin-Careaga V, Peña L, et al. Headache at the emergency room: etiologies, diagnostic usefulness of the ICHD 3 criteria, red and green flags. PloS One. 2019;14:e0208728.

14. Evers S, Marziniak M. Clinical features, pathophysiology, and treatment of medication-overuse headache. Lancet Neurol. 2010;9:391-401.

15. Tassorelli C, Jensen R, Allena M, et al; the COMOESTAS Consortium. A consensus protocol for the management of medication-overuse headache: evaluation in a multicentric, multinational study. Cephalalgia. 2014;34:645-655.

16. Bigal ME, Serrano D, Buse D, et al. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008;48:1157-1168.

17. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38:1-211.

18. Ferrari A, Leone S, Vergoni AV, et al. Similarities and differences between chronic migraine and episodic migraine. Headache. 2007;47:65-72.

19. Hagen K, Linde M, Steiner TJ, et al. Risk factors for medication-overuse headache: an 11-year follow-up study. The Nord-Trøndelag Health Studies. Pain. 2012;153:56-61.

20. Katsarava Z, Schneewiess S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology. 2004;62:788-790.

21. Lipton RB, Fanning KM, Buse DC, et al. Migraine progression in subgroups of migraine based on comorbidities: results of the CaMEO study. Neurology. 2019;93:e2224-e2236.

22. Munksgaard SB, Madsen SK, Wienecke T. Treatment of medication overuse headache—a review. Acta Neurol Scand. 2019;139:405-414.

23. Ferraro S, Grazzi L, Mandelli M, et al. Pain processing in medication overuse headache: a functional magnetic resonance imaging (fMRI) study. Pain Med. 2012;13:255-262.

24. Diener H-C, Holle D, Solbach K, et al. Medication-overuse headache: risk factors, pathophysiology and management. Nat Rev Neurol. 2016;12:575-583.

25. Limmroth V, Katsarava Z, Fritsche G, et al. Features of medication overuse headache following overuse of different acute headache drugs. Neurology. 2002;59:1011-1014.

26. Mauskop A, ed. Migraine and Headache. 2nd ed. Oxford University Press; 2013.

27. Diener H-C, Bussone G, Van Oene JC, et al; TOPMAT-MIG-201(TOP-CHROME) Study Group. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia. 2007;27:814-823.

28. Navratilova E, Behravesh S, Oyarzo J, et al. Ubrogepant does not induce latent sensitization in a preclinical model of medication overuse headache Cephalalgia. 2020;40:892-902.

29. Kristoffersen ES, Straand J, Russell MB, et al. Lasting improvement of medication-overuse headache after brief intervention—a long-term follow-up in primary care. Eur J Neurol. 2017;24:883-891.

30. Carlsen LN, Munksgaard SB, Jensen RH, et al. Complete detoxification is the most effective treatment of medication-overuse headache: a randomized controlled open-label trial. Cephalalgia. 2018;38:225-236.

31. Sarchielli P, Messina P, Cupini LM, et al; SAMOHA Study Group. Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial. Eur Neuropsychopharmacol. 2014;24:1289-1297.

32. Hagen K, Stovner LJ. A randomized controlled trial on medication-overuse headache: outcome after 1 and 4 years. Acta Neurol Scand Suppl. 2011;124(suppl 191):38-43.

33. Munksgaard SB, Bendtsen L, Jensen RH. Detoxification of medication-overuse headache by a multidisciplinary treatment programme is highly effective: a comparison of two consecutive treatment methods in an open-label design. Cephalalgia. 2012;32:834-844.

34. Silberstein S, Lipton R, Dodick D, et al. Topiramate treatment of chronic migraine: a randomized, placebo-controlled trial of quality of life and other efficacy measures. Headache. 2009;49:1153-1162.

35. Silberstein SD, Blumenfeld AM, Cady RK, et al. OnabotulinumtoxinA for treatment of chronic migraine: PREEMPT 24-week pooled subgroup analysis of patients who had acute headache medication overuse at baseline. J Neurol Sci. 2013;331:48-56.

36. Sandrini G, Perrotta A, Tassorelli C, et al. Botulinum toxin type-A in the prophylactic treatment of medication-overuse headache: a multicenter, double-blind, randomized, placebo-controlled, parallel group study. J Headache Pain. 2011;12:427-433.

