Associations of Dietary Calcium Intake and Calcium Supplementation With MI, Stroke Risk, and Overall Cardiovascular Mortality

Harry E. Davis II , MD, FACP

Review

Li K, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg). Heart. 2012;98:920-925.

Inverse associations between dietary calcium intake and the risk of cardiovascular disease have been suggested in epidemiological studies.1,2,3 However, the possibility that a higher intake of calcium might decrease the occurrence of cardiovascular events has not been supported by a majority of observational studies. In fact, two meta-analyses of clinical trials have raised the possibility of an increased risk of myocardial infarction (MI) through the use of calcium supplements.4,5

Study Design

To examine the associations of calcium intake, both dietary and supplemental, Li et al examined data from the Heidelberg cohort, one of 2 German cohorts participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. After excluding participants with diagnosed cardiovascular disease (MI, stroke, or transient ischemic attack) at baseline, as well as participants with extremes of daily energy intake, the total, dairy, and nondairy calcium intake of a total of 23,980 participants was examined in this prospective cohort study.

A previously validated self-administered food frequency questionnaire was used to determine the consumption of 148 food items in the 12-month period prior to recruitment. For both German cohorts, dairy foods and nonalcoholic beverages provided 39.9% and 28.2% of the daily intake of dietary calcium, respectively. The regular use of vitamin and mineral supplements was also determined. The incidence of cardiovascular events during follow-up was reported by participants or next of kin, and verified in medical records or official death certificates.

Statistical analysis was performed after adjusting for total energy intake of 2200 kcal/day for men and 1700 kcal/day for women. Energy-adjusted nutrient intakes were placed into quartiles using sex-specific cut-off points. The lowest quartiles were used as reference points. Adjustments were made for potential confounders including sex, age at recruitment, highest education level, physical activity, body mass index (BMI, kg/m2), smoking, alcohol intake, energy intake (kcal/day), energy-adjusted intakes

of vitamin D, saturated fatty acids, and total protein, self-reported diabetes mellitus at recruitment, and use of calcium supplements.

At baseline, a higher dietary calcium intake tended to be associated with younger age, higher education level, being physically active, less likely to be overweight/obese, less likely to be current smokers and of shorter average smoking duration, and lower lifetime alcohol consumption. Dietary calcium intake was also associated with the likelihood of taking calcium supplements. Users of calcium supplements were more likely to be women, physically more active, less likely to be overweight or obese but of an older age, of lower educational level, and with a longer duration of smoking.

With an average follow-up of 11 years, a total of 354 MIs, 260 strokes, and 267 cardiovascular disease (CVD) deaths were documented. After adjustment for confounders, the only statistically significant inverse association was for total dietary calcium intake and MI risk for the third quartile compared with the lowest quartile (HR = 0.69; 95% CI, 0.50-0.94). When source-specific calcium intake was examined, the MI reduction in the third quartile was again seen in the third quartile of dairy calcium intake (HR = 0.68; 95% CI, 0.50-0.93).

Analysis of data regarding the use of calcium supplements revealed a statistically significant increase in MI risk in comparison with nonusers of any supplements (HR = 1.86; 95% CI, 1.17-2.96). This association was even more marked for calcium supplement—only users (HR = 2.39; 95% CI, 1.12-5.12). The use of calcium supplements was not found to be statistically associated with either stroke risk or overall CVD mortality.

Two of the key findings of this study were the 30% lower risk of MI for a moderately higher dietary calcium intake that was only statistically significant for women (HR = 0.43; 95% CI, 0.22-0.82) and an increased risk of MI for users of calcium supplements. The authors pointed out that theirs was perhaps the first observational study to suggest a possible adverse effect of the use of calcium supplements on MI risk.

References

1. Allender PS, Cutler JA, Follmann D, et al. Dietary calcium and blood pressure: a metaanalysis of randomized clinical trials. Ann Intern Med. 1996;124:825-831.

2. Bucher HD, Cook RJ, Guyatt GH, et al. Effects of dietary calcium supplementation on blood pressure. A meta-analysis of randomized controlled trials. JAMA. 1996;275:1016- 1022.

