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Can calcium supplements cause serious adverse effects in healthy people?
Yes, according to studies with some limitations. Calcium supplements with or without vitamin D increase the risk of myocardial infarction (MI), with numbers needed to harm (NNH) over 5 years of 69 to 240 (strength of recommendation [SOR]: B, meta-analyses of randomized controlled trials [RCTs] that evaluated a predominantly older female population and were limited by study designs).
Calcium supplements with or without vitamin D may increase the risk of stroke, with an NNH over 5 years of 283 (SOR: B, meta-analyses of RCTs).
Calcium supplementation, but not a diet rich in calcium, also increases the risk of renal calculi, with an NNH over 7 years of 272 (SOR: B, RCT and a cohort study, which also evaluated a predominantly older female population).
Evidence summary
A meta-analysis of 11 randomized, double-blinded placebo-controlled studies assessed the relationship between calcium supplements and the risk of cardiovascular events.1 A total of 20,071 predominantly female patients (83%) with a mean age of 72 years (range, 51-77 years) received ≥500 mg elemental calcium per day for at least 1 year. Median follow-up was 3.6 to 4 years. Five studies provided individual patient data and all 11 provided trial-level data.
In the 5 studies contributing patient data, women taking calcium supplements had an increased incidence of MI (hazard ratio [HR]=1.31; 95% confidence interval [CI], 1.02-1.67; P=.035) with an NNH of 69 over 5 years of calcium supplementation. The trial-level data, from 11 trials with 11,921 patients, also showed an increased incidence of MI in women taking calcium (relative risk [RR]=1.27; 95% CI, 1.01-1.59; P=.038). Neither the patient data nor the trial-level data demonstrated a significant increase in strokes.
Limitations of this meta-analysis include the fact that none of the trials was designed to address the risk of cardiovascular disease; in addition, some studies assessed outcomes by patient self-report, raising the possibility of information bias.
Some studies also show an increased stroke risk
The Women’s Health Initiative (WHI) study initially reported no increase in cardiovascular risk among women who received calcium and vitamin D supplements, but it didn’t take into account whether women were already taking calcium or vitamin D at the time of randomization.2 Re-analysis of the 16,718 women (mean age 62.9 years) randomized to calcium and vitamin D and not taking calcium supplements before the study found a statistically significant increase in the risk of MI or revascularization (HR=1.16; 95% CI, 1.01-1.34; P=.04).3
A meta-analysis of these findings and 2 additional RCTs (88% of subjects were female) comparing calcium and vitamin D supplementation with placebo found an increased risk of MI or stroke (RR=1.16; 95% CI, 1.02-1.32; P=.02).
Another meta-analysis that examined the WHI data and 5 placebo-controlled studies of calcium or calcium and vitamin D supplementation (82% of subjects were female) found an increased risk of MI, with NNHs over 5 years of 240 for MI (RR=1.26; 95% CI, 1.07-1.47; P=.005), 283 for stroke (RR=1.19; 95% CI, 1.02-1.39; P=.03), and 178 for the composite of MI or stroke (RR=1.17; 95% CI, 1.05-1.31; P=.005).3 The number needed to treat with calcium (with or without vitamin D) for 5 years to prevent one fracture was 302. The conclusions of this study were limited by post hoc and subgroup analyses.4
These studies did not address dietary sources rich in calcium. Dietary calcium results in lower peak serum levels than supplementary calcium, with less potential for adverse effects.3
Supplemental, but not dietary, calcium raises the risk of kidney stones
To assess the risk of renal calculi, the WHI randomized 36,282 postmenopausal women to calcium with vitamin D or placebo. Calcium and vitamin D increased the risk of renal calculi (HR=1.17; 95% CI, 1.02-1.34), with an NNH of 272 over 7 years.5
In a prospective cohort study of 91,731 women with 12-year follow-up, supplementary calcium was associated with an increased risk of kidney stone formation (RR=1.2; 95% CI, 1.02-1.41), whereas high dietary calcium was linked to a lower risk.6
Recommendations
The Institute of Medicine’s (IOM’s) recommended dietary allowance for calcium from diet plus supplements is 1000 mg a day for women until 50 years of age and no more than 1200 mg a day for women older than 50 years. The IOM advocates a maximum calcium intake of 2000 mg a day for women in both age groups because of the increased risk of kidney stones.7
1. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.-
2. Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation. 2007;115:846-854.