37. Tepper SJ. CGRP and headache: a brief review. Neurol Sci. 2019;40(suppl 1):99-105.

38. Diener H-C, Dodick D, Evers S, et al. Pathophysiology, prevention and treatment of medication overuse headache. Lancet Neurol. 2019;18:891-902.

39. Krymchantowski AV, Barbosa JS. Prednisone as initial treatment of analgesic-induced daily headache. Cephalalgia. 2000;20:107-113.

40. Bøe MG, Mygland A, Salvesen R. Prednisolone does not reduce withdrawal headache: a randomized, double-blind study. Neurology. 2007;69:26-31.

41. Paolucci M, Altamura C, Brunelli N, et al. Methylprednisolone plus diazepam i.v. as bridge therapy for medication overuse headache. Neurol Sci. 2017;38:2025-2029.

42. Taghdiri F, Togha M, Razeghi Jahromi S, et al. Celecoxib vs prednisone for the treatment of withdrawal headache in patients with medication overuse headache: a randomized, double-blind clinical trial. Headache. 2015;55:128-135.

43. Ramsey RR, Ryan JL, Hershey AD, et al. Treatment adherence in patients with headache: a systematic review. Headache. 2014;54:795-816.

44. Katsarava Z, Muessig M, Dzagnidze A, et al. Medication overuse headache: rates and predictors for relapse in a 4-year prospective study. Cephalalgia. 2005;25:12-15.

45. Silberstein SD, Holland S, Freitag F, et al; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012; 78:1137-1145.

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Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.1

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.2

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

Pills over man holding head in pain
IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.3 An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability4; psychiatric comorbidity5; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs8; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.9

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,10 accounting for about 4% of primary care visits11 and approximately 20% of outpatient neurology consultations.12 Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.13 According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.10 Headache is the second leading cause of disability among people 15 to 49 years of age.10

Continue to: The prevalence of MOH...

 

 

The prevalence of MOH in the general population is 2%.7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year16; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.6

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),17 which lists diagnostic criteria for recognized headache disorders.

Diagnostic criteria for medication overuse headache

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 217) because the frequency of analgesic use required to develop MOH differs by agent.

Medication overuse headache subcategories by offending abortive agent

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 35,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Risk factors for increasing headache frequency

Continue to: Pathophysiology

 

 

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.23 Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.24

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache25—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

 

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

 

 

First and best strategy: Avoid onset of MOH

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.6 A similar effect has been seen with triptans.16 Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).26

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.27

Prospective cohort studies6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.28

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

 

 

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.2

A subsequent, long-term follow-up study29 of patients from the Norway trial2 who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies23 recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

 

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.30 There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

 

 

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.31

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.32

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.33 Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.2

Continue to: The research evidence for preventives

 

 

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

  • Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.24
  • Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.27 A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.34
  • Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.35 However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.36
  • Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month37; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.23 Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.38

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

  • A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms39; however, oral prednisolone has been shown to have no benefit.40
  • Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.41
  • Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.42

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.38

Continue to: Cognitive behavioral therapy...

 

 

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.43

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.44 Looking at the correlation between type of medication overused and relapse rate, the research indicates that

  • triptans have the lowest risk of relapse,44
  • simple analgesics have a higher risk of relapse than triptans,22,44 and
  • opioids have the highest risk of relapse.22

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.22 In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.22

 

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

 

 

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology45 and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes23); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; Allison.Crain@dignityhealth.org.

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.1

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.2

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

Pills over man holding head in pain
IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.3 An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability4; psychiatric comorbidity5; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs8; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.9

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,10 accounting for about 4% of primary care visits11 and approximately 20% of outpatient neurology consultations.12 Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.13 According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.10 Headache is the second leading cause of disability among people 15 to 49 years of age.10

Continue to: The prevalence of MOH...

 

 

The prevalence of MOH in the general population is 2%.7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year16; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.6

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),17 which lists diagnostic criteria for recognized headache disorders.

Diagnostic criteria for medication overuse headache

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 217) because the frequency of analgesic use required to develop MOH differs by agent.

