In the Women’s Health Initiative Calcium/Vitamin D Supplementation (WHI CaD) Study personal use of calcium supplement at randomisation significantly influenced the effect of randomisation to calcium and vitamin D on the risk of cardiovascular events. In the entire WHI cohort, there were significant interactions between calcium and vitamin D and personal calcium supplement use for myocardial infarction and for stroke. In the 46% of the WHI CaD participants who were not taking personal calcium supplements at randomisation, the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22. By contrast, in the participants taking personal calcium supplements at randomisation, allocation to calcium and vitamin D did not alter cardiovascular risk. In women not taking personal calcium supplements at randomisation, the hazard ratios for clinical myocardial infarction (1.22) and stroke (1.17) were similar to those observed in our meta-analysis of trials of calcium monotherapy (1.31 and 1.20, respectively).2
By itself, this analysis of the WHI CaD Study data does not provide definitive evidence of an adverse effect of calcium and vitamin D on cardiovascular events. However, when these data are pooled with previously unpublished data from two other placebo controlled trials of calcium and vitamin D, there are consistent increases in the risk of myocardial infarction and stroke that are statistically significant and are of similar size to the risks observed with calcium supplements used without vitamin D. Further, when the results for calcium and vitamin D are taken together with those from trials of calcium used as monotherapy, they provide consistent evidence from 13 randomised, placebo controlled trials involving about 29
000 participants with about 1400 incident myocardial infarctions and strokes that calcium supplements with or without vitamin D increase the risk of cardiovascular events.
The size of this increase is modest, about 25%–30% for myocardial infarction and 15%–20% for stroke, but, because of the widespread use of calcium supplements either alone or with vitamin D, even small increases in cardiovascular disease incidence may translate to a substantial population burden of disease, particularly in older age groups. Furthermore, comparisons of the benefits of calcium on fracture prevention with the risk of cardiovascular events suggest that the risk to benefit profile is unfavourable: in our analysis, treating 1000 patients with calcium or calcium and vitamin D for five years would cause an additional six myocardial infarctions or strokes (number needed to harm of 178) and prevent only three fractures (number needed to treat of 302).
Limitations of study
The current analysis has some limitations. We used the publicly accessible, limited access dataset of the WHI clinical trials for these analyses, so the analysis is limited to the information available in this dataset. Several vascular end points are potentially evaluable; we pre-specified those which allowed the most accurate comparisons with previous analyses. Subgroup analysis raises several issues, including false positive results and over-interpretation of findings.20 21
To minimise these risks, we pre-specified the variable of interest (personal calcium supplement use) for this analysis before obtaining the WHI dataset, assessed its effect using interaction tests, and followed recommended approaches for subgroup analysis and interpretation.21 22
The hypothesis that the use of personal calcium supplements might interact with the calcium and vitamin D treatment effect in the WHI CaD Study was based on plausibility from our finding in trials of calcium monotherapy, and deviation from normal clinical trial practice (allowing trial participants free access to the intervention being studied) is unusual and has the potential to mask both adverse and beneficial effects.
We followed the approach of the WHI authors in not adjusting P values for multiple subgroup analyses, and instead estimated the likelihood of false positive tests,3
an approved approach for addressing multiplicity of statistical tests.23
Nine interaction tests were performed: if the effect of calcium and vitamin D was unrelated to personal calcium use and the end points were independent, the probability of at least one false positive interaction test is <40%.22
Confounding is a possible explanation of our findings as subgroup analysis may interfere with the balancing effects of randomisation on potential confounders. However, within each subgroup, the baseline characteristics of the participants allocated to calcium and vitamin D seemed well matched to those allocated to placebo. In contrast, as expected, women using personal calcium differed from women not using personal calcium in a number of factors that might influence cardiovascular outcomes. However, the WHI investigators have previously reported no significant interactions with these factors, calcium and vitamin D, and risk of death from myocardial infarction or coronary heart disease—except for body mass index, with obese women having a lower risk of death from myocardial infarction or coronary heart disease with calcium and vitamin D than non-obese women.4
Obesity does not explain our findings since it was more common in women not using personal calcium, and would have tended to obscure an interaction effect.
In the WHI CaD participants the incidence of cardiovascular events was relatively low, reflecting the comparative youth of the cohort. Thus, despite its size and long duration, the WHI CaD Study had insufficient power to detect small effect sizes, particularly when subgroups are considered. For example, in women not taking personal calcium supplements at randomisation, the study had 80% power to detect a 33% increase in clinical myocardial infarction.
