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Vitamin D, Calcium Supplements, and Implications for Cardiovascular Health: JACC Focus Seminar

JACC Focus Seminar

J Am Coll Cardiol, 77 (4) 437–449
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Central Illustration

Abstract

Vitamin D and calcium supplements are commonly used, often together, to optimize bone health. Multiple observational studies have linked low serum 25-hydroxyvitamin D concentrations with increased cardiovascular risk. However, subsequent randomized controlled trials (RCTs) failed to demonstrate cardiovascular benefit with vitamin D supplementation. Although vitamin D supplements do not appear to be harmful for cardiovascular health, the lack of benefit in RCTs should discourage their use for this purpose, favoring optimizing vitamin D status through healthy lifestyles such as specific foods and modest sunlight exposure. Furthermore, some (but not all) observational and RCT studies of calcium supplementation have suggested potential for cardiovascular harm. Therefore, calcium supplementation should be used cautiously, striving for recommended intake of calcium predominantly from food sources. In this review, the authors examine the currently available evidence investigating whether vitamin D and calcium supplements are helpful, harmful, or neutral for cardiovascular health.

Highlights

In observational studies, low blood levels of 25-hydroxyvitamin D have been associated with elevated cardiovascular risk.

In randomized trials, however, vitamin D supplementation has not reduced cardiovascular risk.

Some studies have found increased risk with calcium supplementation.

Available data suggest that calcium intake should derive largely from dietary sources.

Introduction

Vitamin D and calcium supplements are commonly used, often together, as means to optimize bone health. In the United States, more than one-third of adults consume these supplements, and among older adults, the prevalence is much higher (1,2). Given their widespread availability, low cost, and escalating use, the cardiovascular effects of such supplements are of great clinical and public health interest from the standpoints of both cardiovascular safety and cardiovascular health promotion (3).

Substantial epidemiological observational science has consistently and independently linked low blood concentrations of vitamin D, as measured by serum 25-hydroxyvitamin D (25[OH]D), to elevated cardiovascular disease (CVD) risk (4–12). However, subsequent large randomized controlled trials (RCTs) of vitamin D supplementation and meta-analyses of these trials did not confirm a cardiovascular benefit, even among subgroups characterized by inadequate or deficient vitamin D status defined by serum 25(OH)D concentrations <20 ng/ml (13–15). In light of null RCT findings, it is now widely considered that the previously reported associations of higher serum 25(OH)D concentrations with favorable cardiovascular outcomes were likely driven by confounding by other risk and health factors (16). For example, low 25(OH)D concentrations might be due to obesity or limited physical activity outdoors, which are associated with worse cardiovascular outcomes, or with unknown factors that reduce 25(OH)D and increase cardiovascular risk. Alternatively, exogenous pill-based supplements may not be able to provide the health benefits obtained through other more natural sources of vitamin D. Regardless, the sun may be setting on the use of the “sunshine vitamin” to improve cardiovascular health through oral supplementation.

Further complicating the vitamin D supplementation picture is the fact that calcium supplements, used by more than 40% of adults (2), are often prescribed concurrently with vitamin D to optimize bone health. Adequate calcium intake is important for the development and maintenance of bone density. However, unlike vitamin D supplements, which are relatively safe except in very high doses, calcium supplements have been associated with an increased risk for CVD events in some studies, but not all (17), including data from both observational (18–21) and RCT (22–24) studies. This excess cardiovascular harm has not been seen with calcium intake from food sources (21,24). Calcium supplements, either alone or in combination with vitamin D, have also been linked to other adverse effects, such as kidney stones (25). Risks related to calcium supplementation may be due to formulation, dosing, and whether used concomitantly with vitamin D.

In this review, we examine the currently available observational and experimental evidence investigating whether vitamin D and calcium supplements are helpful, harmful, or neutral for cardiovascular health (Central Illustration). We provide a critical appraisal of published studies, focusing mostly on RCTs, and make recommendations for clinicians and patients on the basis of currently best available evidence.

Central Illustration
Central Illustration

Vitamin D and Calcium Supplements for Cardiovascular Health: Evidence From Observational and Interventional Studies and Clinical Recommendations

Putting evidence to practice: recommendations for patients and practitioners regarding vitamin D and calcium supplements and implication for cardiovascular health. CV = cardiovascular; CVD = cardiovascular disease; MI = myocardial infarction; RCT = randomized controlled trial.