Medication overuse headache subcategories by offending abortive agent

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 35,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Risk factors for increasing headache frequency

Continue to: Pathophysiology

 

 

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.23 Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.24

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache25—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

 

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

 

 

First and best strategy: Avoid onset of MOH

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.6 A similar effect has been seen with triptans.16 Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).26

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.27

Prospective cohort studies6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.28

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

 

 

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.2

A subsequent, long-term follow-up study29 of patients from the Norway trial2 who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies23 recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

 

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.30 There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

 

 

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.31

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.32

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.33 Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.2

Continue to: The research evidence for preventives

 

 

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

  • Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.24
  • Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.27 A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.34
  • Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.35 However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.36
  • Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month37; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.23 Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.38

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

  • A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms39; however, oral prednisolone has been shown to have no benefit.40
  • Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.41
  • Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.42

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.38

Continue to: Cognitive behavioral therapy...

 

 

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.43

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.44 Looking at the correlation between type of medication overused and relapse rate, the research indicates that

  • triptans have the lowest risk of relapse,44
  • simple analgesics have a higher risk of relapse than triptans,22,44 and
  • opioids have the highest risk of relapse.22

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.22 In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.22

 

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

 

 

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology45 and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes23); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; Allison.Crain@dignityhealth.org.

References

1. Zeeberg P, Olesen J, Jensen R. Discontinuation of medication overuse in headache patients: recovery of therapeutic responsiveness. Cephalalgia. 2006;26:1192-1198.

2. Kristoffersen ES, Straand J, Vetvik KG, et al. Brief intervention for medication-overuse headache in primary care. The BIMOH study: a double-blind pragmatic cluster randomised parallel controlled trial. J Neurol Neurosurg Psychiatry. 2015;86:505-512.

3. Bahra A, Walsh M, Menon S, et al. Does chronic daily headache arise de novo in association with regular use of analgesics? Headache. 2003;43:179-190.

4. Blumenfeld AM, Varon SF, Wilcox TK, et al. Disability, HRQoL and resource use among chronic and episodic migraineurs: results from the International Burden of Migraine Study (IBMS) Cephalalgia. 2011;31:301-315.

5. Chu H-T, Liang C-S, Lee J-T, et al. Associations between depression/anxiety and headache frequency in migraineurs: a cross-sectional study. Headache. 2018;58:407-415.

6. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;71:1821-1828.

7. Colás R, Muñoz P, Temprano R, et al. Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life. Neurology. 2004;62:1338-1342.

8. Linde M, Gustavsson A, Stovner LJ, et al. The cost of headache disorders in Europe: the Eurolight project. Eur J Neurol. 2012;19:703-711.

9. Shah AM, Bendtsen L, Zeeberg P, et al. Reduction of medication costs after detoxification for medication-overuse headache. Headache. 2013;53:665-672.

10. GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17:954-976.

11. Kernick D, Stapley S, Goadsby PJ, et al. What happens to new-onset headache presenting to primary care? A case–cohort study using electronic primary care records. Cephalalgia. 2008;28:1188-1195.

12. Stone J, Carson A, Duncan R, et al. Who is referred to neurology clinics?—the diagnoses made in 3781 new patients. Clin Neurol Neurosurg. 2010;112:747-751.

13. Munoz-Ceron J, Marin-Careaga V, Peña L, et al. Headache at the emergency room: etiologies, diagnostic usefulness of the ICHD 3 criteria, red and green flags. PloS One. 2019;14:e0208728.

14. Evers S, Marziniak M. Clinical features, pathophysiology, and treatment of medication-overuse headache. Lancet Neurol. 2010;9:391-401.

15. Tassorelli C, Jensen R, Allena M, et al; the COMOESTAS Consortium. A consensus protocol for the management of medication-overuse headache: evaluation in a multicentric, multinational study. Cephalalgia. 2014;34:645-655.

16. Bigal ME, Serrano D, Buse D, et al. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008;48:1157-1168.

17. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38:1-211.

18. Ferrari A, Leone S, Vergoni AV, et al. Similarities and differences between chronic migraine and episodic migraine. Headache. 2007;47:65-72.

19. Hagen K, Linde M, Steiner TJ, et al. Risk factors for medication-overuse headache: an 11-year follow-up study. The Nord-Trøndelag Health Studies. Pain. 2012;153:56-61.

20. Katsarava Z, Schneewiess S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology. 2004;62:788-790.

21. Lipton RB, Fanning KM, Buse DC, et al. Migraine progression in subgroups of migraine based on comorbidities: results of the CaMEO study. Neurology. 2019;93:e2224-e2236.

