Calcium supplementation is usually associated with a small increase in serum calcium and a consequent decrease in serum PTH, with both usually remaining in the normal range. This modest rise in serum calcium is considered unlikely to lead to extraskeletal calcification [17]. Clinical trials of PTH and its analogs in osteoporosis subjects have demonstrated mild transient increases in serum calcium, which do not appear to have detrimental cardiovascular effects [18]. That being said, some observational studies still question the link between transient hypercalcemia, endothelial dysfunction, atherosclerosis, and arterial stiffness [19]. These findings are in line with recent Mendelian randomization studies. These studies take a genetic epidemiological approach to estimate causality and have suggested a positive causal influence of transient increases in serum calcium on increased cardiovascular disease risk, especially for myocardial infarction (MI) [20-23]. However, this increase in cardiovascular disease risk was not observed with higher intake of dietary calcium [24]. Calcium supplementation could have favorable effects on lipids and blood pressure. An RCT examining the effect of calcium supplementation (1 g of calcium citrate) compared to placebo on lipid profiles in 223 postmenopausal females showed that calcium citrate supplementation was associated with a 7% increase in high-density lipoprotein (P=0.01) and a 6% decrease in low-density lipoprotein (P=0.09) at 1 year of follow-up [25]. Other data suggest that transient hypercalcemia and reduction in PTH in subjects taking calcium supplements may be associated with decreased blood pressure [17,26]. A systematic review of 42 trials examining the effect of calcium supplementation on blood pressure showed a reduction in systolic blood pressure by 1.44 mm Hg (95% CI, –2.20 to –0.68; P<0.001) and in diastolic blood pressure of 0.84 mm Hg (95% CI, –1.44 to –0.24; P<0.001) [26]. A study specifically investigating insulin sensitivity and calcium supplementation showed an association of calcium supplementation with increased insulin sensitivity [27]. This was also a finding in the multicenter Insulin Resistance Atherosclerosis Study, which examined the cross-sectional association between calcium intake (mean±standard deviation: 970 mg of elemental calcium±647 mg) and insulin resistance in 1,036 adults without diabetes [27]. Furthermore, plaque rupture in advanced cardiovascular disease is not thought to involve calcium [28]. In a post hoc analysis of nine randomized trials investigating the effect of calcium supplementation on calcium indices (CaI) and atheroma volume (AV), calcium supplementation was associated with an increase in the annualized CaI (odds ratio, 1.15; P=0.004) and no change in AV. Although the authors adjusted for multiple confounders, one of the limitations of this study is that the participants were asked about their “medication use” rather than their “supplement” use [29]. Manson et al. [30] investigated the effect of calcium supplementation (1,000 mg) and vitamin D (400 IU) on the coronary artery calcium (CAC) score in a substudy of the WHI trial. The CAC score was measured at baseline and after 7 years of study in 754 women aged between 50 and 59 years old. There was no significant difference in the CAC score between calcium and vitamin D-supplemented versus non-supplemented patients [30]. The Multi-Ethnic Study of Atherosclerosis was a 10-year observational study of calcium intake in elderly individuals. This study concluded that high total calcium intake was associated with a decreased risk of atherosclerosis, specifically if this was achieved from diet. However, after accounting for total calcium intake, calcium supplements were associated with incident CAC [24]. Interestingly, it has been shown that calcified carotid plaques are less likely to cause symptoms than non-calcified ones, suggesting that calcium can make plaques more stable and less likely to rupture [31]. The potential effects of calcium supplementation on parameters associated with cardiovascular risk are summarized in Fig. 1.

The cutoff to define vitamin D deficiency is controversial, with most guidelines considering a level less than 20 to 30 ng/mL as deficient [32-34]. Around one-third of the global population is affected by vitamin D deficiency when a cutoff of 20 ng/mL is used to define hypovitaminosis D [33]. Multiple conditions can lead to vitamin D deficiency, including low vitamin D intake, inadequate exposure to sun, use of sunscreens, obesity, aging, malabsorption syndromes (such as celiac disease, bariatric surgery, small intestine disorders) liver disease, chronic renal failure, hypoparathyroidism, antiseizure medications, and certain genetic diseases (defective 25-hydroxyvitamin D-1α hydroxylase) [35].

