Dietary and Supplemental Calcium Intake and Cardiovascular Disease Mortality

Alison L. Bailey, MD

Review

Calcium supplements are frequently used to promote bone health and as a treatment for osteoporosis.¹ There has been debate on the effects of calcium outside of bone health. Specifically, the cardiovascular effects of both dietary and supplemental calcium are the subject of discrepant research findings.^2-7 As cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide and calcium supplementation is increasingly common, this question becomes more important. The current study investigates whether intake of dietary and supplemental calcium is associated with mortality from total CVD, heart disease, and/or cerebrovascular disease.⁸

Study Details

This was a prospective cohort study designed to assess the association between calcium intake and mortality. The participants were American Association of Retired Persons (AARP) members aged 50 to 71 years who were enrolled in The National Institutes of Health (NIH)- AARP Diet and Health Study in 1995-1996. Vital statistics were assessed through December 31, 2008, giving 12 years of follow-up.

Baseline questionnaires regarding health information and dietary intake were completed by 566,399 participants. Those participants whose questionnaire was completed by proxy were excluded as well as those with a self-reported diagnosis of cancer (except nonmelanoma skin cancer), heart disease, stroke, diabetes, or end-stage renal disease at baseline. Additionally, individuals who reported extreme intakes of total energy and dietary calcium were excluded. The remaining 219,059 men and 169,170 women were included in this analysis.

Baseline dietary intake was assessed with a self-administered, 124- item food frequency questionnaire that collected information on the usual frequency of food intake and portion size during the prior year. Information about the frequency and dosage of calcium supplements and multivitamins was also obtained. Calcium intake was then estimated from food only (dietary calcium); supplements only (supplemental calcium); and from both sources (total calcium). Dietary calcium intake was adjusted for total energy intake. The primary outcome was death; this was confirmed by the Social Security Administration Death Master File. Cause of death was obtained from the National Death Index Plus.

Statistical analyses were performed by calculating relative risks (RRs) and 2-sided 95% confidence intervals (CIs) using the Cox proportional hazards regression model. Person-years of follow-up time were calculated from the baseline until the date of death or the end of follow-up (December 31, 2008). A significant interaction for calcium intake by sex was found (P = .001), thus all data are reported separately for males and females. Multivariate models were adjusted for potential confounders such as race, educational level, marital status, health status, body mass index (BMI), physical activity, smoking status and dose, specific dietary intake, and hormone therapy use in women.

Calcium supplementation was very common in this group, with 51% of men and 70% of women using supplements containing calcium. Individual calcium supplements were used by 23% of men and 56% of women; multivitamins containing calcium were used by 56% of men and 58% of women. There were important differences between participants in the lowest calcium-intake categories versus the highest. Participants in the highest quintile of intake or supplement users were more likely to identify themselves as non-Hispanic white, have a college education and higher self-rated health scores, to be more physically active, have more multivitamin use, higher intake of fruits, vegetables, and whole grains, lower rates of smoking, less hypertension, and lower intake of alcohol, red meat, and total fat. In women, calcium supplementation was associated with lower BMI and more hormone therapy utilization.

There were 7,904 CVD deaths in men and 3,874 CVD deaths in women during 3,549,364 person-years of follow up. When adjusted for CVD risk factors, dietary calcium intake was not associated with CVD mortality in either men or women. However, supplemental calcium intake of >1,000 mg/d in men was associated with a significantly higher risk of total CVD death (multivariate RR_{>1,000 vs 0 mg/d}, 1.20; 95% CI, 1.05-1.36), heart disease death (multivariate RR_{>1,000 vs 0 mg/d}, 1.19; 95% CI, 1.03-1.37), and a trend toward an increased risk of cerebrovascular disease death (Table). Likewise, total calcium intake showed a U-shaped association with CVD mortality in men. When evaluated by quintiles of total calcium intake, the highest quintile was associated with increased total CVD mortality (multivariate RR_{Quintile 5 vs 1}, 1.12; 95% CI, 1.04-1.20) and heart disease mortality (multivariate RR_{Quintile 5 vs 1}, 1.12; 95% CI, 1.04-1.21). No association between either supplemental calcium intake or total calcium intake and CVD death rates was observed in women.

In this large prospective study, self-reported calcium supplementation >1000 mg/d was associated with increased risks of CVD death and heart disease death in men. No such associations were seen in women. Dietary calcium intake was not associated with an increased CVD death risk. The role of calcium supplementation in cardiovascular health is complex and requires additional study.

Commentary Clarifying the Safety of Calcium Supplementation

Calcium is commonly recommended to reduce fracture risk and the rate of bone loss in adults.⁹ Calcium supplementation has other potential benefits including lower risk of colorectal cancer as well as improvements in lipids and blood pressure.^10-12 A recent survey showed that more than 40% of the adult population in the United States used calcium supplements; that percentage increases to over 60% in those over 70 years of age.¹ Thus, calcium is one of the most widely used supplements available. As such, any health effects attributed to calcium are of public health interest, and perhaps concern.

