Link Between Proton Pump Inhibitors, Hip Fractures Confirmed

CHICAGO – Regular use of proton pump inhibitors is associated with an elevated risk of hip fractures, even after adjusting for important lifestyle risk factors, according to the findings of a prospective evaluation from the Nurses’ Health Study.

The association was most striking for women with a history of smoking, observed Dr. Hamed Khalili of Massachusetts General Hospital, Boston.

The Food and Drug Association recently issued an advisory regarding a potential link between PPIs and fractures. While acid-suppressing medications have been hypothesized to increase the risk of osteoporotic fractures, studies examining this association have been inconsistent. These analyses have mostly been based on retrospective studies of small populations that have not controlled for important dietary and lifestyle confounders, and they have ascertained PPI use only at a single time point, Dr. Khalili said.

The current study aimed to be more definitive by prospectively examining the relationship between chronic PPI use and incident hip fracture among 79,899 postmenopausal women enrolled in the Nurses’ Health Study, he said.

"We found that longer duration of use was associated with increased risk, and the strongest risk was confined to individuals with a history of smoking. ... Our findings support the recent decision of the FDA to revise labeling of PPIs to incorporate concerns about a possible increase in the risk of fractures," he said at the annual Digestive Disease Week.

In 1982, participants in the Nurses’ Health Study were first asked to report all previous fractures and were queried biennially for new fractures. Among the nearly 80,000 subjects, with 565,786 person-years of follow-up, there were 893 incident hip fractures over 8 years. PPI use was reported by 7% of participants in 2000 and by 19% of participants in 2008.

Regular use of PPIs posed fracture risks of 35%-45% when adjusted for age, calcium intake, and body mass index. The fully adjusted hazard ratio was 1.37, Dr. Khalili reported.

Current smoking status stood out as a significant effect modifier. Women who were current or past smokers and who regularly took a PPI had a 51% increased risk for fracture. In contrast, women who never smoked had only a 6% increased risk, "almost equal to women who never used PPIs," he noted.

Longer duration of use was associated with greater risk. Compared with never-users, risk in the multivariate analysis was 36% after 2 years of use, 42% after 4 years and 54% when PPIs were used for 6 years or longer (P less than 0.001), he said.

The investigators adjusted for multiple other risk factors, including physical activity; alcohol intake; total daily calcium and vitamin D intake; history of osteoporosis; and use of hormone replacement therapy, bisphosphonates, and thiazides. "This did not materially alter this association," he noted.

When PPIs were discontinued, the risks declined. Two or more years after discontinuation, the risk of hip fracture was just 9%-10%, he noted.

"The strengths of our study are that it offers detailed, prospectively collected and validated information on PPI use and other risk factors. We had a high response rate, and the participants are educated health professionals," he said. "But the study lacks information about PPI use prior to 2000, and it lacks specific information about brand and dose of PPI. It’s not clear whether this is generalizable to other populations."

The study, however, is in line with other reports of an association, and adds weight to the recommendation that clinicians carefully monitor the need for postmenopausal women to continue long-term on PPIs, especially those who smoke.

Response from the audience was robust, with one attendee noting, "This is truly excellent work," and another calling the study "impressive."

Dr. Khalili reported having no conflicts of interest.

CHICAGO – Regular use of proton pump inhibitors is associated with an elevated risk of hip fractures, even after adjusting for important lifestyle risk factors, according to the findings of a prospective evaluation from the Nurses’ Health Study.

The association was most striking for women with a history of smoking, observed Dr. Hamed Khalili of Massachusetts General Hospital, Boston.

The Food and Drug Association recently issued an advisory regarding a potential link between PPIs and fractures. While acid-suppressing medications have been hypothesized to increase the risk of osteoporotic fractures, studies examining this association have been inconsistent. These analyses have mostly been based on retrospective studies of small populations that have not controlled for important dietary and lifestyle confounders, and they have ascertained PPI use only at a single time point, Dr. Khalili said.

The current study aimed to be more definitive by prospectively examining the relationship between chronic PPI use and incident hip fracture among 79,899 postmenopausal women enrolled in the Nurses’ Health Study, he said.

"We found that longer duration of use was associated with increased risk, and the strongest risk was confined to individuals with a history of smoking. ... Our findings support the recent decision of the FDA to revise labeling of PPIs to incorporate concerns about a possible increase in the risk of fractures," he said at the annual Digestive Disease Week.

In 1982, participants in the Nurses’ Health Study were first asked to report all previous fractures and were queried biennially for new fractures. Among the nearly 80,000 subjects, with 565,786 person-years of follow-up, there were 893 incident hip fractures over 8 years. PPI use was reported by 7% of participants in 2000 and by 19% of participants in 2008.