3. Bolland M, Grey A, Avenell A, et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.-
4. Abrahamsen B, Sahota O. Do calcium plus vitamin D supplements increase cardiovascular risk? BMJ. 2011;342:d2080.-
5. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683.
6. Curhan GC, Willett WC, Speizer FE, et al. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997;126:497-504.
7. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Report brief, November 2010. Washington, DC: Institute of Medicine; 2001. Available at: www.iom.edu/~/ media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20 Calcium%202010%20Report%20Brief.pdf. Access September 14, 2012.
Yes, according to studies with some limitations. Calcium supplements with or without vitamin D increase the risk of myocardial infarction (MI), with numbers needed to harm (NNH) over 5 years of 69 to 240 (strength of recommendation [SOR]: B, meta-analyses of randomized controlled trials [RCTs] that evaluated a predominantly older female population and were limited by study designs).
Calcium supplements with or without vitamin D may increase the risk of stroke, with an NNH over 5 years of 283 (SOR: B, meta-analyses of RCTs).
Calcium supplementation, but not a diet rich in calcium, also increases the risk of renal calculi, with an NNH over 7 years of 272 (SOR: B, RCT and a cohort study, which also evaluated a predominantly older female population).
Evidence summary
A meta-analysis of 11 randomized, double-blinded placebo-controlled studies assessed the relationship between calcium supplements and the risk of cardiovascular events.1 A total of 20,071 predominantly female patients (83%) with a mean age of 72 years (range, 51-77 years) received ≥500 mg elemental calcium per day for at least 1 year. Median follow-up was 3.6 to 4 years. Five studies provided individual patient data and all 11 provided trial-level data.
In the 5 studies contributing patient data, women taking calcium supplements had an increased incidence of MI (hazard ratio [HR]=1.31; 95% confidence interval [CI], 1.02-1.67; P=.035) with an NNH of 69 over 5 years of calcium supplementation. The trial-level data, from 11 trials with 11,921 patients, also showed an increased incidence of MI in women taking calcium (relative risk [RR]=1.27; 95% CI, 1.01-1.59; P=.038). Neither the patient data nor the trial-level data demonstrated a significant increase in strokes.
Limitations of this meta-analysis include the fact that none of the trials was designed to address the risk of cardiovascular disease; in addition, some studies assessed outcomes by patient self-report, raising the possibility of information bias.
Some studies also show an increased stroke risk
The Women’s Health Initiative (WHI) study initially reported no increase in cardiovascular risk among women who received calcium and vitamin D supplements, but it didn’t take into account whether women were already taking calcium or vitamin D at the time of randomization.2 Re-analysis of the 16,718 women (mean age 62.9 years) randomized to calcium and vitamin D and not taking calcium supplements before the study found a statistically significant increase in the risk of MI or revascularization (HR=1.16; 95% CI, 1.01-1.34; P=.04).3
A meta-analysis of these findings and 2 additional RCTs (88% of subjects were female) comparing calcium and vitamin D supplementation with placebo found an increased risk of MI or stroke (RR=1.16; 95% CI, 1.02-1.32; P=.02).
