Calcium Supplementation and Coronary Artery Disease: A Methodological Confound?

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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

Osteoporosis and low bone mass (formerly known as osteopenia) are a significant public health threat in the U.S. and worldwide. The National Bone Health Alliance (NBHA) now estimates that 16.0 and 29.9% of men and women age 50+ years in the U.S. have osteoporosis,⁽¹⁾ as defined by newly proposed criteria for clinical diagnosis.⁽²⁾ More than 200 million people worldwide suffer from osteoporosis, and the numbers continue to grow due to demographic changes, such as increases in life expectancy. The International Osteoporosis Foundation (IOF) estimates that worldwide, osteoporosis causes more than 8.9 million fractures annually, resulting in an osteoporotic fracture every three seconds.⁽³⁾ Worldwide, one in three women and one in five men will experience an osteoporotic fracture in their lifetime.^(4–6) By 2050, the worldwide incidence of hip fractures is projected to increase by 310% and 240% in men and women, respectively, compared to rates in 1990.⁽⁷⁾ Hip fractures cause the most morbidity and economic impact to the healthcare system with reported mortality rates of up to 20 to 24% in the first year post hip fracture.^(8),(9) The National Osteoporosis Foundation (NOF) has published clinical guidelines for the prevention and treatment of osteoporosis.⁽¹⁰⁾ A cornerstone to these guidelines is obtaining the recommended intake for calcium (1000 mg/d for men 50 to 70 years; 1200 mg/d for women 51+ years and men 71+ years), incorporating supplements only when dietary intake is not obtainable.⁽¹⁰⁾ Data from the National Health and Nutrition Examination Survey (NHANES) indicate that calcium supplement use among U.S. older adults ≥71 years is approximately 62 ± 2%,⁽¹¹⁾ for the self-reported purpose of promoting bone health.⁽¹²⁾ However, the relationship between calcium supplements and risk of osteoporosis and related fractures has been controversial and various recommendations currently exist. Data from the Women’s Health Initiative (WHI), the only large randomized controlled trial of postmenopausal women (n = 36,282), showed calcium with vitamin D supplementation to be associated with a significant improvement in bone mineral density (BMD) but not fractures in the intention to treat analysis. However, when censored at the time of deviation from the protocol the investigators reported a 29% reduction (HR: 0.71, CI 95%: 0.52–0.97) in hip fractures.⁽¹³⁾ Subsequent analysis of the WHI showed that among women not taking personal calcium or vitamin D supplements at baseline (women were allowed to continue personal supplement regimen for ethical reasons), hip fracture occurrence following 5 years or more of supplementation decreased by 38% (HR: 0.62, CI 95%: 0.38–1.00) compared to the placebo group.⁽¹⁴⁾ The U.S. Preventive Services Task Force (USPSTF) found I-level or “insufficient” evidence to assess the benefits and harms of calcium and vitamin D supplementation, alone or combined for the primary prevention of fractures in men and premenopausal women, and recommends against daily supplementation for primary prevention of fractures in community-dwelling postmenopausal women.⁽¹⁵⁾ At the time, their recommendations were based upon an early evidence report from the Agency for Healthcare Quality and Research (AHRQ).⁽¹⁶⁾ A later NOF commissioned update of this AHRQ report that incorporated data on adherence and personal supplement use within the WHI found supplementation to reduce both total and hip fractures by 15 and 30% in community-dwelling and institutionalized postmenopausal women, supporting their utility for the primary prevention of fractures.⁽¹⁷⁾ To date, the majority of international expert bodies with expertise in nutrition including those in the U.K.,⁽¹⁸⁾ Canada,⁽¹⁹⁾ Japan,⁽²⁰⁾ and U.S.,^(10),(21) maintain the view that calcium with vitamin D supplements are effective in preventing primary fractures among those with low dietary intakes, and may also reduce risk of falls due to the vitamin D content.⁽²²⁾