22. Munksgaard SB, Madsen SK, Wienecke T. Treatment of medication overuse headache—a review. Acta Neurol Scand. 2019;139:405-414.

23. Ferraro S, Grazzi L, Mandelli M, et al. Pain processing in medication overuse headache: a functional magnetic resonance imaging (fMRI) study. Pain Med. 2012;13:255-262.

24. Diener H-C, Holle D, Solbach K, et al. Medication-overuse headache: risk factors, pathophysiology and management. Nat Rev Neurol. 2016;12:575-583.

25. Limmroth V, Katsarava Z, Fritsche G, et al. Features of medication overuse headache following overuse of different acute headache drugs. Neurology. 2002;59:1011-1014.

26. Mauskop A, ed. Migraine and Headache. 2nd ed. Oxford University Press; 2013.

27. Diener H-C, Bussone G, Van Oene JC, et al; TOPMAT-MIG-201(TOP-CHROME) Study Group. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia. 2007;27:814-823.

28. Navratilova E, Behravesh S, Oyarzo J, et al. Ubrogepant does not induce latent sensitization in a preclinical model of medication overuse headache Cephalalgia. 2020;40:892-902.

29. Kristoffersen ES, Straand J, Russell MB, et al. Lasting improvement of medication-overuse headache after brief intervention—a long-term follow-up in primary care. Eur J Neurol. 2017;24:883-891.

30. Carlsen LN, Munksgaard SB, Jensen RH, et al. Complete detoxification is the most effective treatment of medication-overuse headache: a randomized controlled open-label trial. Cephalalgia. 2018;38:225-236.

31. Sarchielli P, Messina P, Cupini LM, et al; SAMOHA Study Group. Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial. Eur Neuropsychopharmacol. 2014;24:1289-1297.

32. Hagen K, Stovner LJ. A randomized controlled trial on medication-overuse headache: outcome after 1 and 4 years. Acta Neurol Scand Suppl. 2011;124(suppl 191):38-43.

33. Munksgaard SB, Bendtsen L, Jensen RH. Detoxification of medication-overuse headache by a multidisciplinary treatment programme is highly effective: a comparison of two consecutive treatment methods in an open-label design. Cephalalgia. 2012;32:834-844.

34. Silberstein S, Lipton R, Dodick D, et al. Topiramate treatment of chronic migraine: a randomized, placebo-controlled trial of quality of life and other efficacy measures. Headache. 2009;49:1153-1162.

35. Silberstein SD, Blumenfeld AM, Cady RK, et al. OnabotulinumtoxinA for treatment of chronic migraine: PREEMPT 24-week pooled subgroup analysis of patients who had acute headache medication overuse at baseline. J Neurol Sci. 2013;331:48-56.

36. Sandrini G, Perrotta A, Tassorelli C, et al. Botulinum toxin type-A in the prophylactic treatment of medication-overuse headache: a multicenter, double-blind, randomized, placebo-controlled, parallel group study. J Headache Pain. 2011;12:427-433.

37. Tepper SJ. CGRP and headache: a brief review. Neurol Sci. 2019;40(suppl 1):99-105.

38. Diener H-C, Dodick D, Evers S, et al. Pathophysiology, prevention and treatment of medication overuse headache. Lancet Neurol. 2019;18:891-902.

39. Krymchantowski AV, Barbosa JS. Prednisone as initial treatment of analgesic-induced daily headache. Cephalalgia. 2000;20:107-113.

40. Bøe MG, Mygland A, Salvesen R. Prednisolone does not reduce withdrawal headache: a randomized, double-blind study. Neurology. 2007;69:26-31.

41. Paolucci M, Altamura C, Brunelli N, et al. Methylprednisolone plus diazepam i.v. as bridge therapy for medication overuse headache. Neurol Sci. 2017;38:2025-2029.

42. Taghdiri F, Togha M, Razeghi Jahromi S, et al. Celecoxib vs prednisone for the treatment of withdrawal headache in patients with medication overuse headache: a randomized, double-blind clinical trial. Headache. 2015;55:128-135.

43. Ramsey RR, Ryan JL, Hershey AD, et al. Treatment adherence in patients with headache: a systematic review. Headache. 2014;54:795-816.