The WHI CaD Study accounts for 75%–80% of the weighting in the meta-analyses of co-administered calcium and vitamin D, and 45%–55% of the weighting in the meta-analysis of calcium with or without vitamin D. However, the results for the individual studies in all the meta-analyses are quite consistent and do not suggest an undue influence of a single outlying study or WHI CaD.
Interpretation of results
For most of its participants, the WHI CaD Study assessed the impact of adding calcium and vitamin D to personal calcium supplements, effectively comparing a higher dose of calcium with a lower dose of calcium. By restricting the analyses to women not taking personal calcium supplements, we were able to estimate the effect of calcium and vitamin D on cardiovascular events, observing increased risks of these events with calcium and vitamin D. In women taking personal calcium supplements at randomisation, the addition of calcium and vitamin D did not increase cardiovascular risk, and the risk of cardiovascular events with calcium and vitamin D was also not affected by the dose of personal calcium supplements. This suggests that there may not be a dose-response relationship between calcium supplements and the risk of cardiovascular events. Thus, even doses of <500 mg/day might be associated with an increased risk of cardiovascular events similar to doses ≥1000 mg/day. This would be consistent with the notion that the abrupt change in plasma calcium concentration after supplement ingestion causes the adverse effect, rather than it being related to the total calcium load ingested.24 25
In the entire WHI cohort there was no significant interaction between calcium and vitamin D, personal calcium supplement use, and mortality—and therefore no evidence of a difference in mortality risk with calcium and vitamin D in the subgroups defined by personal calcium use. In women not taking personal calcium supplements, no increase in mortality was observed with calcium and vitamin D despite the increased risk of cardiovascular events. The most likely explanation is that participants in WHI were at low risk of cardiovascular events and death. A 15% increase in myocardial infarction and stroke would lead to only a 1%–3% increase in total mortality if 10%–20% of the additional events led to death during follow-up. The subgroup analysis did not have sufficient power to detect such a difference, but the 95% confidence intervals for mortality (0.86 to 1.14) encompass an effect of this size.
If calcium supplements do increase cardiovascular risk it is important to consider the potential underlying mechanisms.25
Calcium supplements acutely increase serum calcium concentration by a modest amount,24
an effect that is sustained during long term treatment, as evidenced by lower levels of parathyroid hormone.15
Serum calcium concentrations are positively associated with carotid artery plaque thickness,26
incidence of myocardial infarction,28 29 30
These findings are consistent with observational data suggesting increased risk of cardiovascular events and death in primary hyperparathyroidism, a condition in which serum calcium concentration is elevated.32 33
The process of vascular calcification is a complex, regulated process similar to osteogenesis.34
It is possible that the increase in serum calcium concentrations from calcium supplements influences vascular calcification by altering regulators of calcification such as fetuin A, pyrophosphate, and bone morphogenic protein-7, or by directly binding to the calcium-sensing receptor that is expressed on vascular smooth muscle cells.25
Exposing cultures of vascular smooth muscle cells to increased concentrations of calcium results in increased mineralisation of the cultures.35
Supporting this hypothesis are studies of patients with renal impairment, in whom calcium supplements accelerate vascular calcification and increase mortality in both dialysis and pre-dialysis populations.36 37 38
It is also possible that calcium supplements adversely affect risk of arterial thrombus formation. Acute hypercalcaemia in rats increases blood coaguability,39
potentially via an effect on platelets since calcium-sensing receptors are found on these cells.40
Therefore, extracellular calcium concentrations might affect the function of several cells that are implicated in the pathogenesis of vascular events. All these possibilities require further evaluation.
Calcium and vitamin D supplements increased the risk of cardiovascular events in the WHI CaD participants who were not taking personal calcium supplements at the time of randomisation. When these results are taken together with the results of other clinical trials of calcium supplements, with or without vitamin D, they strongly suggest that calcium supplements modestly increase the risk of cardiovascular events, particularly myocardial infarction. These data justify a reassessment of the use of calcium supplements in older people.
What is already known on this topic
- A recent meta-analysis suggested that calcium supplements taken without vitamin D increase the risk of myocardial infarction
- The Women’s Health Initiative reported no effect of calcium and vitamin D supplements on cardiovascular events, but most of the participants were taking personal, non-protocol calcium supplements at study entry
What this study adds
- Re-analysis of the Women’s Health Initiative data shows women allocated to calcium and vitamin D administration who were not taking personal calcium supplements were at increased risk of cardiovascular events
- Meta-analyses of trials involving 29000 people found that calcium supplements used with or without vitamin D modestly increase cardiovascular risk, suggesting their use in osteoporosis management should be reassessed