Vitamin D Metabolism

Vitamin D, a fat-soluble vitamin, is critical for the maintenance of bone mineral density (26,27). Vitamin D is the precursor to the active steroid hormone of 1,25-dihydroxyvitamin D (1,25[OH]2D), known as calcitriol, a key regulator of calcium and phosphorous homeostasis through actions in the intestine, kidneys, and bones. Activated vitamin D binding to the vitamin D receptor regulates transcription of hundreds of genes, including those involved in cell cycling, proliferation, differentiation, and apoptosis (28,29).

Vitamin D is obtained either exogenously as vitamin D3 (cholecalciferol) or D2 (ergocalciferol) from diet or supplements, or endogenously as D3 produced in skin. After ultraviolet B radiation from sunlight to the skin, 7-dehydrocholesterol is converted into pre-vitamin D3, which then isomerizes to vitamin D3 (30). The degree of endogenous vitamin D production depends on various factors, including latitude, season, skin pigmentation, degree of skin exposure, use of sunscreen, and age. Persons at risk for low 25(OH)D concentrations include those with obesity (as adipose tissue sequesters vitamin D), those with malabsorption conditions (who do not absorb enough vitamin D from foods), older adults (who have fewer 7-dehydrocholesterol precursors in their skin, reducing their capacity for vitamin D3 production), certain racial and ethnic groups including black individuals (as increased skin pigmentation inhibits vitamin D production), and those who live at higher latitudes, have reduced outdoor activity, or use sunscreen, which are factors associated with reduced ultraviolet B radiation and thus less vitamin D production (26). Traditionally, endogenous cutaneous synthesis was a main source of vitamin D for most people (31), as there are few food sources that naturally contain vitamin D (found primarily in oily fish, liver, and egg yolks), and even fortified foods generally contain only low amounts of vitamin D (for example, 100 IU in 8 oz of milk [26]). Now, a major source of vitamin D is from supplements, which have steadily increased in use over the past 2 decades (32,33).

Vitamins D3 and D2 are then further hydroxylated into 25(OH)D, which takes place predominantly in the liver. Circulating 25(OH)D concentration thus reflects both exogenous and endogenous sources and is considered the best biomarker of overall vitamin D status. It is important to note that 25(OH)D circulates predominantly in the bound form, with 85% to 90% of 25(OH)D bound to vitamin D–binding protein, 10% to 15% bound to albumin, and <1% being free (34,35). Clinical assays do not distinguish between bound and unbound 25(OH)D, so 25(OH)D may not accurately represent one’s bioavailable vitamin D status. Hence, searching for better markers of vitamin D status has been an active area of investigation (36). In the meantime, 25(OH)D is the current biomarker for assessing deficiency, inadequacy, and adequacy status.

25(OH)D is predominantly biologically inactive. However, under regulation by parathyroid hormone and fibroblast growth factor–23, 25(OH)D is converted to its active form of 1,25(OH)2D (calcitriol) by the 1α-hydroxylase enzyme, a process that occurs predominantly in the kidney (37). The half-life of calcitriol is short, and concentrations of 1,25(OH)2D are often normal or even elevated among individuals with vitamin D deficiency; therefore, calcitriol levels do not accurately represent vitamin D stores. Although circulating calcitriol reflects kidney production, the identification of extrarenal 1α-hydroxylase enzyme in nearly all nonskeletal tissue—including cardiomyocytes, vascular endothelial cells, and immune cells (38–40)—has led to speculation that local production of 1,25(OH)2D may have autocrine and paracrine functions important for many organs and biological systems, including the cardiovascular system (28).

Adequate Vitamin D Levels and Epidemiology of Vitamin D Insufficiency

On the basis of national data from 2011 to 2014, it is estimated that approximately 37% of the U.S. population took vitamin D supplements (41), and up to 61% of adults ≥65 years of age (1). To optimize bone health, the National Academy of Medicine (NAM) (formerly the Institute of Medicine) has stated that the recommended dietary intake of vitamin D for adults 19 to 70 years of age is 600 IU and for adults >70 years is 800 IU (42,43) (Table 1). The upper tolerable limit for vitamin D intake was stated at 4,000 IU/day, although this recommendation dates from 2010, and subsequent studies have suggested that the 4,000 IU/day dose may be associated with an increased risk for adverse events (44,45). However, a considerable proportion of U.S. adults use vitamin D supplementation in excess of these recommended allowances. In fact, the frequency of vitamin D supplement use >1,000 IU/day increased more than 60-fold between 1999 and 2014 (from 0.3% to 18.2%), and vitamin D supplement use >4000 IU/day increased by more than 30-fold (from 0.1% to 3.2%) (32). In many cases, users of supplements seem to do so without any clear medical indication but rather by their own initiative.

