Can supplemental calcium increase cardiovascular risk?
A meta-analyses of randomised controlled studies of calcium supplementation (some including concurrent modest intakes of vitamin D) has observed a modest increase in risk for vascular events in the calcium-supplemented subjects.1 Some recent observational epidemiology in prospective cohorts has also linked supplemental calcium to increased vascular risk.2–4 Yet, rather perplexingly, relatively high dietary intakes of calcium have been associated with cardiovascular protection, or a neutral outcome in this regard.2 3 5 6 Moreover, there are theoretical grounds for expecting that superior calcium nutrition could be protective for vascular health. High-calcium diets decrease secretion of parathyroid hormone; even mild secondary hyperparathyroidism, common in the elderly, is suspected to increase vascular risk.7 8 A high calcium intake also tends to suppress absorption of dietary phosphate by forming an insoluble complex with it; emerging data suggest that high phosphate intakes may increase cardiovascular risk, even in those with normal renal function.9 High calcium intakes have not been found to correlate with increased risk for vascular calcification.10 The acute vascular impact of the modest rise in serum calcium following a bolus oral dose of calcium citrate has been studied; relative to placebo, arterial stiffness declined and myocardial perfusion increased in the calcium group.11 However, the diurnal decline in blood pressure was not as high in calcium-supplemented subjects and a coagulation index (thromboelastography) increased.12
What could explain the increased risk for vascular events associated specifically with calcium supplementation in some controlled studies? Even if subsequent analyses fail to confirm a net negative impact of calcium supplementation on vascular health—this issue is hotly debated and cannot be considered resolved5 13–15—the fact that calcium could be expected to protect the vasculature for certain reasons suggests that it must be exerting some countervailing negative effect even if its impact on vascular health is neutral.
The acute impact of bolus calcium on coagulation mechanisms, as noted above, merits further study. Also, a high calcium intake might increase secretion of renin—which increases cardiovascular risk16 via the prohypertensive, pro-oxidative effects of angiotensin II—by suppressing renal synthesis of calcitriol.17 Only a few pertinent clinical studies are currently available in this regard,18 19 however, and this prediction requires more verification in clinical studies using realistic supplemental intakes of calcium. Moreover, this explanation leaves unexplained the seeming discrepancy between the apparent cardioprotection of dietary calcium versus the potential cardiotoxicity of supplemental calcium.
Consideration should, therefore, be given to the possibility that, in some individuals, high supplemental intakes of calcium may disturb magnesium balance.20 A great deal of recent epidemiology, including meta-analyses, points to higher dietary magnesium intakes, and/or higher serum magnesium levels, as associated with reduced risk for vascular events, arrhythmias, diabetes, hypertension, metabolic syndrome, vascular calcification and mortality.21–41 Although to some degree these observations likely reflect the benefits of consuming nutrient-rich whole foods, rather than just magnesium per se, magnesium still often emerges as protective after multiple regression analyses which try to adjust for this effect. Moreover, short-term studies of magnesium supplementation in persons at high cardiovascular risk have often found protective effects, particularly in those with low baseline magnesium status. Notably, in patients with coronary disease, magnesium supplementation has been found to decrease ex vivo platelet-dependent thrombosis, increase flow-mediated vasodilation of the brachial artery and during exercise, increase exercise tolerance, VO2max and left ventricular ejection fraction.42–46 A meta-analysis of placebo-controlled studies evaluating the impact of supplemental magnesium on treated hypertensives with baseline systolic pressure >155 mm Hg, found a mean reduction of 18.7 and 10.9 mm Hg in systolic and diastolic pressures, respectively, with high statistical significance.47 The mechanism of the apparent benefits conferred by good magnesium status requires further study, but it is suspected that magnesium antagonises some of the proinflammatory effects of increased cytoplasmic calcium.20 48–52 Indeed, magnesium has sometimes been referred to as ‘nature’s physiological calcium blocker’.53–55 For example, in physiological intracellular concentrations, magnesium competes with calcium for binding to calmodulin and other ‘EF-hand’ calcium-binding proteins, such that magnesium-bound proteins assume an ‘off’ configuration.50 52 The apparent ability of good magnesium status to diminish risk for vascular calcification is intriguing in light of recent epidemiology pointing to increased risk of coronary calcification in people using calcium supplements.4 40 41 56 Figure 1 depicts the inverse association between total dietary magnesium intake and risk for arterial calcification.56