A number of observational studies have reported that subjects with low serum 25-OHD have increased risks of cardiovascular diseases, including MI, congestive heart failure, stroke, peripheral vascular diseases, and mortality [36-41]. A meta-analysis of prospective studies with 6,123 cardiovascular events in 65,994 individuals showed a linear, inverse association between circulating 25-OHD in the range of 8 to 24 ng/mL and the risk of cardiovascular disease with a RR of 1.03 (95% CI, 1.00 to 1.06) per 10 ng/mL decrement in 25-OHD levels [42]. Such observational studies are limited by their inability to prove causality and by the presence of multiple confounding factors [43]. The proposed mechanisms for the cardiovascular effects of low vitamin D are activation of the renin angiotensin aldosterone system, hypercoagulability, increased arterial stiffness, and endothelial dysfunction [43,44].

Mendelian randomization studies have not found a link between genetically determined differences in 25-OHD levels and cardiovascular endpoints [45-47]. In a recent very large Mendelian randomization study, there was an inverse relationship of vitamin D levels with all-cause mortality in people with 25-OHD levels <10 ng/mL; however, the associations with stroke and coronary heart disease were not statistically significant [48].

Vitamin D receptors are ubiquitous, with expression in many tissues; this explains the pleiotropic effects of vitamin D. Vitamin D receptor-deficient mice have increased renin expression, increased thrombogenesis, and more hypertension and cardiac hypertrophy than controls [49,50]. Chronic kidney disease patients are at risk of vitamin D deficiency, mainly driven by the decline in the activation of 25-OHD to 1,25-dihydroxyvitamin D. Fibroblast growth factor 23 (FGF23) levels are high in chronic kidney disease patients, and it was shown that this elevated level is associated with atherosclerosis and ventricular remodeling [51].