Regular use of PPIs posed fracture risks of 35%-45% when adjusted for age, calcium intake, and body mass index. The fully adjusted hazard ratio was 1.37, Dr. Khalili reported.

Current smoking status stood out as a significant effect modifier. Women who were current or past smokers and who regularly took a PPI had a 51% increased risk for fracture. In contrast, women who never smoked had only a 6% increased risk, "almost equal to women who never used PPIs," he noted.

Longer duration of use was associated with greater risk. Compared with never-users, risk in the multivariate analysis was 36% after 2 years of use, 42% after 4 years and 54% when PPIs were used for 6 years or longer (P less than 0.001), he said.

The investigators adjusted for multiple other risk factors, including physical activity; alcohol intake; total daily calcium and vitamin D intake; history of osteoporosis; and use of hormone replacement therapy, bisphosphonates, and thiazides. "This did not materially alter this association," he noted.

When PPIs were discontinued, the risks declined. Two or more years after discontinuation, the risk of hip fracture was just 9%-10%, he noted.

"The strengths of our study are that it offers detailed, prospectively collected and validated information on PPI use and other risk factors. We had a high response rate, and the participants are educated health professionals," he said. "But the study lacks information about PPI use prior to 2000, and it lacks specific information about brand and dose of PPI. It’s not clear whether this is generalizable to other populations."

The study, however, is in line with other reports of an association, and adds weight to the recommendation that clinicians carefully monitor the need for postmenopausal women to continue long-term on PPIs, especially those who smoke.

Response from the audience was robust, with one attendee noting, "This is truly excellent work," and another calling the study "impressive."

Dr. Khalili reported having no conflicts of interest.

CHICAGO – Regular use of proton pump inhibitors is associated with an elevated risk of hip fractures, even after adjusting for important lifestyle risk factors, according to the findings of a prospective evaluation from the Nurses’ Health Study.

The association was most striking for women with a history of smoking, observed Dr. Hamed Khalili of Massachusetts General Hospital, Boston.

The Food and Drug Association recently issued an advisory regarding a potential link between PPIs and fractures. While acid-suppressing medications have been hypothesized to increase the risk of osteoporotic fractures, studies examining this association have been inconsistent. These analyses have mostly been based on retrospective studies of small populations that have not controlled for important dietary and lifestyle confounders, and they have ascertained PPI use only at a single time point, Dr. Khalili said.

The current study aimed to be more definitive by prospectively examining the relationship between chronic PPI use and incident hip fracture among 79,899 postmenopausal women enrolled in the Nurses’ Health Study, he said.

"We found that longer duration of use was associated with increased risk, and the strongest risk was confined to individuals with a history of smoking. ... Our findings support the recent decision of the FDA to revise labeling of PPIs to incorporate concerns about a possible increase in the risk of fractures," he said at the annual Digestive Disease Week.

In 1982, participants in the Nurses’ Health Study were first asked to report all previous fractures and were queried biennially for new fractures. Among the nearly 80,000 subjects, with 565,786 person-years of follow-up, there were 893 incident hip fractures over 8 years. PPI use was reported by 7% of participants in 2000 and by 19% of participants in 2008.

Regular use of PPIs posed fracture risks of 35%-45% when adjusted for age, calcium intake, and body mass index. The fully adjusted hazard ratio was 1.37, Dr. Khalili reported.

Current smoking status stood out as a significant effect modifier. Women who were current or past smokers and who regularly took a PPI had a 51% increased risk for fracture. In contrast, women who never smoked had only a 6% increased risk, "almost equal to women who never used PPIs," he noted.

Longer duration of use was associated with greater risk. Compared with never-users, risk in the multivariate analysis was 36% after 2 years of use, 42% after 4 years and 54% when PPIs were used for 6 years or longer (P less than 0.001), he said.

The investigators adjusted for multiple other risk factors, including physical activity; alcohol intake; total daily calcium and vitamin D intake; history of osteoporosis; and use of hormone replacement therapy, bisphosphonates, and thiazides. "This did not materially alter this association," he noted.

When PPIs were discontinued, the risks declined. Two or more years after discontinuation, the risk of hip fracture was just 9%-10%, he noted.

"The strengths of our study are that it offers detailed, prospectively collected and validated information on PPI use and other risk factors. We had a high response rate, and the participants are educated health professionals," he said. "But the study lacks information about PPI use prior to 2000, and it lacks specific information about brand and dose of PPI. It’s not clear whether this is generalizable to other populations."

The study, however, is in line with other reports of an association, and adds weight to the recommendation that clinicians carefully monitor the need for postmenopausal women to continue long-term on PPIs, especially those who smoke.

Response from the audience was robust, with one attendee noting, "This is truly excellent work," and another calling the study "impressive."

Dr. Khalili reported having no conflicts of interest.