The first evidence for the adverse cardiovascular effects of calcium supplements in non-uraemic patients came from our five-year randomised controlled trial of calcium monotherapy in 1471 healthy postmenopausal women. There were increases in cardiovascular event rates in the women allocated to calcium (23.3 vs 16.3 events/1000 patient-years, p=0.043), but the size of the study and number of cardiovascular events meant that the results were not definitive.14
Further randomised controlled trials of calcium to address the concern were not practical as the primary endpoint would be one of harm. We therefore undertook a meta-analysis of unpublished cardiovascular data from randomised controlled trials. The lead authors of five trials provided patient-level data, and trial-level data on cardiovascular events were available for 11 trials. Meta-analyses showed that calcium supplements increased the risk of myocardial infarction by approximately 30%. There were also smaller, statistically non-significant, increases in mortality, the risk of stroke and in a composite cardiovascular endpoint.15
Co-administered calcium and vitamin D
The findings of our meta-analysis related to calcium supplements used as monotherapy, whereas the use of calcium with vitamin D is more common in clinical practice. The Women’s Health Initiative calcium and vitamin D trial, a seven-year randomised controlled trial in more than 36 000 postmenopausal women, had previously reported that calcium and vitamin D did not alter cardiovascular risk.16 An unusual feature of this trial was that personal, non-protocol use of the trial medications was permitted. The majority of the participants were taking their own calcium supplements at randomisation. Widespread personal use of calcium in the trial might have obscured an adverse effect of calcium supplements on cardiovascular risk.
We re-analysed the data from the trial comparing the effects of calcium and vitamin D in non-users and users of personal calcium. In women who were not taking their own calcium at baseline but were allocated to take calcium and vitamin D in the trial, there were increases in the risk of cardiovascular events of similar magnitude to those in the previous meta-analysis of calcium monotherapy. However, in women who were already taking personal calcium supplements, taking calcium with vitamin D in the trial had no effect on cardiovascular risk.17 The results suggested that the widespread use of personal calcium supplements in the Women’s Health Initiative trial had obscured the adverse cardiovascular effects of calcium with vitamin D.
We then pooled the data from the women not using personal calcium supplements in the Women’s Health Initiative trial with all other randomised controlled trials of calcium with vitamin D for which cardiovascular data were available. In this analysis, calcium with vitamin D increased the risk of myocardial infarction by 21% and stroke by 20%.17
Calcium with or without vitamin D
We pooled our two meta-analyses of calcium monotherapy and calcium with vitamin D, to determine the effect of calcium with or without vitamin D on cardiovascular risk. Calcium or calcium with vitamin D increased the risk of myocardial infarction by 25% and stroke by 15–19%. Based on these meta-analyses, in 1000 people treated for five years, calcium or calcium with vitamin D would cause six heart attacks or strokes and prevent three fractures.17
These findings are consistent with studies of patients with renal impairment, in whom calcium supplements accelerate vascular calcification and increase mortality, in both dialysis and pre-dialysis populations.18-20 A more recent randomised controlled trial of sunlight exposure to raise vitamin D concentrations in Australian nursing home residents also found that the addition of calcium supplements to sunlight exposure was associated with increases in all-cause and cardiovascular mortality. 21,22
Given the widespread use of calcium and its presumed safety, it is unsurprising that these unexpected findings have not been universally accepted, although few substantive criticisms have been raised.23 Misclassification of other events as heart attacks was suggested as a possible explanation, but the increased risk is consistent whether events were self-reported, obtained from hospital discharges, death certificates or independently adjudicated. Others have suggested that the results are not valid because the trials were not primarily designed to assess cardiovascular events. This reasoning would make it impossible to ever detect unexpected adverse events. Others have suggested that more evidence is required before practice should be changed. However, there are no ongoing trials large enough to influence the results from the current meta-analyses, future trials are unlikely given the potential for harm from participating, and results of observational studies will not outweigh the Level 1 evidence from a systematic review of randomised controlled trials. Decisions about the use of calcium supplements must therefore be based on these current data.
Mechanisms
A cause for the increased cardiovascular risk remains unclear. The consistency of the results for calcium monotherapy and calcium and vitamin D suggests that the effect is caused by calcium supplements, and is not mitigated by the co-administration of vitamin D. One possible mechanism is that calcium supplements abruptly increase serum calcium.24 Higher serum calcium concentrations are associated with many measures of atherosclerosis such as carotid artery plaque thickness25 and aortic calcification.26 They are also associated with the incidence of myocardial infarction27-29 and mortality30 . It is possible that the rapid increases in serum calcium after taking a calcium supplement may alter vascular calcification and other pathophysiological processes occurring at the blood vessel surface.