There has been much speculation about both beneficial, and adverse, cardiovascular effects of calcium. Observational data suggest that dietary intake of calcium is not associated with an increased risk of CVD events or death.^3,13,14 In fact, those with the highest intake of dietary calcium may have a lower risk of death or CVD events.^15-17 In a theoretical framework, this is supported by data showing low serum calcium levels correlate with overall increased CVD death rates in men and women.¹⁸

Calcium supplementation has been studied as a means to increase calcium. Although no randomized trial data looking at CVD end points with calcium supplementation exist, older observational studies showed a trend toward decreased CVD events with higher levels of calcium supplementation.^14,15 More recently, several contemporary studies and meta-analyses have suggested an increased risk of CVD events in users of calcium supplements.^3,5,6,19,20 This ambiguity regarding the role of calcium in cardiovascular health is the basis for the analysis by Xiao.⁸

The results of this large prospective cohort study again signal concern over higher doses of calcium supplementation. High intake of supplemental calcium was associated with an increase in CVD death and heart disease death in men. For women, this association did not exist. The large number of people included in the analyses, long follow-up time, and significant numbers of CVD deaths (7,904 in men; 3,874 in women) add strength to these findings. Using the available data, research techniques were well validated, including ascertainment of death and cause of death lending additional strength to the findings.

Limitations include the inherent limitations of any observational analysis and survey-based study. Namely, unmeasured factors or behaviors that may have contributed to increased CVD death rates in the calcium supplement group cannot be excluded. Likewise, changes in diet and/or calcium supplementation use over time could not be assessed and could change the results of the analysis if available.

In this study, dietary calcium intake was not associated with any adverse findings. This data is also concordant with existing studies that support the role of dietary calcium in optimal health. Until randomized, controlled trial data exist or more mechanistic data are available, caution should be used with calcium supplementation. A diet that is high in calcium-rich foods such as low-fat dairy products, beans, leafy green vegetables, certain fruits, and nuts is a viable way to obtain recommended calcium levels and has the added benefit of being part of a heart-healthy lifestyle.

References

1. Bailey RL, Dodd KW, Goldman JA, et al. Estimation of total usual calcium and vitamin D intakes in the United States. J Nutr. 2010;140:817-822.

2. Wang L, Manson JE, Sesso HD. Calcium intake and risk of cardiovascular disease: a review of prospective studies and randomized clinical trials. Am J Cardiovasc Drugs. 2012;12:105-116.

3. 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.

4. Kaluza J, Orsini N, Levitan EB, Brzozowska A, Roszkowski W, Wolk A. Dietary calcium and magnesium intake and mortality: a prospective study of men. Am J Epidemiol. 2010;171:801-807.

5. Pentti K, Tuppurainen MT, Honkanen R, et al. Use of calcium supplements and the risk of coronary heart disease in 52-62-year-old women: the Kuopio Osteoporosis Risk Factor and Prevention Study. Maturitas. 2009;63:73-78.

6. Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. Br Med J. 2008;336:262-266.

7. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and metaanalysis. Br Med J. 2011;342:d2040.

8. Xiao, Q, Murphy RA, Houston DK, Harris TB, Chow W, Park Y. JAMA Intern Med. 2013;173:639-646.

9. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet. 2007;370:657-666.

10. Cho E, Smith-Warner SA, Spiegelman D, et al. Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies. J Natl Cancer Inst. 2004;96:1015-1022.

11. Bucher HC, 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.

12. Reid IR, Mason B, Horne A, et al. Effects of calcium supplementation on serum lipid concentrations in normal older women: a randomized controlled trial. Am J Med. 2002;112:343-347.

13. Van der Vijver LP, van der Waal MA, Weterings KG, Dekker JM, Schouten EG, Kok FJ. Calcium intake and 28-year cardiovascular and coronary heart disease mortality in Dutch civil servants. Int J Epidemiol. 1992;21:36-39.

14. Al-Delaimy WK, Rimm E, Willett WC, Stampfer MJ, Hu FB. A prospective study of calcium intake from diet and supplements and risk of ischemic heart disease among men. Am J Clin Nutr. 2003;77:814-818.

15. Bostick RM, Kushi LH, Wu Y, Meyer KA, Sellers TA, Folsom AR. Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women. Am J Epidemiol. 1999;149:151-161.

16. Iso H, Stampfer MJ, Manson JE, et al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke. 1999;30:1772-1779.

17. Kaluza J, Orsini N, Levitan EB, Brzozowska A, Roszkowski W, Wolk A. Dietary calcium and magnesium intake and mortality: a prospective study of men. Am J Epidemiol. 2010;171:801-807.

18. Van Hemelrijck M, Michaelsson K, Linseisen J, Rohrmann S. Calcium Intake and Serum Concentration in Relation to Risk of Cardiovascular Death in NHANES III. PLoS ONE. 8:e61037.

19. Bolland MJ, Avenell A, Bron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. Br Med J. 2010;341:c3691.

20. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and metaanalysis. Br Med J. 2011;342:d2040.

About the Author

Alison L. Bailey, MD, is Assistant Professor of Medicine and Director of Cardiac Rehabilitation at the Gill Heart Institute, Division of Cardiovascular Medicine, at the University of Kentucky in Lexington. She is also Associate Director of the cardiovascular fellowship program. Dr. Bailey received her MD from the University of Kentucky College of Medicine and completed her residency and fellowship at the University of Kentucky Chandler Hospital. Her clinical interests include cardiovascular disease in women and cardiovascular disease prevention. Dr. Bailey has been published in numerous peer-reviewed medical journals.

Xiao Q, Murphy RA, Houston DK, Harris TB, Chow W, Park Y. Dietary and supplemental calcium intake and cardiovascular disease mortality. JAMA Intern Med. 2013;173:639-646.