The controversies regarding cardiovascular safety of calcium and vitamin D replacement started with the WHI study. The study had a calcium/vitamin D arm where women with generally adequate calcium and vitamin D (including women taking supplements at baseline) were given additional calcium (1,000 mg) and vitamin D (400 IU) daily supplements or placebo. During 7 years of follow-up, neither MI/coronary heart disease, death, nor stroke showed differences between treatment groups (HR, 1.04; 95% CI, 0.92 to 1.18 and HR, 0.95; 95% CI, 0.82 to 1.10, respectively). Although this trial indicated a safe profile of calcium and vitamin D supplementation, it should be noted that the cardiovascular outcomes were prespecified as secondary outcomes (Table 1) [52]. The cardiovascular safety of calcium and vitamin D supplements was accepted until the work of Bolland et al. [53] in 2008 regarding a secondary analysis of an RCT where 1,471 postmenopausal New Zealand females, with a mean age of 74 years, were randomized to 1,000 mg of elemental calcium (without vitamin D) or placebo. Unlike the WHI trial, women taking calcium supplements at baseline were excluded. Although there was a statistically significant increase in the rate of self-reported MI in the calcium group compared to placebo (RR, 2.24; 95% CI, 1.20 to 4.17), the risk of angina, stroke, or the composite outcome (angina, chest pain, MI, or sudden death) was not significantly different between groups (Table 1). Moreover, an analysis of confirmed cardiovascular events attenuated the MI RR to 2.12 (95% CI, 1.01 to 4.47), and there was no significant difference in the composite endpoint of stroke, MI, and sudden death (RR, 1.47; 95% CI, 0.97 to 2.23) [53]. These study results have been challenged for a number of reasons. This was a secondary analysis of a study that was powered to detect bone density and fracture data, but not cardiovascular endpoints; there was a higher baseline risk for CV outcomes in patients assigned to the active calcium arm; and the results were inconsistent between the different cardiovascular outcomes [53]. These questions led Bolland et al. [54] to re-examine the WHI data according to baseline calcium and vitamin D supplementation. They hypothesized that calcium and vitamin D supplementation at baseline in the WHI study may have masked any potential cardiovascular risk of calcium supplementation [54]. Surprisingly, the data showed that in women not taking calcium supplements at baseline, the HR for cardiovascular events in subjects taking calcium and vitamin D supplements ranged from 1.13 to 1.22 (P=0.05 for clinical MI or stroke, P=0.04 for clinical MI or revascularization), while in women taking calcium supplements at baseline, the cardiovascular risk did not differ between treatment arms [54]. The gastrointestinal side effects of calcium supplementation can be mistaken by patients as symptoms of MI when this outcome is defined by patient self-reports; adjudication of cardiovascular events is therefore important [55]. To overcome this, Lewis et al. [56] conducted an RCT comparing calcium (1,200 mg daily) to placebo in 1,460 elderly women, with adjudicated cardiovascular endpoints. In that study, calcium supplementation was not associated with a higher risk of death or first-time hospitalization from atherosclerotic cardiovascular disease (HR,0.938; 95% CI, 0.690 to 1.275) (Table 1) [56]. In the long-term follow-up of the Randomized Evaluation of Calcium Or vitamin D (RECORD) trial, a subsequent randomized trial of calcium and vitamin D supplementation versus placebo, taking supplements was not associated with an increased risk of cardiac events (Table 1) [57]. More recent studies have also failed to demonstrate any increased cardiovascular risk in those taking calcium supplements. In 2013, Cauley et al. [58] reported the 5-year post-intervention outcomes of the WHI study. There were no significant differences in the risk of MI, stroke, and death between the calcium/vitamin D group and placebo. Interestingly, the same results were also seen when patients were examined according to their being on prior calcium at randomization or not [58]. Further safety data were reported from the UK biobank, a large prospective cohort including 475,255 participants (median age 58 years, 55.8% women). In a publication investigating the association between calcium and vitamin D supplementation and incident cardiovascular events including mortality, there was no association between calcium supplements and incident hospital admission for either ischemic heart disease or death [59]. In a large prospective cohort study of 132,823 participants followed for 17.5 years who consumed at baseline 1.5 to 1.7 dairy servings, higher all-cause mortality was observed in men who were taking ≥1,000 mg calcium supplements (RR, 1.17; 95% CI, 1.03 to 1.33) [60]. There was a dose-dependent inverse relationship between calcium supplementation and all-cause mortality in females for calcium intake of 0.1 to <500, 500–<1,000, and ≥1,000 mg/day, respectively (RR, 0.90; 95% CI, 0.87 to 0.94; RR, 0.84; 95% CI, 0.80 to 0.88; and RR, 0.93; 95% CI, 0.87 to 0.99). Interestingly, there was no association between dietary calcium and mortality in both males and females [60]. In a population-based, prospective cohort study of 34,468 patients with a median dietary calcium intake of 792 mg/day (interquartile range, 428 mg/day), calcium intake was not associated with higher cardiovascular death, MI, and stroke [61]. Several observational studies found that dietary calcium (total less than 1,500 mg) levels were not associated with cardiovascular disease endpoints [62,63]. An analysis of data from 35,983 women in the WHI study did not show a reduction in incident heart failure in the calcium and vitamin D group compared to placebo in the overall population (HR, 0.95; P=0.46) but a lower risk for heart failure in the low-risk group (patients without heart failure precursors at baseline, such as coronary artery disease, hypertension, and diabetes) (HR, 0.63, 95% CI, 0.46 to 0.87) [64]. Several other cohort studies reported conflicting results as to whether calcium supplementation can cause cardiovascular harm [65-73].

Given the heterogeneity in the results of studies of calcium supplementation, Bolland et al. [74] in 2010 published a meta-analysis of the effect of calcium supplementation on cardiovascular outcomes. The trial-level analysis showed that calcium supplementation was associated with a higher risk of MI (RR, 1.27; 95% CI, 1.01 to 1.59), but not with stroke, composite endpoints, or death. Similarly, the patient-level analysis showed that the risk of MI increased by 31% in the group taking calcium (HR, 1.31; 95% CI, 1.02 to 1.67), with no significant differences in other cardiovascular outcomes [74]. This meta-analysis had multiple limitations, including the fact that cardiovascular outcomes were secondary outcomes, there was some self-reporting of outcomes, and there were differences in the administered calcium supplements [74]. In order to incorporate the WHI patients without baseline calcium supplementation in the meta-analysis, Bolland et al. [54] conducted another systematic review, including three RCTs. The pooled analysis showed again that calcium and vitamin D supplementation was associated with an increased risk of MI (RR, 1.21; P=0.04), stroke (RR, 1.2; P= 0.05), and the composite of MI or stroke (RR, 1.16; P=0.02) [54]. These data are limited by the heterogeneity of the studies and cardiovascular outcomes reported, the selection bias by including only the WHI patients not on baseline supplementation, and the fact that cardiovascular endpoints were secondary outcomes [54]. In 2013, a systematic review of calcium and vitamin D supplementation by Mao et al. [75] showed that calcium and vitamin D supplementation was not associated with a statistically significant difference in major cardiovascular events. In 2015, Lewis et al. [76] published a systematic review of 18 RCTs comparing calcium and vitamin D supplementation versus placebo. They found no significant differences in coronary heart disease hospitalization or death in five trials between calcium with or without vitamin D and control with a pooled RR of 1.02 (95% CI, 0.96 to 1.09; P=0.51). Pooled data from 17 trials showed no difference in all-cause mortality, with an RR of 0.96 (95% CI, 0.91 to 1.02; P=0.18). There were also no significant differences in the individual outcomes of MI, angina, and chronic coronary heart disease. A sensitivity analysis excluding patients in the WHI trial with baseline intake of calcium and vitamin D also showed no cardiovascular associations [76]. In 2016, a systematic review by Chung et al. [77] included clinical trials, prospective cohort studies, and case-control studies. This review again did not show a significant difference in cardiovascular events or mortality between calcium and vitamin D supplementation and placebo, although cardiovascular disease endpoints were secondary outcomes in all included trials [77]. A more recent systematic review in 2020 pooled 89,251 community-dwelling participants from RCTs examining the effect of calcium and vitamin D supplements compared to placebo. There was no significant difference in all-cause mortality between the experimental groups (calcium alone, vitamin D alone, or combination) and the control group. A pooled analysis showed that calcium supplementation was not associated with risk of MI and major adverse cardiovascular events [78].

