Calcium Supplementation and Coronary Artery Disease: Time to Act?

This article is part of a series including:

The Evidence and Controversy Between Dietary Calcium Intake and Calcium Supplementation and the Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis of Cohort Studies and Randomized Controlled Trials

Osteopenia and osteoporosis leading to fractures affect a huge proportion of the population older than 50 years of age, and osteoporosis is considered a serious public health problem. Currently, more than 200 million people worldwide experience osteoporosis, and the numbers are increasing due to demographic changes. Approximately 30% of all postmenopausal women in the United States and in Europe have osteoporosis. According to the International Osteoporosis Foundation, in 2000 there were an estimated 9 million new osteoporotic fractures, of which 1.6 million were at the hip, 1.7 million were in the forearm, and 1.4 million were clinical vertebral fractures. Worldwide, 1 in 3 women older than 50 will experience osteoporotic fractures, as will 1 in 5 men older than 50. By 2050, the worldwide incidence of hip fracture is projected to increase by 310% in men and 240% in women, compared to rates in 1990 (1). Hip fractures are accompanied by a high mortality, and prevention and treatment are obviously of major importance. Among the preventive efforts are tobacco avoidance, physical activity, and adequate nutrition to provide enough amounts of calcium, vitamin D, protein, and other nutrients necessary for bone formation and preservation. Supplementation of the diet with calcium and vitamin D has been a basic principle shown to reduce loss of bone mineral and to reduce fracture risks (2,3). Although other meta-analyses challenge the overall effect of both calcium and vitamin D supplementation (4,5), international expert bodies maintain the view that they are useful for those with low dietary intakes and at high risk and that the combined supplementation may reduce risk of falls (6).

Whereas the cardiovascular safety of vitamin D supplementation is well established (7), the safety of calcium supplementation has been challenged over the last decades following publication of observational studies reporting increased incidence of various cardiovascular (CVD) endpoints including coronary artery disease (CAD) or coronary heart disease (CHD; which develops when the coronary arteries become too narrow), among users. This safety issue continues to be a scientific controversy, with several meta-analyses of studies with diverging outcomes having been published (8,9). In this issue of the journal, Yang et al. report a novel meta-analysis of both observational studies and of randomized controlled trials (RTCs) on the safety of dietary calcium and supplementation with calcium and/or vitamin D in particular (10).

Yang et al. found the observational studies of total dietary calcium intake to be either neutral or potentially positive for various CVD endpoints, whereas the RCTs found that calcium supplementation alone or with vitamin D increased the risk of CHD significantly by 8% (10). Moreover, calcium supplementation alone increased the risk of CHD by 20%, which was mainly due to an increase of 21% in myocardial infarction. These effects were mainly due to findings among men and with intakes in the range of 1000 to 1400 mg/d.

Therefore, it is important to identify the cause of the difference in safety of dietary and supplementary calcium. It has been suggested that the dose may be important. Dietary calcium intakes are usually, but not always, below the intakes achieved by supplements. In populations where median calcium intake exceeds 1000 mg/d due to high intake of dairy, no adverse effects on incidence of CVD have been reported, so it is unlikely that the dose per se is the cause (11). Alternative explanations should be considered. It has been found that the dairy matrix reduces cardiovascular risk, particularly the fermented products such as cheese and yogurts, so potential harmful effects of dietary calcium may be counteracted by other food components and structures (12). Another potential explanation is that the calcium complexes in diet and in supplements are very different. Dairy products contain calcium hydroxyl apatite (a complex calcium phosphate salt) that may be more easily incorporated into human bones than the calcium salts from supplements and consequently have less impact on plasma calcium levels and hormonal regulation. Calcium supplements increase serum calcium acutely by typically 0.8 mg/dL (0.2 mmol/L) (13,14), and this increase may be the link to CAD. Evidence to support the causal nature of increased plasma calcium levels with risk of cardiovascular disease is supported by Mendelian randomization studies (15,16). Taking advantage of genetic variants (SNPs) related to serum calcium levels in a study of 184,305 individuals, the six SNPs related to serum calcium levels were studied. It was found that the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically predicted serum calcium levels were 1.25 (95% confidence interval [CI], 1.08–1.45; p = 0.003) for CAD and 1.24 (95% CI, 1.05–1.46; p = 0.009) for myocardial infarction (15). Another Mendelian randomization study found that each 1-mg/dl increase in serum calcium increased risk of CAD by 49% (OR: 1.49; 95% CI, 1.02–2.17) and of myocardial infarction by 58% (OR: 1.58; 95% CI, 1.06–2.35), but also with increased levels of low-density lipoprotein cholesterol and triglycerides (16). Experimental studies have demonstrated that calcium supplementation with calcium carbonate produces more pronounced postprandial triglyceride response than calcium from dairy (17).

Heaney (18) has argued that the functional outcomes of vitamin D and calcium interaction in vivo may be reflected by “synergistic effects of vitamin D status and calcium intake on calcium absorption,” “effects of calcium intake on vitamin D status,” and “potential association between calcium and vitamin D status and non-skeletal outcomes” such as cancer and inflammatory bowel disease (IBD). For the latter, Vernia et al. (19) have indicated that inadequate calcium intake is present in IBD patients and that this represents a reversible risk factor given that diets in these patients contained significantly less calcium than healthy controls. The context that calcium and vitamin D supplementation disparities can be benchmarked on gender, age, race/ethnicities, dietary preferences, and household economics has been widely advocated (20,21), but the review of Wallace et al. (20) pointed out that “low-income, overweight and/or obese minority population may be at greater risk of calcium and vitamin D insufficiency.” While Reid et al. (22) made a case that calcium supplements may have very little role to play in the prevention or treatment of osteoporosis, this editorial view is that cardiovascular integrity and heart health is of utmost and paramount importance. The physiological and clinical implications/interpretations of the of the analysis by Yang et al. needs to be underscored pursuant of dietary management of CVD and conditions involving bone health, both of which can benefit from an understanding of how calcium metabolism may affect many of the associated risks. There is enough knowledge to warrant starting to develop dietary calcium supplements based on milk calcium, with the same chemical structure as dairy, and preferably formulated in combination with vitamin D. The question of metabolism positions the need to educate health care providers and consumers on the merits of nutrigenomics and pharmacogenomics (15,22), given that the inherent interindividual variabilities can significantly impact the benefits of dietary supplementations across a population.

Arne Astrup
Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
[email protected]
Okezie I. Aruoma
Department of Chemistry and Biochemistry, College of Natural and Social Sciences, California State University Los Angeles, Los Angeles, CA, USA
[email protected]

Disclosure statement

AA has received financial support from Danish Dairy Foundation, Global Dairy Platform, Arla Foods Amba, Denmark, and European Milk Foundation for projects conducted at the University of Copenhagen exploring the effects of dairy on human health. The European Milk Foundation sponsored the Expert Symposium on the Dairy Matrix 2016, organized by AA. AA has received travel expenses and honoraria in connection with meetings and lectures from DSM, Pfizer, Danone, Arla Foods, European Milk Forum, and Global Dairy Platform.

OIA has no conflict of interest to declare.