Another meta-analysis that examined the WHI data and 5 placebo-controlled studies of calcium or calcium and vitamin D supplementation (82% of subjects were female) found an increased risk of MI, with NNHs over 5 years of 240 for MI (RR=1.26; 95% CI, 1.07-1.47; P=.005), 283 for stroke (RR=1.19; 95% CI, 1.02-1.39; P=.03), and 178 for the composite of MI or stroke (RR=1.17; 95% CI, 1.05-1.31; P=.005).3 The number needed to treat with calcium (with or without vitamin D) for 5 years to prevent one fracture was 302. The conclusions of this study were limited by post hoc and subgroup analyses.4
These studies did not address dietary sources rich in calcium. Dietary calcium results in lower peak serum levels than supplementary calcium, with less potential for adverse effects.3
Supplemental, but not dietary, calcium raises the risk of kidney stones
To assess the risk of renal calculi, the WHI randomized 36,282 postmenopausal women to calcium with vitamin D or placebo. Calcium and vitamin D increased the risk of renal calculi (HR=1.17; 95% CI, 1.02-1.34), with an NNH of 272 over 7 years.5
In a prospective cohort study of 91,731 women with 12-year follow-up, supplementary calcium was associated with an increased risk of kidney stone formation (RR=1.2; 95% CI, 1.02-1.41), whereas high dietary calcium was linked to a lower risk.6
Recommendations
The Institute of Medicine’s (IOM’s) recommended dietary allowance for calcium from diet plus supplements is 1000 mg a day for women until 50 years of age and no more than 1200 mg a day for women older than 50 years. The IOM advocates a maximum calcium intake of 2000 mg a day for women in both age groups because of the increased risk of kidney stones.7
Yes, according to studies with some limitations. Calcium supplements with or without vitamin D increase the risk of myocardial infarction (MI), with numbers needed to harm (NNH) over 5 years of 69 to 240 (strength of recommendation [SOR]: B, meta-analyses of randomized controlled trials [RCTs] that evaluated a predominantly older female population and were limited by study designs).
Calcium supplements with or without vitamin D may increase the risk of stroke, with an NNH over 5 years of 283 (SOR: B, meta-analyses of RCTs).
Calcium supplementation, but not a diet rich in calcium, also increases the risk of renal calculi, with an NNH over 7 years of 272 (SOR: B, RCT and a cohort study, which also evaluated a predominantly older female population).
Evidence summary
A meta-analysis of 11 randomized, double-blinded placebo-controlled studies assessed the relationship between calcium supplements and the risk of cardiovascular events.1 A total of 20,071 predominantly female patients (83%) with a mean age of 72 years (range, 51-77 years) received ≥500 mg elemental calcium per day for at least 1 year. Median follow-up was 3.6 to 4 years. Five studies provided individual patient data and all 11 provided trial-level data.
In the 5 studies contributing patient data, women taking calcium supplements had an increased incidence of MI (hazard ratio [HR]=1.31; 95% confidence interval [CI], 1.02-1.67; P=.035) with an NNH of 69 over 5 years of calcium supplementation. The trial-level data, from 11 trials with 11,921 patients, also showed an increased incidence of MI in women taking calcium (relative risk [RR]=1.27; 95% CI, 1.01-1.59; P=.038). Neither the patient data nor the trial-level data demonstrated a significant increase in strokes.
Limitations of this meta-analysis include the fact that none of the trials was designed to address the risk of cardiovascular disease; in addition, some studies assessed outcomes by patient self-report, raising the possibility of information bias.
Some studies also show an increased stroke risk
The Women’s Health Initiative (WHI) study initially reported no increase in cardiovascular risk among women who received calcium and vitamin D supplements, but it didn’t take into account whether women were already taking calcium or vitamin D at the time of randomization.2 Re-analysis of the 16,718 women (mean age 62.9 years) randomized to calcium and vitamin D and not taking calcium supplements before the study found a statistically significant increase in the risk of MI or revascularization (HR=1.16; 95% CI, 1.01-1.34; P=.04).3
A meta-analysis of these findings and 2 additional RCTs (88% of subjects were female) comparing calcium and vitamin D supplementation with placebo found an increased risk of MI or stroke (RR=1.16; 95% CI, 1.02-1.32; P=.02).