Table 1 Recommended and Maximal Tolerable Daily Intake of Vitamin D and Calcium (National Academy of Medicine)

Daily IntakeVitamin D Recommended Daily Allowance (IU)Vitamin D Maximal Tolerable Limit (IU)Calcium Recommended Daily Allowance (mg)Calcium Maximal Tolerable Limit (mg)
Age 19–50 yrs6004,0001,0002,500
Age 51–70 yrs (men)6004,0001,0002,000
Age 51–70 yrs (women)6004,0001,2002,000
Age >70 yrs8004,0001,2002,000

Vitamin D supplementation is typically used clinically to treat deficiency or insufficiency. However, there has been ongoing controversy about what 25(OH)D concentrations are considered “adequate” (46). Vitamin D deficiency had historically been defined as a 25(OH)D concentration <20 ng/ml (<50 nmol/l), with ≥20 to 29 ng/ml considered insufficient and ≥30 ng/ml considered optimal, cut points endorsed by the Endocrine Society (47) (Table 2). In contrast, the 2011 statement from NAM concluded that: 1) persons are at risk for vitamin D deficiency relative to bone health at serum 25(OH)D concentrations <12 ng/ml; 2) some, but not all, are potentially at risk for inadequacy at 25(OH)D between 12 and 20 ng/ml; 3) 25(OH)D ≥20 to 50 ng/ml should be adequate for bone health and overall health for the vast majority of Americans; and 4) concentrations >50 ng/ml place persons at potential risk for adverse events (42). Other experts have disagreed with the NAM cut points for adequacy (48) (Table 2). Importantly, the NAM suggests that serum 25(OH)D concentrations for optimal health have a distribution of values within a population, and therefore no single threshold level can define deficiency for an individual (42).

Table 2 Vitamin D Status by 25(OH)D Concentration per the National Academy of Medicine and the Endocrine Society

Vitamin D Status25(OH)D Concentration (ng/ml)
Institute of Medicine/National Academy of Medicine
 At risk for deficiency<12
 At risk for inadequacy≥12 to <20
 Adequate for health≥20 to 50
 At risk for adverse events>50
Endocrine Society
 Deficiency<20
 Insufficiency≥20 to <30
 Adequacy≥30

25(OH)D = 25-hydroxyvitamin D.

Using 2011 to 2014 data from the National Health and Nutrition Examination Survey, vitamin D deficiency (<12 ng/ml) was present in 7.6%, 5.7%, and 2.9% of adults 20 to 39, 40 to 59, and ≥60 years of age, and vitamin D inadequacy (12 to <20 ng/ml) in 23.8%, 18.6%, and 12.3% of those same age groups (41). Non-Hispanic blacks had greater prevalence of both vitamin D deficiency (17.5%) and inadequacy (35.8%) compared with non-Hispanic whites (2.1% and 11.8%, respectively). Using the higher insufficiency thresholds (<30 ng/ml) from the Endocrine Society, a substantial proportion of the U.S. population (overall 28% of whites and 81% of blacks) would be considered vitamin D insufficient, and among well-functioning community-dwelling older adults (70 to 79 years of age), 18% of whites and 54% of blacks met deficiency criteria (<20 ng/ml) (49). Note that despite their lower 25(OH)D concentrations, blacks on average have higher bone mineral density and lower fracture risks than whites. Thus, it has been challenged whether the same adequacy thresholds for 25(OH)D should apply to all racial groups (36).

Vitamin D and Cardiovascular Health

For many years, there was interest in the role of vitamin D in maintenance of cardiovascular health. Multiple mechanisms were proposed by which vitamin D might favorably interact with the cardiovascular system, including inhibition of the renin-angiotensin-aldosterone pathway, insulin sensitization, immune regulation, and antifibrotic, antihypertrophic, and antiatherosclerotic effects (50,51) (Figure 1). Low concentrations of vitamin D stores were thought to increase CVD risk in part through increased subclinical inflammation, endothelial dysfunction, arterial stiffness, and hypercoagulability, and by increasing the risk of established risk factors (hypertension, diabetes, and dyslipidemia) (3,16,52–55).