3. Cappuccio FP, Elliott P, Allender PS, et al. Epidemiologic association between dietary calcium intake and blood pressure: a metaanalysis of published data. Am J Epidemiol. 1995;142:935-945.

4. Bolland MJ, Grey A, Gamble GD, et al. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women’s Health Initiative (WHI) limited-access data sets. Am J Clin Nutr. 2011;94:1144-1149.

5. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.

6. Institute of Medicine. 2011 Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press.

7. Kumar V, Abbas AK, Fausto N, et al, eds. Robbins and Cotran Pathologic Basis of Disease. St. Louis, MO: Elsevier-Saunders; 2005:518.

8. Rubin R, Strayer D, Rubin D, et al, eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 6th ed. Wolters Kluwer/ Lippincott Williams & Wilkins; 2012:448.

9. Polonsky TS, McClelland RL, Jorgensen NW, et al. Coronary artery calcium score and risk classification for coronary artery heart disease prediction. JAMA. 2010;303:1610- 1616.

10. Ioannidis JPA, Tzoulaki I. What makes a good predictor? the evidence applied to coronary artery calcium score. JAMA. 2010;303:1646-1647.

COMMENTARY

Concerns Raised About CAD Risk With Calcium Supplements

Li and associates have evaluated a large database looking for possible relationships between the intake of calcium, be it dietary or supplemental, and the likelihood

of cardiovascular disease. Given the improbability of conducting large-scale randomized, controlled dietary trials in humans, a careful examination of this type of data

is justified. Although causality cannot be confirmed with this approach, some clinically relevant guidance may be suggested. Of particular note in this study are the findings that dietary calcium in an optimal amount may foster cardiovascular health, and supplemental calcium may be detrimental to cardiovascular health.

In 2011, the Institute of Medicine (IOM) reported the results of a comprehensive review of the evidence for both skeletal and extraskeletal outcomes relating to the dietary intake of calcium and vitamin D.6 It concluded that the evidence linking the intake of these nutrients with extraskeletal outcomes, including cardiovascular disease, “was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements.” However, the report did note that “emerging evidence suggested a curvilinear or U-shaped curve for several outcomes related to vitamin D, including cardiovascular disease…with the lowest risk at moderate levels and increased risk at both

low and high levels” of serum 25-hydroxyvitamin D levels. Interestingly, the study by Li et al raises a possibility of another U-shaped curve regarding the risk of MI and

dietary intake of calcium, with the lowest risk in the third quartile of dietary calcium intake.

An association between the use of calcium supplements and coronary artery disease (CAD) is suggested by the Heidelberg cohort data. It is recognized that atherosclerotic plaques undergo calcification. Further, advanced coronary calcification may portend an increased risk for coronary events.7 Among the roles of smooth muscle cells in the pathogenesis of atherosclerosis is the potential for “a change in phenotype to show osteoblastic functions promoting calcification in the atherosclerotic lesion.”8 Recognition of the relationship of calcification in coronary arteries to atherosclerosis has led to efforts to determine the risk this calcification suggests by quantifying the amount of calcium in these vessels. While there may be legitimate debate regarding the predictive value of this determination,9,10 the study by Li et al suggests a need to explore the possible contribution of taking calcium supplements to this risk.

In conclusion, the Heidelberg cohort data suggest a positive correlation between a diet containing a moderate amount of calcium and cardiovascular health. It raises concerns about the risk of CAD with the use of calcium supplements. Pending the availability of specific guidelines in this regard, it suggests a need for the clinician to consider the relative benefit of calcium supplementation for skeletal health versus the possible risk of calcium supplementation for cardiovascular health. It may be that the routine use of these supplements in some patients may not be warranted and could even be harmful.

About the Author

Harry E. Davis II , MD, FACP, is Associate Professor of Medicine and Vice Chair for Education in the Department of Internal Medicine, Texas Tech University Medical Sciences Center, El Paso, TX. Dr Davis received his medical degree from West Virginia University in Morgantown, WV, and did his internal medicine residency at Philadelphia General Hospital in Philadelphia, PA, and Letterman Army Medical Center in San Francisco, CA. He has practiced medicine with the US Army in many capacities.