Overall, there is no convincing evidence of cardiovascular harm from either dietary calcium or supplemental calcium (total up to 1,200 mg) and vitamin D.

Historically, the effect of vitamin D on cardiovascular outcomes was controversial and based mainly on studies where the primary endpoints were related to bone health [43]. In the last few years, three large RCTs have helped to answer the question of the cardiovascular effects of vitamin D supplementation. The Vitamin D Assessment Study (ViDA) was a 3.3-year randomized placebo-controlled trial investigating the effect of a vitamin D loading dose of 200,000 IU, followed by 100,000 IU monthly or placebo in 5,110 participants aged 50 to 84 years. The subjects had a mean serum 25-OHD of 25.3±9.5 ng/mL at baseline, and were recruited mostly from family practices in Auckland, New Zealand, with the primary outcomes of incident cardiovascular disease and death. The study showed no significant difference between vitamin D and placebo for all cardiovascular endpoints, with a combined HR of 1.02 (95% CI, 0.87 to 1.20) (Table 2) [79]. However, vitamin D-deficient individuals on vitamin D supplements demonstrated lower systolic blood pressure than controls (–7.5 mm Hg; 95% CI, –14.4 to –0.6 mm Hg; P=0.03) [80].

The VITamin D and OmegA-3 TriaL (VITAL) trial was an RCT randomizing subjects to vitamin D3 (2,000 IU daily) over 5.3 years with a primary endpoint of cardiovascular events. The trial enrolled 25,871 subjects including men over 50 years and women over 55 years. There was no significant difference in composite major cardiovascular events (MI, stroke, and cardiovascular death) (HR, 0.97; 95% CI, 0.85 to 1.12) (Table 2) [81]. The D-Health trial was a randomized placebo-controlled trial of 21,315 participants over 60 years in Australia comparing 60,000 IU of vitamin D3 monthly to placebo for 5 years. This study showed no significant difference between vitamin D supplementation and placebo in the primary outcome of all-cause mortality and the secondary outcome of cardiovascular mortality (HR, 1.04; 95% CI, 0.93 to 1.18) and 0.96 (95% CI, 0.72 to 1.28) respectively. Serum 25-OHD was not measured as the hypothesis was to examine the potential benefit of vitamin D supplementation in the unscreened population. It is worth mentioning that all-cause mortality was the primary outcome and cause specific mortality was not prespecified in the protocol (Table 2) [82].

In a recent meta-analysis of 21 RCTs (including both the ViDA and VITAL trials, but not the D-Health trial) with over 83,000 patients mean age 65.8 years, vitamin D supplementation was not associated with a reduced risk of major adverse cardiovascular events (RR, 1.00; 95% CI, 0.95 to 1.06; P=0.85), individual cardiovascular endpoints (MI, stroke, or cardiovascular disease mortality), or all-cause mortality compared to placebo [83]. The result of these RCTs and a systematic review consistently showed the safety of modest doses of vitamin D supplementation, but a lack of cardiovascular benefits.