Figure 1
Figure 1

Vitamin D and Cardiovascular Disease: Proposed Mechanisms

Potential mechanisms linking low levels of serum vitamin D with increased cardiovascular risk. 25-OH-D = 25-hydroxyvitamin D; BP = blood pressure; CKD = chronic kidney disease; LV = left ventricular; R-A-A = renin-angiotensin-aldosterone.

The potential of vitamin D for blood pressure regulation has received considerable attention, with both observational meta-analyses (56) and Mendelian randomization studies suggesting a link between low 25(OH)D concentrations and hypertension risk (57), which was further bolstered by experimental evidence in animal studies (58). Vitamin D might also protect against diabetes through regulation of plasma calcium, which in turn regulates insulin synthesis and secretion or through direct action on pancreatic beta-cell function (59). Additionally, vitamin D might have antiatherosclerotic effects by inhibiting cholesterol uptake by macrophages and their conversion into foam cells (60).

Observational evidence on vitamin D level and risk for CVD

Observational studies have consistently linked low concentrations of 25(OH)D with increased risk for CVD events (4), including coronary heart disease (CHD) (5,7), myocardial infarction (MI) (6), stroke (8,9), peripheral arterial disease (10), heart failure (11), and all-cause mortality (61). Taken together, this line of research initially garnered much enthusiasm for the use of the “sunshine” vitamin to boost cardiovascular health. Nonetheless, associations do not mean causation, and observational studies can be plagued, among other biases, with issues of reverse causation and residual confounding, as many markers of good health versus poorer health are not measured or adequately assessed. For example, individuals with adequate vitamin D levels might be engaging in other health-promoting activities, such as being physically active outdoors (12) and eating a healthy diet. Additionally, as vitamin D is sequestered in fat tissue, individuals with lower concentrations of 25(OH)D may be less healthy because of increased adiposity and lower lean mass, which may not be fully accounted for in analyses that adjust for body mass index (62).

Furthermore, Mendelian randomization studies did not suggest a causal link between genetically predicted 25(OH)D concentrations and cardiovascular outcomes (63–65). Mendelian randomization studies, which test genetically determined biomarker levels with outcomes, are less susceptible to confounding or reverse causation than more classic observational studies.

RCTs of vitamin D supplements

The best evidence to guide clinical recommendations for patients comes from well-designed RCTs. Initially, there was insufficient evidence from RCTs to guide such recommendations. Older RCTs that reported on the association of vitamin D with CVD outcomes had relatively small sample sizes, used low doses of vitamin D, did not include CVD as a pre-specified outcome, or did not ascertain CVD outcomes in a rigorous fashion (Supplemental Table 1). For example, no cardiovascular benefit was seen in the WHI (Women’s Health Initiative) Calcium and Vitamin D Trial, which compared 400 IU/day vitamin D3 plus 1,000 mg calcium supplement with placebo (66), but the applicability of this study’s findings was questioned because of the low dose of vitamin D used. Hence, until recently, there was uncertainty regarding the cardiovascular benefits and harms of vitamin D supplementation.

Now, there is a substantial body of evidence from well-designed trials, most of which does not support a cardiovascular benefit of vitamin D supplements. The first trial was the ViDA (Vitamin D Assessment) study in New Zealand, an RCT of 5,108 community-dwelling residents 50 to 84 years of age who were randomized to vitamin D3 (initial dose of 200,000 IU followed by monthly doses of 100,000) versus placebo (13). After a median of 3.3 years, vitamin D supplementation was shown to increase serum 25(OH)D concentrations by more than 20 ng/ml compared with placebo (6-month levels of 51.7 vs 30.0 ng/ml for vitamin D vs. placebo, respectively), but the increase in 25(OH)D concentrations did not translate into a reduction in the primary outcome of incident CVD and death (hazard ratio [HR]: 1.02; 95% confidence interval [CI]: 0.87 to 1.20). Nor did vitamin D confer any reduction in any of the secondary outcomes of MI, stroke, heart failure, or venous thromboembolism. Importantly, there was no benefit in the approximately 25% of study participants with deficient or inadequate 25(OH)D concentrations <20 ng/ml. Of note, although vitamin D is used predominantly for bone health, high-dose vitamin D supplementation in the ViDA study did not reduce the risk for fractures or falls either (67). However, the generalizability of the ViDA results has been questioned given the high-dose monthly supplementation regimen instead of daily dosing, which is more commonly used by the public and which might be more physiological than monthly bolus dosing.

