Do calcium plus vitamin D supplements increase cardiovascular risk?

Calcium supplements are widely used in the prevention of osteoporosis and as an adjunct to specific osteoporosis treatment but have been associated with a possible increase in the risk of adverse cardiovascular outcomes.1 In the linked study (doi:10.1136/bmj.d2040),2 Bolland and colleagues investigate the effects of personal use of calcium supplements on cardiovascular risk in the Women’s Health Initiative Calcium/Vitamin D (WHI CaD) study and update their meta-analysis of calcium supplements and cardiovascular risk.3 This new analysis is particularly relevant because it includes calcium supplements given with vitamin D.

The meta-analysis extends one previously undertaken by the same group in which calcium supplementation was associated with a significantly increased risk of stroke and myocardial infarction.1 That study was followed by a lively debate on the BMJ website and elsewhere, when it was criticised for reporting individual outcomes when the global end point was not significant, for counting events rather than people with events, and for building on studies that were not designed for cardiovascular outcomes and adjudicated accordingly.

In the current study Bolland and colleagues explore the possibility that findings in the WHI study may have been masked by the widespread use of personal calcium supplements.2 In 16 718 women, 46% of whom were not taking personal calcium supplements at randomisation, the hazard ratios for cardiovascular events with calcium and vitamin D supplements ranged from 1.13 to 1.22 (P=0.05 for clinical myocardial infarction or stroke, P=0.04 for clinical myocardial infarction or revascularisation), whereas in women taking personal calcium supplements, calcium and vitamin D supplements did not alter cardiovascular risk. In the meta-analyses of placebo controlled trials of calcium supplements or calcium plus vitamin D supplements, complete trial level data were available for 28 072 participants from eight trials of calcium supplements and WHI CaD participants not taking personal calcium supplements. One thousand three hundred and eighty four people had an incident myocardial infarction or stroke. Calcium supplements and calcium plus vitamin D supplements increased the risk of myocardial infarction (relative risk 1.24, 95% confidence interval 1.07 to 1.45; P=0.004) and the composite of myocardial infarction or stroke (1.15, 1.03 to 1.27; P=0.009).

Although this clearly suggests that calcium and vitamin D supplements increase the risk of cardiovascular events, there are caveats, as the authors discuss. Although for the WHI study as a whole, randomisation can be assumed to have been equal across the two arms in terms of confounders, measured and unmeasured, this may not have been true for the additional strata created in the post hoc analysis. This could have contributed to the surprising findings of a 16% increased risk of clinical myocardial infarction or stroke in women allocated to calcium plus vitamin D supplements who did not use personal supplements and a 16% reduction in mortality in women given the same intervention who did use such supplements. The decision to focus on the WHI participants who did not use calcium supplements is reasonable given that the effects would be difficult to discern if both study arms had access to what was intended to be a randomised intervention. Unfortunately, although it is straightforward to remove those who were taking their own supplements from the cohort when they make up uneven parts of the randomised arms, interpreting the results is difficult because of the loss of equal randomisation.

The findings of extended survival are interesting, although they were significant only in participants who had elected to take calcium supplements before randomisation. To complicate the interpretation further, a recent meta-analysis from the group showed that the increased risk of cardiovascular events with calcium supplements was present only in subjects with baseline dietary calcium intake above the median. It may seem counterintuitive that this study identifies one group who do not take supplements at baseline as being at increased risk of myocardial infarction if allocated to calcium and vitamin D supplements, whereas their previous study identified the group with adequate dietary calcium intake as the high risk group.

What are the implications of current evidence in clinical practice? The evidence for using calcium and vitamin D supplements as an adjunct to bisphosphonates in the treatment of osteoporosis is reassuring, both in terms of cardiovascular safety4 5 and improved survival.6 7 8 In a retrospective cohort of 23 615 patients, calcium plus vitamin D or vitamin D supplements used in combination with anti-osteoporotic drugs reduced mortality in men by 28% (hazard ratio 0.72, 0.50 to 1.03) and women by 38% (0.62, 0.50 to 0.76).7 Because of limitations in the cardiovascular adjudication or study design of the underlying trials, it is not possible to provide reassurance that calcium supplements given with vitamin D do not cause adverse cardiovascular events or to link them with certainty to increased cardiovascular risk. Clearly further studies are needed and the debate remains ongoing.