While the cardiovascular safety of supplemental vitamin D has been previously established,⁽²³⁾ use of supplemental calcium has been controversial. No suggestions of serious adverse cardiovascular effects from calcium supplements had been reported in the scientific literature until 2008, when a series of secondary analyses from a New Zealand based research group began to raise concern of potential detrimental effects in both men and women.^(24,25) The first secondary analysis of an RCT designed to assess changes in BMD in postmenopausal women suggested a significant increased risk (HR: 1.43, CI 95%: 1.01–2.04; p = 0.043) for the combined endpoints of myocardial infarction, stroke, or sudden death in the unadjusted analysis; however, after adjustment for known cardiovascular risk factors statistical significance was lost.⁽²⁴⁾ The next secondary analysis of a separate RCT designed to assess changes in BMD in men reported only 3 myocardial infarctions among the 323 study participants.⁽²⁵⁾ At the time, the newly published WHI reported no statistical differences in the treatment vs. placebo in regard to cardiovascular disease.⁽¹³⁾ The New Zealand group followed-up with publication of meta-analysis of RCTs of high vs. low calcium supplementation,⁽²⁶⁾ as well as, a separate manuscript reporting an updated meta-analysis of high vs. low calcium supplementation that included subgroup analyses from the WHI limited access dataset.⁽²⁷⁾ Experts in the field of refuted these findings in response to widespread media coverage, several methodological discrepancies within the four studies, and the lack of biological plausibility.^(28–35) In 2010 investigators from Brigham and Women’s Hospital and Harvard School of Public Health conducted a systematic review and high vs. low meta-analysis that included data from both RCTs and prospective cohort studies. The group reported limited evidence suggesting vitamin D supplements at moderate to high doses may reduce CVD risk, whereas calcium supplements did not seem to exert any cardiovascular effects.⁽³⁶⁾ To further provide clarity, the NOF provided an unrestricted educational grant to the WHI investigators to conduct an independent and comprehensive analysis of the WHI dataset. The investigators reported no evidence for an adverse effect of calcium supplementation on risk for myocardial infarction, coronary heart disease, total heart disease, stroke, or total cardiovascular disease from the clinical trial, observational follow-up study (n = 93,676), or combined analysis. The observational follow-up study data alone suggested a reduction in total heart disease risk and total cardiovascular disease risk among supplement users. Interestingly, the small but significant incremental risk of urinary tract stones reported in the original WHI intent-to-treat analyses was not apparent in the secondary analysis, even among women taking personal calcium supplements on top of the prescribed treatment regimen.⁽¹⁴⁾ Since this time, researchers have continued to conduct secondary analyses of markers and endpoints present across numerous prospective cohorts, most of which report null findings.

To inform a joint position statement and clinical guideline from the NOF and American Society for Preventive Cardiology (ASPC), the groups commissioned an independent focused update and reanalysis⁽³⁷⁾ of two broader evidence reports utilizing dose-response meta-analyses,^(16,38) originally developed to inform the development of new Dietary Reference Intakes (DRIs) for calcium and vitamin D⁽³⁹⁾ and recommendations from the U.S. Preventive Services Task Force.⁽⁴⁰⁾ Data analyses from RCTs, prospective cohort studies, and one nestled case-controlled study failed to show any consistent dose-response relationships between calcium intake levels and CVD risk in generally healthy adults.⁽³⁷⁾ The expert panel authoring the position and clinical guideline also considered a novel rare isotope ⁽⁴¹⁾Ca study that found no detectable effect of calcium carbonate on coronary calcium deposition (discussed below).⁽⁴¹⁾ In 2016, the NOF and ASPC adopted the position and clinical guideline that there is “moderate-quality evidence (B-level) that calcium with or without vitamin D from food and supplements has no relationship (beneficial or harmful) on the risk of cardiovascular, cerebrovascular, or all-cause mortality in generally healthy adults. In light of evidence available to date, calcium intake from food and supplements that does not exceed the tolerable upper intake level (UL) should be considered safe from a cardiovascular standpoint.”⁽⁴²⁾

In a recent issue of the Journal of the American College of Nutrition, Yang et al. (2019) report findings from yet another meta-analysis of high vs. low calcium RCTs and prospective cohort studies. A handful of studies have been published since the NOF and ASPC position and clinical guideline; none demonstrate statistically significant beneficial or detrimental effects. It is unlikely that these new studies would influence the results of the Chung et al. (2016)⁽³⁷⁾ dose-response meta-analysis, a more appropriate statistical model for assessing a potential benefit or detriment of nutrient intakes on chronic disease markers or outcomes. Exclusion of studies with doses <800 mg/d of supplemental calcium in the Yang et al. 2019 meta-analysis is particularly problematic, since the adult human GI tract can only absorb 500 to 600 mg of calcium at one time⁽⁴³⁾ and because the majority of over-the-counter calcium supplements currently on the market contain less than 800 mg of calcium per serving. Furthermore, high vs. low meta-analyses or “extreme-quantile meta-analyses” produce uninterpretable pooled results, because the ranges of highest and lowest quantile categories of calcium intake vary substantially across studies,⁽³⁷⁾ a broad disadvantage of these types of meta-analyses in nutrition science. However, systematic review and dose-response meta-analysis of prospective cohort studies play an important role in evidence-based clinical guidelines, as often RCTs of dietary interventions examine only biomarkers and/or intermediate outcomes of chronic disease.⁽⁴⁴⁾ Data syntheses from population-based, prospective cohort studies of the dose-response relationship between dietary exposure and long-term chronic disease outcomes may provide the best available clinical outcome evidence for clinical or policy decision-making.