The most definitive RCT to date is VITAL (Vitamin D and Omega-3 Trial), which investigated the potential benefits of vitamin D supplementation on CVD events and cancer in the general population (14). VITAL was a U.S.-based trial that enrolled 25,871 participants (5,106 of black or African American race) who were free of CVD and cancer at baseline. Participants, who were community-dwelling women ≥55 years of age and men ≥50 years of age, were randomized to 2,000 IU/daily dose of vitamin D3 versus placebo and followed for the dual primary endpoints of invasive cancer and major adverse cardiovascular events (a composite of MI, stroke, or cardiovascular death). After a mean follow-up period of 5.3 years, there was no significant reduction in CVD events (HR: 0.97; 95% CI: 0.85 to 1.12) for vitamin D compared with placebo, nor was there a benefit for any of the secondary individual cardiovascular endpoints (MI, stroke, or cardiovascular death). Findings were similar by race. Even for the subgroups found to have inadequate or deficient 25(OH)D concentrations at baseline (serum 25[OH]D <20 ng/ml [n = 2,001] or less than the median value of 31 ng/ml [n = 7,812]), there was still no cardiovascular benefit with vitamin D supplementation (14); however, the study may have been underpowered to detect a statistically significant effect among those with low 25(OH)D concentrations. Reassuringly, there were no significant adverse events or hypercalcemia in the trial.

Subsequently, results of the D2D (Vitamin D and Type 2 Diabetes) Research Group were published. This trial tested whether vitamin D supplementation prevents incident diabetes among participants with pre-diabetes. The trial randomized 2,423 participants to 4,000 IU/day of vitamin D3 versus placebo, and participants were followed for a median of 2.5 years. Although the trend was favorable, there was no statistically significant reduction in new-onset diabetes with vitamin D supplementation (HR: 0.88; 95% CI: 0.75 to 1.04) (68).

Following the publication of VITAL, but not including D2D, an updated meta-analysis of 21 RCTs (4 that had CVD as a pre-specified endpoint) including 83,291 participants reported that vitamin D supplementation compared with placebo did not reduce the risk for major adverse cardiovascular events (relative risk [RR]: 1.00; 95% CI: 0.95 to 1.06) or secondary endpoints of MI, stroke, CVD mortality, and all-cause mortality (15). Furthermore, this lack of benefit was consistent across subgroups defined by sex, baseline 25(OH)D concentration, daily versus bolus dosing, and concomitant calcium supplement use. Meta-analyses of RCTs also have not demonstrated any significant reduction in blood pressure with vitamin D therapy (69).

Even vitamin D’s purported benefits on bone health have been recently challenged, with lack of a demonstrable benefit of fracture reduction or bone mineral density (70–73). Although vitamin D alone has not been shown to reduce fractures, a meta-analysis of 6 RCTs (49,282 participants) did find a modest reduction in fractures when vitamin D was combined with calcium supplementation (1,000 to 1,200 mg/day) (6% reduction in any fracture, 16% reduction in hip fracture) (71). Additionally, there remains ongoing interest in vitamin D and cancer outcomes. Although in the VITAL trial, vitamin D supplementation did not reduce cancer incidence (HR: 0.96; 95% CI: 0.88 to 1.06), the 5-year average length of the trial might not have been sufficiently long to detect a cancer benefit. A subsequent meta-analysis of RCTs suggested that vitamin D reduced total cancer mortality but not cancer incidence (74). The benefit of vitamin D in preventing respiratory infections, potentially coronavirus disease 2019 conferred by the severe acute respiratory syndrome coronavirus-2, is also under investigation (75), although at this point it remains speculative.

Safety

Vitamin D supplementation at doses recommended by NAM is generally safe (no adverse events were seen in VITAL with slightly higher doses of 2,000 IU/day [14]), but toxicity can occur with extremely high doses (>10,000 IU/day) (76), or possibly even doses at the upper tolerable limit of 4,000 IU/day (44), driven largely by the adverse consequences of hypercalcemia (77). Vitamin D combined with calcium supplementation has been associated with increased risk for kidney stones (78). In a meta-analysis of RCTs, vitamin D plus calcium supplementation was associated with a modest increase in the risk for stroke (RR: 1.17; 95% CI: 1.05 to 1.30) (79).