Another meta-analysis that examined the WHI data and 5 placebo-controlled studies of calcium or calcium and vitamin D supplementation (82% of subjects were female) found an increased risk of MI, with NNHs over 5 years of 240 for MI (RR=1.26; 95% CI, 1.07-1.47; P=.005), 283 for stroke (RR=1.19; 95% CI, 1.02-1.39; P=.03), and 178 for the composite of MI or stroke (RR=1.17; 95% CI, 1.05-1.31; P=.005).3 The number needed to treat with calcium (with or without vitamin D) for 5 years to prevent one fracture was 302. The conclusions of this study were limited by post hoc and subgroup analyses.4
These studies did not address dietary sources rich in calcium. Dietary calcium results in lower peak serum levels than supplementary calcium, with less potential for adverse effects.3
Supplemental, but not dietary, calcium raises the risk of kidney stones
To assess the risk of renal calculi, the WHI randomized 36,282 postmenopausal women to calcium with vitamin D or placebo. Calcium and vitamin D increased the risk of renal calculi (HR=1.17; 95% CI, 1.02-1.34), with an NNH of 272 over 7 years.5
In a prospective cohort study of 91,731 women with 12-year follow-up, supplementary calcium was associated with an increased risk of kidney stone formation (RR=1.2; 95% CI, 1.02-1.41), whereas high dietary calcium was linked to a lower risk.6
Recommendations
The Institute of Medicine’s (IOM’s) recommended dietary allowance for calcium from diet plus supplements is 1000 mg a day for women until 50 years of age and no more than 1200 mg a day for women older than 50 years. The IOM advocates a maximum calcium intake of 2000 mg a day for women in both age groups because of the increased risk of kidney stones.7
1. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.-
2. Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation. 2007;115:846-854.
3. Bolland M, Grey A, Avenell A, et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.-
4. Abrahamsen B, Sahota O. Do calcium plus vitamin D supplements increase cardiovascular risk? BMJ. 2011;342:d2080.-
5. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683.
6. Curhan GC, Willett WC, Speizer FE, et al. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997;126:497-504.
7. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Report brief, November 2010. Washington, DC: Institute of Medicine; 2001. Available at: www.iom.edu/~/ media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20 Calcium%202010%20Report%20Brief.pdf. Access September 14, 2012.
1. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.-
2. Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation. 2007;115:846-854.
3. Bolland M, Grey A, Avenell A, et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.-
4. Abrahamsen B, Sahota O. Do calcium plus vitamin D supplements increase cardiovascular risk? BMJ. 2011;342:d2080.-
5. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683.
6. Curhan GC, Willett WC, Speizer FE, et al. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997;126:497-504.
7. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Report brief, November 2010. Washington, DC: Institute of Medicine; 2001. Available at: www.iom.edu/~/ media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20 Calcium%202010%20Report%20Brief.pdf. Access September 14, 2012.
Evidence-based answers from the Family Physicians Inquiries Network
What is the diagnostic approach to a patient with leg cramps?
Leg cramps are very common (strength of recommendation [SOR]: C, case series), and most cases have no detectable cause (SOR: C, expert opinion). Arterial vascular disease and neurological diseases are more prevalent among male patients with leg cramps (SOR: C, small case series).
History and physical should focus on detecting precipitating factors for iron deficiency anemia (gastrointestinal bleeding, frequent blood donations, menorrhagia), electrolyte imbalance (renal disease, fluid losses), endocrine disorders (thyroid, Addison’s disease), neuromuscular disorders (neuropathies and myopathies), and medication use (antidepressants and diuretics). Laboratory testing is guided by the history and physical and may include ferritin, electrolytes, blood sugar, magnesium, zinc, creatinine, blood urea nitrogen, liver function test, and thyroid-stimulating hormone (SOR: C, expert opinion and nonsystematic review).
If a thorough search reveals no cause, keep your patient educated
Timothy E. Huber, MD, LCDR, MC, USNR
Department of Family Medicine, Naval Hospital Camp Pendleton
Leg cramps are a common nonspecific complaint that can have a significant impact on quality of life. The literature on the potential causes and treatments of leg cramps is limited to small studies and expert opinion. This leaves the clinician on the spot with their own knowledge of medicine and their relationship with the patient. A careful history and physical may suggest some avenues of inquiry while simultaneously excluding other serious causes. Lab and radiology testing can be useful when used in a thoughtful manner. A confusing clinical picture has frustrated me when I was too aggressive with studies. If a thorough search reveals no specific cause, I attempt to keep my patient educated regarding possible complications while keeping my differential diagnosis broad when addressing this problem in future visits.
