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 Question

What is the significance of reports of adverse cardiac outcomes associated with calcium supplements?

Response from Darrell Hulisz, PharmD 

Associate Professor, Case Western Reserve University School of Medicine; Clinical Specialist in Family Medicine, University Hospitals, Case Medical Center, Cleveland, Ohio

It is well established that consumption of calcium-rich foods or calcium supplementation can help prevent osteopenia and osteoporosis, especially in postmenopausal women.^[1,2] Consequently, calcium supplements are widely used to combat estrogen- and age-related declines in bone mineral density, especially in those with a diet deficient in calcium-rich foods. A few studies have shown an inverse correlation of dietary calcium intake on hypertension and stroke,^[3-5] leading some to speculate that calcium supplementation might reduce cardiovascular disease (CVD).

However, studies examining the effect of calcium intake on cardiovascular mortality do not support the hypothesis that high calcium intake decreases cardiovascular mortality.^[6-8] Moreover, recent meta-analysis data suggest that high calcium intake might increase the risk for myocardial infarction (MI).^[9,10] It is uncertain exactly how calcium supplements work to increase MI risk, but calcium supplements can accelerate vascular calcification and increase mortality in patients with renal failure.^[11,12] Increased vascular calcification, especially within coronary arteries, would be expected to increase CVD event rates.

Current guidelines suggest that most adults should receive between 1000 mg and 1200 mg of elemental calcium daily.^[2] Individuals who consume a healthy diet, rich in dairy products and calcium-fortified foods, should reach these thresholds. Such individuals who are vitamin D sufficient may not benefit from taking calcium supplements for osteoporosis prevention. Serum calcium levels would increase acutely with supplement intake to a greater degree than that seen with dietary calcium ingestion. A positive correlation exists between serum calcium levels and vascular calcification.^[13]

This potential adverse association between high calcium intake and MI is receiving national media attention because of the recent Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg).^[14] The EPIC-Heidelberg study aimed to prospectively evaluate the associations of dietary calcium intake and calcium supplementation with MI, stroke risk, and overall CVD mortality.^[14] This observational cohort study (N = 23,980) collected extensive food intake data as well as calcium supplement use. It should be noted that exact calcium supplement dosages, formulations, and salt forms were not reported for most patients. Data on 354 MI cases, 260 stroke cases, and 267 CVD deaths were documented over an 11-year period. A large number of potential confounding variables were adjusted for, but a detailed description of study methods are beyond the scope of this article. The results indicated that calcium supplement users experienced a statistically significant increase in MI risk when compared with those who did not use any supplements. The hazard ratio was reported at 1.86, with a 95% confidence interval of 1.17-2.96. No statistically significant association was found between calcium supplementation and either stroke risk or overall CVD mortality.

The findings from this observational study should be interpreted with caution because they do not provide evidence for a causal link between calcium supplements and MI. However, this study does suggest that increasing dietary calcium intake might not confer significant cardiovascular benefits, while calcium supplements, which might raise MI risk, should be consumed with greater caution than previously warranted. Perhaps greater caution should be advised in vitamin D-sufficient patients with an adequate dietary calcium intake not to exceed the recommended 1000-1200 mg daily intake.

The latest finding to shed light on this topic was a National Institutes of Health trial that prospectively enrolled 388,229 men and women.^[15] Participants recorded their daily food composition and intake over 1 year, including use of multivitamins, calcium-containing antacids, and calcium supplements. Mean follow-up time was 12 years, with 7904 CVD deaths reported in men and 3874 reported in women. After adjusting for CVD risk factors, supplemental calcium (1000 mg daily vs no calcium supplementation) was associated with a 19% increase in CVD death, including heart disease death in men but not in women. Cerebrovascular mortality was not increased with calcium supplements in either men or woman. It is important to note that high intake of supplemental calcium,not dietary calcium, was associated with the excess risk for CVD death in men.

Calcium supplements should be reserved for patients who, through careful dietary history, do not consume adequate amounts of calcium, unless otherwise clinically indicated. Perhaps the sage advice of getting one's vitamins and minerals primarily from dietary sources applies here too, at least for a majority of patients. Given the recent finding that calcium supplements may increase CVD mortality in men, the consumption of calcium-rich foods, such as low-fat dairy products, beans, and green leafy vegetables, may be preferred over calcium supplements in men, unless otherwise clinically indicated. Future prospective, randomized, controlled trials should clarify whether calcium supplements actually cause MI or alter stroke risk or CVD mortality.

Acknowledgement: The author wishes to thank Carina Haught for providing technical assistance.

References

1. Cumming RG, Cummings SR, Nevitt MC, et al. Calcium intake and fracture risk: results from the study of osteoporotic fractures. Am J Epidemiol. 1997;145:926-934. Abstract

2. Hodgson SF, Watts NB, Bilezikian JP, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract. 2003;9:544-564. Abstract

3. 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. Abstract

4. Cappuccio FP, Elliott P, Allender PS, Pryer J, Follman DA, Cutler JA. Epidemiologic association between dietary calcium intake and blood pressure: a meta-analysis of published data. Am J Epidemiol. 1995;142:935-945. Abstract

5. Umesawa M, Iso H, Ishihara J, et al. Dietary calcium intake and risks of stroke, its subtypes, and coronary heart disease in Japanese: the JPHC Study Cohort I. Stroke. 2008;39:2449-2456. Abstract

6. 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. Abstract

7. 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. Abstract

8. 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.Abstract

9. Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr. 2011;94:1144-1149. Abstract

10. 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.

11. Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478-1483. Abstract

12. Russo D, Miranda I, Ruocco C, et al. The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer. Kidney Int. 2007;72:1255-1261. Abstract

13. Wang TK, Bolland MJ, van Pelt NC, et al. Relationships between vascular calcification, calcium metabolism, bone density, and fractures. J Bone Miner Res. 2010;25:2777-2785. Abstract

14. 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. Abstract

15. Xiao Q, Murphy RA, Houston DK, Harris TB, Chow WH, Park Y. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health-AARP Diet and Health Study. JAMA Intern Med. 2013 Feb 4:1-8. doi:10.1001/jamainternmed.2013.3283. [Epub ahead of print]