44. Katsarava Z, Muessig M, Dzagnidze A, et al. Medication overuse headache: rates and predictors for relapse in a 4-year prospective study. Cephalalgia. 2005;25:12-15.

45. Silberstein SD, Holland S, Freitag F, et al; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012; 78:1137-1145.

References

1. Zeeberg P, Olesen J, Jensen R. Discontinuation of medication overuse in headache patients: recovery of therapeutic responsiveness. Cephalalgia. 2006;26:1192-1198.

2. Kristoffersen ES, Straand J, Vetvik KG, et al. Brief intervention for medication-overuse headache in primary care. The BIMOH study: a double-blind pragmatic cluster randomised parallel controlled trial. J Neurol Neurosurg Psychiatry. 2015;86:505-512.

3. Bahra A, Walsh M, Menon S, et al. Does chronic daily headache arise de novo in association with regular use of analgesics? Headache. 2003;43:179-190.

4. Blumenfeld AM, Varon SF, Wilcox TK, et al. Disability, HRQoL and resource use among chronic and episodic migraineurs: results from the International Burden of Migraine Study (IBMS) Cephalalgia. 2011;31:301-315.

5. Chu H-T, Liang C-S, Lee J-T, et al. Associations between depression/anxiety and headache frequency in migraineurs: a cross-sectional study. Headache. 2018;58:407-415.

6. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;71:1821-1828.

7. Colás R, Muñoz P, Temprano R, et al. Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life. Neurology. 2004;62:1338-1342.

8. Linde M, Gustavsson A, Stovner LJ, et al. The cost of headache disorders in Europe: the Eurolight project. Eur J Neurol. 2012;19:703-711.

9. Shah AM, Bendtsen L, Zeeberg P, et al. Reduction of medication costs after detoxification for medication-overuse headache. Headache. 2013;53:665-672.

10. GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17:954-976.

11. Kernick D, Stapley S, Goadsby PJ, et al. What happens to new-onset headache presenting to primary care? A case–cohort study using electronic primary care records. Cephalalgia. 2008;28:1188-1195.

12. Stone J, Carson A, Duncan R, et al. Who is referred to neurology clinics?—the diagnoses made in 3781 new patients. Clin Neurol Neurosurg. 2010;112:747-751.

13. Munoz-Ceron J, Marin-Careaga V, Peña L, et al. Headache at the emergency room: etiologies, diagnostic usefulness of the ICHD 3 criteria, red and green flags. PloS One. 2019;14:e0208728.

14. Evers S, Marziniak M. Clinical features, pathophysiology, and treatment of medication-overuse headache. Lancet Neurol. 2010;9:391-401.

15. Tassorelli C, Jensen R, Allena M, et al; the COMOESTAS Consortium. A consensus protocol for the management of medication-overuse headache: evaluation in a multicentric, multinational study. Cephalalgia. 2014;34:645-655.

16. Bigal ME, Serrano D, Buse D, et al. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008;48:1157-1168.

17. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38:1-211.

18. Ferrari A, Leone S, Vergoni AV, et al. Similarities and differences between chronic migraine and episodic migraine. Headache. 2007;47:65-72.

19. Hagen K, Linde M, Steiner TJ, et al. Risk factors for medication-overuse headache: an 11-year follow-up study. The Nord-Trøndelag Health Studies. Pain. 2012;153:56-61.

20. Katsarava Z, Schneewiess S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology. 2004;62:788-790.

21. Lipton RB, Fanning KM, Buse DC, et al. Migraine progression in subgroups of migraine based on comorbidities: results of the CaMEO study. Neurology. 2019;93:e2224-e2236.

22. Munksgaard SB, Madsen SK, Wienecke T. Treatment of medication overuse headache—a review. Acta Neurol Scand. 2019;139:405-414.

23. Ferraro S, Grazzi L, Mandelli M, et al. Pain processing in medication overuse headache: a functional magnetic resonance imaging (fMRI) study. Pain Med. 2012;13:255-262.

24. Diener H-C, Holle D, Solbach K, et al. Medication-overuse headache: risk factors, pathophysiology and management. Nat Rev Neurol. 2016;12:575-583.

25. Limmroth V, Katsarava Z, Fritsche G, et al. Features of medication overuse headache following overuse of different acute headache drugs. Neurology. 2002;59:1011-1014.