Evidence summary
More than two thirds of people aged >50 years have experienced leg cramps.1 Though leg cramps are common, little is known about their actual causation.2,3
A small, retrospective chart review, limited to male patients, identified an association of vascular and neurologic diseases among patients taking quinine, presumably for leg cramps.2 Although commonly idiopathic, leg cramps are sometimes associated with various disorders including endocrine, metabolic, occupational, structural, neuromuscular, vascular, and congenital disorders, as well as toxin- and drug-related causes (TABLE).4,5 All reviews suggest that the best diagnostic approach to leg cramps is a thorough history, and careful physical and neurological examination.1,3,4 The health care provider should clarify the onset and duration of leg cramps, any precipitating activity, and factors that provide relief. A detailed history should focus on precipitating factors for iron deficiency anemia (gastro-intestinal bleeding, frequent blood donations, menorrhagia), a history of renal disease (especially end-stage renal failure) and medication use (antidepressants and diuretics).
The physical examination should include a search for obvious physical signs of symptoms noted in the history.6 Neurological examination can exclude most disorders that simulate leg cramps such as contractures, dystonia, myalgia and peripheral neuropathy.1,2,4
The choice of laboratory investigations such as ferritin, electrolytes, blood sugar, magnesium, zinc, creatinine, blood urea nitrogen, liver function test, and thyroid function test are largely governed by the findings from the history and physical examination.1 Though neurophysiological research shows that true muscle cramps are caused by explosive hyperactivity of motor nerves, using diagnostic tools such as electromyography, muscle biopsy, and muscle enzymes are seldom needed.7
Because of the lack of well-designed, randomized controlled studies, this diagnostic approach is based on nonsystematic reviews, and may differ for individuals based on history and clinical examination.
TABLE
Possible causes of leg cramps
| CATEGORY | DISEASES |
|---|---|
| Congenital | McArdle’s disease, “Glycogen storage disease,” autosomal dominant cramping disease |
| Endocrine disorder | Thyroid disease, diabetes mellitus, Addison’s disease |
| Fluid and electrolyte disorder | Hypocalcemia, hyponatremia, hypomagnesemia, hypokalemia, hyperkalemia, chronic diarrhea, hemodialysis |
| Neuromuscular | Nerve root compression, motor neuron disease, mononeuropathies, polyneuropathies, dystonias |
| Drugs | Calcium channel blockers (nifedipine), diuretics, phenothiazines, fibrates, selective estrogen receptive modulators, ethanol, morphine withdrawal |
| Vascular | Peripheral vascular disease |
| Toxins | Lead or strychnine poisoning, spider bites |
| Occupational | Focal dystonias (in writers, athletes, miners, and musicians) |
| Others | Diarrhea, liver cirrhosis, chronic alcoholism, sarcoidosis |
| Hematological | Iron deficiency anemia |
| Modified from Kanaan and Sawaya, Geriatrics2001.3 | |
Recommendations from others
UpToDate states, “a careful history and examination can exclude the majority of disorders in the differential diagnosis” of leg cramps.7
1. Hall AJ. Cramp and salt balance in ordinary life. Lancet 1947;3:231-233.
2. Haskell SG, Fiebach NH. Clinical epidemiology of nocturnal leg cramps in male veterans. Am J Med Sci 1997;313:210-214.
3. Kanaan N, Sawaya R. Nocturnal leg cramps. Clinically mysterious and painful—but manageable. Geriatrics 2001;56:34, 39-42.
4. Butler JV, Mulkerrin EC, O’Keeffe ST. Nocturnal leg cramps in older people. Postgrad Med J 2002;78:596-598
5. Riley JD, Antony SJ. Leg cramps: differential diagnosis and management. Am Fam Physician 1995;52:1794-1798.
6. Jansen PH, Joosten EM, Vingerhoets HM. Clinical diagnosis of muscle cramp and muscular cramp syndrome. Eur Arch Psychiatry Clin Neurosci 1991;241:98-101.
