Experimental studies have demonstrated that calcium is involved in multiple physiologic processes potentially related to development of CVD. There have also been several epidemiologic studies examining dietary and supplemental calcium intake in relation to CVD risk, with considerable heterogeneity in study design, participant characteristics, and potential for confounding. Randomized trials specifically designed to evaluate the cardiovascular effects of short- and long-term calcium supplementation remain lacking; current available data is primarily derived from secondary analyses of existing trials. In assessing the totality of evidence to date, it appears that calcium intake, either from diet or from supplements, has little or no effect on CVD risk.
Pooled analyses combining data from several large-scale, population-based, prospective cohort studies showed a non-significant inverse association of dietary calcium intake with incident CHD, incident stroke, and total CVD. A seemingly stronger association with risk of stroke might be attributed to an established blood pressure-lowering effect of dietary calcium.[47
] Fewer studies have examined the association between calcium supplement use and incident CVD. The generally null findings noted to date suggest that calcium supplementation is unlikely to confer a strong effect on CVD risk. The Kuopio Osteoporosis Risk Factor and Prevention Study[36
] was the only study that reported a significantly increased risk of CHD among users of calcium supplements versus nonusers.[36
] Of note, in this study the mean dietary calcium intake from liquid milk products and cheese was 773.8 mg/day for calcium supplements users and 818.2 mg/day for nonusers. Although the study did not determine the daily dose of calcium supplements, total calcium intake likely exceeded the upper limit of 2000 mg/day by NIH[4
] and IOM guidelines[5
] for participants with both high habitual dietary and supplemental calcium intake, and these individuals might be at risk for hypercalcemia and its complications. In addition, since this study did not separate calcium and calcium plus vitamin D supplement users, it is not clear whether the increased CHD risk is specifically related to calcium or vitamin D.
There are some discrepancies in our findings on dietary versus supplemental calcium intake with CVD risk. It has been postulated that these discrepancies may be explained in part by their differential impact on circulating calcium.[48
] For calcium supplements, usually taken on their own and without food, there would be an immediate and sizable increase in blood calcium concentrations within a couple of hours, and the calciotropic hormone secretion and bone resorption may be affected.[49
] In contrast, calcium from foods, typically during a mixed meal, will be absorbed slowly over several hours. This absorption process is less likely to cause detectable change in blood calcium concentration, and the metabolic response will vary according to simultaneous ingestion of other nutrients.[50
] Since available studies on blood calcium in association with risk of CVD are very limited and inconclusive, more studies are needed to provide further insight into a complex relation between intake, metabolism, and biologic effect of calcium on pathogenesis of CVD.
Clinical trial data on the effect of calcium supplementation on CVD risk are limited to secondary analyses. Following the first original study that raised concerns about a possible adverse cardiovascular effect of calcium supplementation,[42
] a recently published meta-analysis combined data from a total of 15 eligible clinical trials and investigated whether calcium supplements increase the risk of CVD events.[51
] In the analysis of 5 trials with patient level data, RR of MI for participants allocated to calcium supplementation compared with those allocated to placebo was 1.31 (95% CI: 1.02–1.67). The corresponding RRs for stroke, composite endpoint of MI, stroke, or sudden death, and all-cause mortality were 1.20 (95% CI: 0.96–1.50), 1.18 (95% CI: 1.00–1.39), and 1.09 (95% CI: 0.96–1.23) respectively. The analysis of trial level data showed similar results, with a pooled RR for MI of 1.27 (95% CI: 1.01–1.59). The authors concluded that calcium supplements (without coadministered vitamin D) are associated with an increased risk of MI and suggested a reassessment of calcium supplement use.
Although the randomized, controlled trial design provides the strongest support for potential causality, post-hoc analyses of secondary endpoints as presented in this meta-analysis should be interpreted with caution. First, none of the included trials was specifically designed to test the effect of calcium supplementation on risk of CVD, and the numbers of CVD events in many trials were too small to draw clinically meaningful conclusions. Second, CVD events were not pre-specified endpoints in most trials and therefore were not systematically ascertained. Only 2 of the 15 trials had CVD events adjudicated by blinded investigators. Third, not a single trial included in this meta-analysis reported a significant difference in CVD events between calcium and placebo groups, but only the pooled RR showed a statistically significant effect. Conclusion of this meta-analysis also heavily depends on unpublished data, which can not be evaluated rigorously. Fourth, the combined trial data seem to suggest that calcium supplements increase the risk of MI, but not the risk of stroke or all-cause mortality. The biological mechanisms explaining this specific effect remain uncertain. Taken these limitations together, currently available evidence from clinical trials does not definitively indicate an adverse effect of calcium supplementation on risk of CVD.
The new report recently released by IOM[5
] on dietary reference intakes for calcium and vitamin D cited vast evidence for a role of calcium in promoting skeletal growth and maintenance. However, the evidence for any benefits of calcium beyond bone health remains insufficient. Though the report noted that once intake of calcium surpasses 2000 mg per day for both men and women aged ≥51 years, the risk for harm may increase, it is premature to make definitive statements about the cardiovascular effects associated with high intake of calcium. Our review of epidemiologic studies and clinical trials support the IOM report. Future studies need to include not only more prospective cohorts but also randomized trials specifically designed to evaluate the risks or benefits of calcium supplementation on CVD endpoints as the primary pre-specified outcome.