Calcium supplements implicated in increased risk for CV events

Bolland M. BMJ. 2011;doi:10.1136/bmj.d2040.

Issue: June 2011

Calcium supplements, taken with or without vitamin D, have been shown to modestly increase the risk for cardiovascular events, including myocardial infarction and stroke.

These results, reported in a new study published by the British Medical Journal, incorporated findings from a re-analysis of the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD), as well as a meta-analysis of several additional trials.

Initially, results from WHI CaD, which was a 7-year, randomized, placebo-controlled trial with 36,282 postmenopausal women, showed no adverse effect of calcium and vitamin D on any CV endpoint. The results were obscured, however, because participants had free access to those supplements, according to the researchers. Specifically, at randomization, 54% of the participants were taking personal calcium supplements and 47% personal vitamin D supplements, which researchers said rendered the trial a comparison of higher- and lower-dose calcium and vitamin D for most of those participating.

According to results of their re-analysis, the 46% (n=16,718) of women not taking personal calcium supplements had an HR of 1.13 for any CV endpoint and 1.20 for total MI (P=.07 for both). Results on the other endpoints, including revascularization and stroke, were similar, with the exception of all-cause mortality (HR=0.99). Designation to calcium and vitamin D among women taking personal calcium supplements did not change CV risk.

“By restricting the analyses to women not taking personal calcium supplements, we were able to estimate the effect of calcium and vitamin D on CV events, observing increased risks of these events with calcium and vitamin D,” the researchers wrote.

To gain further insight into this issue, researchers then supplemented these results with data from placebo-controlled trials that examined CV events among individuals taking calcium or calcium and vitamin D. The complete trial-level data were obtained from 28,072 individuals from eight trials, as well as the WHI CaD participants who did not take personal calcium supplements.

Overall, 1,835 died during the mean trial duration of 5.7 years, which was weighted by study size. Researchers reported that 1,384 individuals had an incident MI or stroke, which resulted in RRs of 1.24 (P=.004) for MI and 1.15 (P=.009) for the composite of MI and stroke.

“When [WHI CaD] 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 CV events, particularly MI,” the researchers concluded. “These data justify a reassessment of the use of calcium supplements in older people.”

The situation seems quite complex to me because there are different reasons to supplement with calcium. For example, there are people who have conditions like osteoporosis or renal disease, and who are receiving treatment under clinical supervision. There are people at varying levels of osteoporosis risk, some of whom take calcium with or without vitamin D on their own prophylactically, and some who take it under clinical supervision based on recommendations from their physicians. There are people who take calcium and other supplements for general health reasons with the belief that anything natural must be good. Some people take calcium as part of antacid preparations — it is not clear to me how this is captured in the studies included in this meta-analysis. It is also unclear to me how antacid use was cross-referenced with calcium use in WHI.

The situation is further complicated by food fortification — milk and orange juice are just two foods that contain calcium supplements. Thus, dividing a population into supplement users and non-users sounds impossible to me; it is really a division into pill users and non-pill users. My assumption is that calcium supplements not only vary in dose, but also in bioavailability. Thus there is likely significant heterogeneity across different brands and preparations.

That all being said, the meta-analysis raises concerns about the safety of calcium supplementation, and this topic certainly warrants further study because of its potentially large impact on the population.

– Vera Bittner, MD
Professor of Medicine
Section Head, Preventive Cardiology
University of Alabama at Birmingham

Disclosure: Dr. Bittner reported no relevant financial disclosures.

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