Although there are potential adverse effects of calcium supplementation on vascular calcification in patients with chronic kidney disease (CKD),⁽⁴⁵⁾ the mechanism differs in adults with normal kidney function (note: kidney function is not typically adjusted for in the majority of published prospective cohorts analyses). Patients with CKD, as well as those with diabetes, typically develop vascular calcification in the medial layers that causes arterial stiffness,⁽⁴⁶⁾ and this occurs even when dietary calcium intakes are low and absent of supplemental intake. In contrast, individuals with normal renal function tend to develop plaque calcification in the intima that causes reduced vascular compliance. Myocardial infarction occurs because of occlusion of a coronary artery. Atherosclerotic lesions calcify as a result of local tissue factors and not circulating calcium concentrations, which are under tight homeostatic control. Among generally healthy individuals, calcium deposits in the body occur in areas of previous tissue damage and consist principally of calcium phosphate (CaHPO₄) and for that crystal form, the serum (at physiological pH and pCO₂) is only half saturated (i.e., for this salt there is no solubility issue or “physical-chemical pressure” to form calcific deposits).⁽²⁸⁾ There is a minute absorptive increase in extracellular fluid calcium (Ca²⁺) amounting, at C_max to ∼0.025 mmol/L for each 100 mg of calcium in an ingested load. That is a maximum figure, and most extracellular fluid concentrations will be less. The small increase in serum calcium concentrations with supplementation has long been suggested by experts to be unlikely to influence calcification of damaged tissue anywhere in the body.⁽²⁸⁾ Contrary, an acute 1 g dose of calcium citrate in humans was found to elevate serum calcium, suppress serum PTH, decrease arterial wave reflection, and increase myocardial perfusion by pulse wave analysis,⁽⁴⁷⁾ suggesting that cardiovascular function is not adversely affected by an acute rise in serum calcium. Data from the Framingham Study also suggest a null relationship between high calcium intakes and coronary artery calcification, as measured by computed tomography.⁽⁴⁸⁾ This was recently confirmed using the rare isotope⁽⁴¹⁾ Ca, that can be detected at 10⁻¹⁸ M concentrations by Accelerator Mass Spectrometry, in order to determine early coronary artery calcium deposition. Using Ossabaw miniature swine that develop diet-induced atherosclerosis similar to humans, high calcium diets approaching the tolerable upper intake level (UL) for humans from neither calcium carbonate supplements or dairy increased coronary artery calcification nor decreased endothelial function,⁽⁴¹⁾ raising serious doubt about calcium supplementation and the risk of CVD. A recent Mendelian randomization study reported a genetic predisposition to higher serum calcium levels was weakly associated with increased coronary artery disease (CAD) and myocardial infarction; however, the study did not report whether dietary or supplemental calcium influenced this risk.⁽⁴⁹⁾ Prolonged calcium supplementation has been shown to have little effect on serum calcium levels, because of its homeostatic regulation, but significantly affects urinary calcium levels. In postmenopausal women serum calcium levels did not to change after one year of consuming of calcium supplements.⁽⁵⁰⁾ This finding is consistent with a shorter-term RCT of adults 50+ years showing no difference in serum calcium levels after 3-months of supplementation with 600 mg calcium triphosphate.⁽⁵¹⁾ Only large-scale randomized trials designed to investigate the effects of calcium supplementation on CVD events as the primary end point, as well as short-term trial investigating the effect on coronary biomarkers can provide a definitive answer.

Tissues sense diet-induced changes in serum nutrient concentrations or in hormonal factors altered by the diet, but not the source of a nutrient (dietary or supplemental). Calcium supplements typically constitute either carbonate or citrate salts, with phosphate, hydroxide and other anions representing a minor fraction of the products on the market. These calcium salts are fortified into many staple food products (e.g., orange juice, milk-alternatives and cereal) which have not been shown to exert any detrimental effects regarding CVD risk. Meeting calcium requirements from the diet is prudent since many other nutrients and dietary bioactive compounds are also present in the food matrix. Dairy products provide most of the calcium in the diet. Few calcium fortified foods provide similar bioavailable forms of calcium in amounts that can serve as alternatives to dairy.⁽⁵²⁾ The Dietary Guidelines for Americans recommend 3 servings/d of low or nonfat dairy products or dairy alternatives.⁽⁵³⁾ For every absent serving supplementation with 300 of calcium is advised to meet recommended intakes.⁽⁵⁴⁾ The hypothesis that calcium supplements may have a causal inference on cardiovascular events is founded upon a small portion of secondary analyses of RCTs and observational analyses lacking appropriate primary outcome measures, consideration of kidney function and other potential confounders as covariates, and a small number of events mostly self-reported and non-adjudicated. More importantly, the hypothesis currently lacks biological plausibility and is likely a methodological Confound.

Taylor C. Wallace Think Healthy Group, Inc, Washington, DC, USA; Department of Nutrition and Food Studies, George Mason University, Fairfax, Virginia, USA [email protected] Connie M. Weaver Weaver & Associates Consulting, LLC, West Lafayette, Indiana, USA

Disclosure statement

TCW has received competitive research grants from Pfizer Consumer Healthcare (now GSK), the National Dairy Council, and various food/beverage manufacturers. All of his conflicts of interest can be found at www.drtaylorwallace.com.

CMW has received competitive research grants from the National Dairy Council and is a member of the scientific advisory board for Pharmavite, LLC.