26. Mauskop A, ed. Migraine and Headache. 2nd ed. Oxford University Press; 2013.

27. Diener H-C, Bussone G, Van Oene JC, et al; TOPMAT-MIG-201(TOP-CHROME) Study Group. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia. 2007;27:814-823.

28. Navratilova E, Behravesh S, Oyarzo J, et al. Ubrogepant does not induce latent sensitization in a preclinical model of medication overuse headache Cephalalgia. 2020;40:892-902.

29. Kristoffersen ES, Straand J, Russell MB, et al. Lasting improvement of medication-overuse headache after brief intervention—a long-term follow-up in primary care. Eur J Neurol. 2017;24:883-891.

30. Carlsen LN, Munksgaard SB, Jensen RH, et al. Complete detoxification is the most effective treatment of medication-overuse headache: a randomized controlled open-label trial. Cephalalgia. 2018;38:225-236.

31. Sarchielli P, Messina P, Cupini LM, et al; SAMOHA Study Group. Sodium valproate in migraine without aura and medication overuse headache: a randomized controlled trial. Eur Neuropsychopharmacol. 2014;24:1289-1297.

32. Hagen K, Stovner LJ. A randomized controlled trial on medication-overuse headache: outcome after 1 and 4 years. Acta Neurol Scand Suppl. 2011;124(suppl 191):38-43.

33. Munksgaard SB, Bendtsen L, Jensen RH. Detoxification of medication-overuse headache by a multidisciplinary treatment programme is highly effective: a comparison of two consecutive treatment methods in an open-label design. Cephalalgia. 2012;32:834-844.

34. Silberstein S, Lipton R, Dodick D, et al. Topiramate treatment of chronic migraine: a randomized, placebo-controlled trial of quality of life and other efficacy measures. Headache. 2009;49:1153-1162.

35. Silberstein SD, Blumenfeld AM, Cady RK, et al. OnabotulinumtoxinA for treatment of chronic migraine: PREEMPT 24-week pooled subgroup analysis of patients who had acute headache medication overuse at baseline. J Neurol Sci. 2013;331:48-56.

36. Sandrini G, Perrotta A, Tassorelli C, et al. Botulinum toxin type-A in the prophylactic treatment of medication-overuse headache: a multicenter, double-blind, randomized, placebo-controlled, parallel group study. J Headache Pain. 2011;12:427-433.

37. Tepper SJ. CGRP and headache: a brief review. Neurol Sci. 2019;40(suppl 1):99-105.

38. Diener H-C, Dodick D, Evers S, et al. Pathophysiology, prevention and treatment of medication overuse headache. Lancet Neurol. 2019;18:891-902.

39. Krymchantowski AV, Barbosa JS. Prednisone as initial treatment of analgesic-induced daily headache. Cephalalgia. 2000;20:107-113.

40. Bøe MG, Mygland A, Salvesen R. Prednisolone does not reduce withdrawal headache: a randomized, double-blind study. Neurology. 2007;69:26-31.

41. Paolucci M, Altamura C, Brunelli N, et al. Methylprednisolone plus diazepam i.v. as bridge therapy for medication overuse headache. Neurol Sci. 2017;38:2025-2029.

42. Taghdiri F, Togha M, Razeghi Jahromi S, et al. Celecoxib vs prednisone for the treatment of withdrawal headache in patients with medication overuse headache: a randomized, double-blind clinical trial. Headache. 2015;55:128-135.

43. Ramsey RR, Ryan JL, Hershey AD, et al. Treatment adherence in patients with headache: a systematic review. Headache. 2014;54:795-816.

44. Katsarava Z, Muessig M, Dzagnidze A, et al. Medication overuse headache: rates and predictors for relapse in a 4-year prospective study. Cephalalgia. 2005;25:12-15.

45. Silberstein SD, Holland S, Freitag F, et al; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012; 78:1137-1145.

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The Journal of Family Practice - 70(1)
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The Journal of Family Practice - 70(1)
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PRACTICE RECOMMENDATIONS

› Avoid prescribing barbiturates or opioids for a headache disorder. A

› Limit use of a headache-abortive medication to twice a week when starting a patient on the drug. C

› Consider providing bridging therapy during detoxification of the overused medication. C

› Do not provide a preventive medication without withdrawing the overused agent. A

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

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