7. Sheon RP. Nocturnal leg cramps, night starts, and nocturnal myoclonus. UpToDate, version 13.1. Wellesley, Mass: UpToDate. Last updated December 2004.
Leg cramps are very common (strength of recommendation [SOR]: C, case series), and most cases have no detectable cause (SOR: C, expert opinion). Arterial vascular disease and neurological diseases are more prevalent among male patients with leg cramps (SOR: C, small case series).
History and physical should focus on detecting precipitating factors for iron deficiency anemia (gastrointestinal bleeding, frequent blood donations, menorrhagia), electrolyte imbalance (renal disease, fluid losses), endocrine disorders (thyroid, Addison’s disease), neuromuscular disorders (neuropathies and myopathies), and medication use (antidepressants and diuretics). Laboratory testing is guided by the history and physical and may include ferritin, electrolytes, blood sugar, magnesium, zinc, creatinine, blood urea nitrogen, liver function test, and thyroid-stimulating hormone (SOR: C, expert opinion and nonsystematic review).
If a thorough search reveals no cause, keep your patient educated
Timothy E. Huber, MD, LCDR, MC, USNR
Department of Family Medicine, Naval Hospital Camp Pendleton
Leg cramps are a common nonspecific complaint that can have a significant impact on quality of life. The literature on the potential causes and treatments of leg cramps is limited to small studies and expert opinion. This leaves the clinician on the spot with their own knowledge of medicine and their relationship with the patient. A careful history and physical may suggest some avenues of inquiry while simultaneously excluding other serious causes. Lab and radiology testing can be useful when used in a thoughtful manner. A confusing clinical picture has frustrated me when I was too aggressive with studies. If a thorough search reveals no specific cause, I attempt to keep my patient educated regarding possible complications while keeping my differential diagnosis broad when addressing this problem in future visits.
Evidence summary
More than two thirds of people aged >50 years have experienced leg cramps.1 Though leg cramps are common, little is known about their actual causation.2,3
A small, retrospective chart review, limited to male patients, identified an association of vascular and neurologic diseases among patients taking quinine, presumably for leg cramps.2 Although commonly idiopathic, leg cramps are sometimes associated with various disorders including endocrine, metabolic, occupational, structural, neuromuscular, vascular, and congenital disorders, as well as toxin- and drug-related causes (TABLE).4,5 All reviews suggest that the best diagnostic approach to leg cramps is a thorough history, and careful physical and neurological examination.1,3,4 The health care provider should clarify the onset and duration of leg cramps, any precipitating activity, and factors that provide relief. A detailed history should focus on precipitating factors for iron deficiency anemia (gastro-intestinal bleeding, frequent blood donations, menorrhagia), a history of renal disease (especially end-stage renal failure) and medication use (antidepressants and diuretics).
The physical examination should include a search for obvious physical signs of symptoms noted in the history.6 Neurological examination can exclude most disorders that simulate leg cramps such as contractures, dystonia, myalgia and peripheral neuropathy.1,2,4
The choice of laboratory investigations such as ferritin, electrolytes, blood sugar, magnesium, zinc, creatinine, blood urea nitrogen, liver function test, and thyroid function test are largely governed by the findings from the history and physical examination.1 Though neurophysiological research shows that true muscle cramps are caused by explosive hyperactivity of motor nerves, using diagnostic tools such as electromyography, muscle biopsy, and muscle enzymes are seldom needed.7
Because of the lack of well-designed, randomized controlled studies, this diagnostic approach is based on nonsystematic reviews, and may differ for individuals based on history and clinical examination.
