Article date: October 2011
A research article1 in 2010 by Bolland and colleagues seemed to show that calcium supplements without coadministered vitamin D are associated with a modest increased risk of myocardial infarction (MI, hazard ratio [HR] 1.31 [95% CI 1.02–1.67]; p=0.035). Non-significant increases occurred in the incidence of stroke and death; the risk for the composite endpoint (MI, stroke, or sudden death) was of borderline significance (HR 1.18 [1.00–1.39], p=0.057).
The researchers have recently published2 a reanalysis of data from a large randomised controlled trial (the Women’s Health Initiative study—WHI), and a further meta-analysis of trials of calcium with or without vitamin D versus placebo.
In the reanalysis of the WHI trial of calcium plus vitamin D versus placebo, the risk of clinical MI was slightly increased in women not self-medicating with calcium supplements at baseline who were randomly assigned to calcium plus vitamin D (HR 1.22 [1.00–1.50]; p=0.054), but this was of borderline significance. There were 209 events of clinical MI in the calcium plus vitamin D group compared with 168 events in the placebo group (an incidence of 3.5 compared with 2.9 per 1000 patient-years). Overall, the reanalyses do not provide conclusive evidence of clinically significant harm, partly because all-cause mortality was not increased in this group (HR 0.99 [0.86–1.14]; p=0.89). Furthermore, for women in WHI who self-medicated with calcium supplements at baseline and who were randomly assigned to calcium plus vitamin D, all-cause mortality was significantly decreased compared with placebo (HR 0.84 [0.73–0.97]; p=0.01).
Inclusion of the WHI subgroup findings (women not self-medicating with calcium supplements at baseline only) in a new meta-analysis of trials of calcium plus vitamin D versus placebo resulted in a slightly lower and more precise risk estimate for MI and stroke associated with calcium plus vitamin D (relative risk 1.16 [95% CI 1.02–1.32], p=0.02). However, there was no increase in the risk of all-cause death.
The reanalysis was reviewed by the Commission on Human Medicines (CHM) and its expert advisors. There were concerns over methodology and data interpretation, and they advised that the data did not provide convincing evidence that calcium and vitamin D supplements were associated with an increased risk of cardiovascular events. They considered that any further research should be carefully evaluated and that it would be desirable to study separately the effects of calcium and vitamin D on cardiovascular risk.
Concerns over methodology and data interpretation included that, for the reanalysis, the increased risk of MI (or the composite of MI or stroke) in women not taking calcium supplements at baseline was only just significant and there was no increased risk in overall mortality in that group. Furthermore, for the new meta-analysis, concerns included: inclusion of trials with different endpoints; exclusion of more than half the participants in the WHI trial; a small, marginally significant increased risk of MI and stroke in the subgroup but not in the overall WHI trial; and multiple testing, which increases the risk of false-positive results. Finally, there may be alternative explanations for the findings, such as misclassification bias whereby upper gastrointestinal side effects (which are common with calcium supplements) are misclassified as symptoms of cardiac disease.
Advice for healthcare professionals:
- prescribers should consider the potential benefits and risks of using calcium and vitamin D for prevention of osteoporotic fractures on an individual basis in line with NICE guidance on drugs for the primary and secondary prevention of osteoporosis. Prescribers should consider offering these supplements to postmenopausal women who receive treatment for osteoporosis (eg, with bisphosphonates), unless they are confident that the patient has an adequate calcium intake and is vitamin D replete
- The National Osteoporosis Society advises that increasing dietary intake in those with low intakes of calcium and vitamin D is considered preferable to supplements. They also advise that supplementation may be warranted, but needs to be done with consideration based on dietary intake
BNF section 6.6 Drugs affecting bone metabolism—osteoporosis
Article citation: Drug Safety Update Oct 2011, vol 5 issue 3: H1.