TABLE
Possible causes of leg cramps
| CATEGORY | DISEASES |
|---|---|
| Congenital | McArdle’s disease, “Glycogen storage disease,” autosomal dominant cramping disease |
| Endocrine disorder | Thyroid disease, diabetes mellitus, Addison’s disease |
| Fluid and electrolyte disorder | Hypocalcemia, hyponatremia, hypomagnesemia, hypokalemia, hyperkalemia, chronic diarrhea, hemodialysis |
| Neuromuscular | Nerve root compression, motor neuron disease, mononeuropathies, polyneuropathies, dystonias |
| Drugs | Calcium channel blockers (nifedipine), diuretics, phenothiazines, fibrates, selective estrogen receptive modulators, ethanol, morphine withdrawal |
| Vascular | Peripheral vascular disease |
| Toxins | Lead or strychnine poisoning, spider bites |
| Occupational | Focal dystonias (in writers, athletes, miners, and musicians) |
| Others | Diarrhea, liver cirrhosis, chronic alcoholism, sarcoidosis |
| Hematological | Iron deficiency anemia |
| Modified from Kanaan and Sawaya, Geriatrics2001.3 | |
Recommendations from others
UpToDate states, “a careful history and examination can exclude the majority of disorders in the differential diagnosis” of leg cramps.7
Leg cramps are very common (strength of recommendation [SOR]: C, case series), and most cases have no detectable cause (SOR: C, expert opinion). Arterial vascular disease and neurological diseases are more prevalent among male patients with leg cramps (SOR: C, small case series).
History and physical should focus on detecting precipitating factors for iron deficiency anemia (gastrointestinal bleeding, frequent blood donations, menorrhagia), electrolyte imbalance (renal disease, fluid losses), endocrine disorders (thyroid, Addison’s disease), neuromuscular disorders (neuropathies and myopathies), and medication use (antidepressants and diuretics). Laboratory testing is guided by the history and physical and may include ferritin, electrolytes, blood sugar, magnesium, zinc, creatinine, blood urea nitrogen, liver function test, and thyroid-stimulating hormone (SOR: C, expert opinion and nonsystematic review).
If a thorough search reveals no cause, keep your patient educated
Timothy E. Huber, MD, LCDR, MC, USNR
Department of Family Medicine, Naval Hospital Camp Pendleton
Leg cramps are a common nonspecific complaint that can have a significant impact on quality of life. The literature on the potential causes and treatments of leg cramps is limited to small studies and expert opinion. This leaves the clinician on the spot with their own knowledge of medicine and their relationship with the patient. A careful history and physical may suggest some avenues of inquiry while simultaneously excluding other serious causes. Lab and radiology testing can be useful when used in a thoughtful manner. A confusing clinical picture has frustrated me when I was too aggressive with studies. If a thorough search reveals no specific cause, I attempt to keep my patient educated regarding possible complications while keeping my differential diagnosis broad when addressing this problem in future visits.
Evidence summary
More than two thirds of people aged >50 years have experienced leg cramps.1 Though leg cramps are common, little is known about their actual causation.2,3
A small, retrospective chart review, limited to male patients, identified an association of vascular and neurologic diseases among patients taking quinine, presumably for leg cramps.2 Although commonly idiopathic, leg cramps are sometimes associated with various disorders including endocrine, metabolic, occupational, structural, neuromuscular, vascular, and congenital disorders, as well as toxin- and drug-related causes (TABLE).4,5 All reviews suggest that the best diagnostic approach to leg cramps is a thorough history, and careful physical and neurological examination.1,3,4 The health care provider should clarify the onset and duration of leg cramps, any precipitating activity, and factors that provide relief. A detailed history should focus on precipitating factors for iron deficiency anemia (gastro-intestinal bleeding, frequent blood donations, menorrhagia), a history of renal disease (especially end-stage renal failure) and medication use (antidepressants and diuretics).
The physical examination should include a search for obvious physical signs of symptoms noted in the history.6 Neurological examination can exclude most disorders that simulate leg cramps such as contractures, dystonia, myalgia and peripheral neuropathy.1,2,4
The choice of laboratory investigations such as ferritin, electrolytes, blood sugar, magnesium, zinc, creatinine, blood urea nitrogen, liver function test, and thyroid function test are largely governed by the findings from the history and physical examination.1 Though neurophysiological research shows that true muscle cramps are caused by explosive hyperactivity of motor nerves, using diagnostic tools such as electromyography, muscle biopsy, and muscle enzymes are seldom needed.7
Because of the lack of well-designed, randomized controlled studies, this diagnostic approach is based on nonsystematic reviews, and may differ for individuals based on history and clinical examination.
TABLE
Possible causes of leg cramps
| CATEGORY | DISEASES |
|---|---|
| Congenital | McArdle’s disease, “Glycogen storage disease,” autosomal dominant cramping disease |
| Endocrine disorder | Thyroid disease, diabetes mellitus, Addison’s disease |
| Fluid and electrolyte disorder | Hypocalcemia, hyponatremia, hypomagnesemia, hypokalemia, hyperkalemia, chronic diarrhea, hemodialysis |
| Neuromuscular | Nerve root compression, motor neuron disease, mononeuropathies, polyneuropathies, dystonias |
| Drugs | Calcium channel blockers (nifedipine), diuretics, phenothiazines, fibrates, selective estrogen receptive modulators, ethanol, morphine withdrawal |
| Vascular | Peripheral vascular disease |
| Toxins | Lead or strychnine poisoning, spider bites |
| Occupational | Focal dystonias (in writers, athletes, miners, and musicians) |
| Others | Diarrhea, liver cirrhosis, chronic alcoholism, sarcoidosis |
| Hematological | Iron deficiency anemia |
| Modified from Kanaan and Sawaya, Geriatrics2001.3 | |
Recommendations from others
UpToDate states, “a careful history and examination can exclude the majority of disorders in the differential diagnosis” of leg cramps.7
1. Hall AJ. Cramp and salt balance in ordinary life. Lancet 1947;3:231-233.
2. Haskell SG, Fiebach NH. Clinical epidemiology of nocturnal leg cramps in male veterans. Am J Med Sci 1997;313:210-214.
3. Kanaan N, Sawaya R. Nocturnal leg cramps. Clinically mysterious and painful—but manageable. Geriatrics 2001;56:34, 39-42.
4. Butler JV, Mulkerrin EC, O’Keeffe ST. Nocturnal leg cramps in older people. Postgrad Med J 2002;78:596-598
5. Riley JD, Antony SJ. Leg cramps: differential diagnosis and management. Am Fam Physician 1995;52:1794-1798.
6. Jansen PH, Joosten EM, Vingerhoets HM. Clinical diagnosis of muscle cramp and muscular cramp syndrome. Eur Arch Psychiatry Clin Neurosci 1991;241:98-101.
7. Sheon RP. Nocturnal leg cramps, night starts, and nocturnal myoclonus. UpToDate, version 13.1. Wellesley, Mass: UpToDate. Last updated December 2004.
1. Hall AJ. Cramp and salt balance in ordinary life. Lancet 1947;3:231-233.
2. Haskell SG, Fiebach NH. Clinical epidemiology of nocturnal leg cramps in male veterans. Am J Med Sci 1997;313:210-214.
3. Kanaan N, Sawaya R. Nocturnal leg cramps. Clinically mysterious and painful—but manageable. Geriatrics 2001;56:34, 39-42.
4. Butler JV, Mulkerrin EC, O’Keeffe ST. Nocturnal leg cramps in older people. Postgrad Med J 2002;78:596-598
5. Riley JD, Antony SJ. Leg cramps: differential diagnosis and management. Am Fam Physician 1995;52:1794-1798.
6. Jansen PH, Joosten EM, Vingerhoets HM. Clinical diagnosis of muscle cramp and muscular cramp syndrome. Eur Arch Psychiatry Clin Neurosci 1991;241:98-101.
7. Sheon RP. Nocturnal leg cramps, night starts, and nocturnal myoclonus. UpToDate, version 13.1. Wellesley, Mass: UpToDate. Last updated December 2004.
Evidence-based answers from the Family Physicians Inquiries Network