Vitamin D: Implications for Clinical Practice

Where do we go from here? In aggregate, experimental evidence is conclusive: vitamin D supplements do not benefit cardiovascular health in the general population and therefore should not be taken for this purpose. The pendulum has shifted, and the hype for vitamin D supplements as a panacea for multiple diseases, including CVD, is over. Even the benefits of supplemental vitamin D on bone health appear overstated for the general population, while the evaluation of vitamin D for cancer or COVID-19 prevention requires further study. Whether there is a benefit of vitamin D supplementation for cardiovascular health among those who are truly vitamin D deficient (<12 ng/ml) remains uncertain.

However, the signal from observational studies of vitamin D levels was relatively robust, and a number of biological mechanisms through which vitamin D would be beneficial for the cardiovascular system have been described in high-quality mechanistic research. How do we reconcile these apparently contradictory findings (null findings from experimental and Mendelian vs. observational and mechanistic research)? Some middle paths are possible. For example, exogenous vitamin D supplementation, which was the exposure evaluated in landmark RCTs, and isolated endogenous predicted vitamin D (Mendelian studies) may not be able to capture the health benefits of the activities and habits that typically increase vitamin D levels, such as engaging in outdoor physical activities, eating specific healthy foods, and socializing outdoors. Other hypotheses are plausible.

For now, most adults should try to meet the NAM-recommended daily allowance of vitamin D from food sources if possible and with modest sunlight exposure if not at elevated risk for skin cancer. Vitamin D supplementation can be considered for those who are unable to achieve NAM-recommended vitamin D intake daily through diet. Higher doses of vitamin D supplementation should be reserved for those at risk for deficiency (<12 ng/ml) with monitoring of laboratory values.

Calcium Metabolism

Calcium is the most abundant mineral in the body, with 99% of body calcium stored in bone and teeth. Adequate intake of calcium is important for both bone development and maintenance over a lifetime. Blood levels of calcium are under tight physiological feedback control and thus do not reflect one’s calcium intake status or skeletal stores. Calcium homeostasis is important for muscle contractility, electric signaling, and vascular tone. The biological relationships of calcium and vitamin D are intrinsically intertwined. Thus, the concomitant use of vitamin D supplements may influence the effects of calcium intake on bone health and other health outcomes, including cardiovascular health.

Calcium supplementation is very common. Slightly more than 40% of the U.S. population take calcium supplements, including >65% of women older than 70 years (2). The recommended dietary intake of calcium for adults 19 to 50 years of age and for men 51 to 70 years of age is 1,000 mg/day, with 1,200 mg/day recommended for women 51 to 70 years of age and all adults >70 years of age (42) (Table 1). Absorption is dependent on the total amount of elemental calcium ingested at one time, and calcium is best absorbed in smaller doses (≤500 mg in one setting). Age, vitamin D, and other components in food influence calcium absorption. Persons at risk for inadequate calcium intake including those with lactose intolerance or cow milk’s allergy, those with osteopenia or osteoporosis, and women who are amenorrheic or postmenopausal, among other risk groups (80). In such persons who are unable to obtain sufficient calcium supply through food sources, oral calcium supplementation might be needed on top of diet to achieve recommended daily allowances.

Most patients do not take calcium supplementation for cardiovascular health but rather for bone health. Although the modest benefit on fracture reduction with daily calcium doses of 1,000 to 1,200 mg in combination with vitamin D (71) does align with the range of dosing in the NAM recommendations, intake of more than recommended amounts has not been shown to be better and may even convey risk for harm (discussed later). In light of this, it may be best to achieve the recommended daily allowance of calcium intake through dietary food sources and reserve supplemental calcium only for those with low-calcium diets (<800 mg/day) who are unable to achieve greater calcium intake through foods. Many healthy food sources, such as leafy green vegetables, low-fat dairy, beans, and almonds, contain calcium and should be encouraged. If calcium supplementation is given, smaller doses (<500 mg) may be absorbed better and associated with less risk than higher daily doses and boluses.

Calcium and Cardiovascular Health

In 2008, the Auckland Calcium Study first raised concerns that calcium supplements may increase cardiovascular risk (22). Since that time, multiple further reports have explored the effects of calcium supplementation on CVD outcomes. Several observational studies have shown that calcium supplement users have greater risk for CVD events than nonusers (18,19), particularly for calcium intake in excess of 1,400 mg/day (20). In MESA (Multi-Ethnic Study of Atherosclerosis), calcium supplement use was associated with an increased risk for incident coronary artery calcification (RR: 1.22; 95% CI: 1.07 to 1.39) (21). In contrast, higher intake of dietary calcium from food sources has not been associated with elevated cardiovascular risk (18,21).

Again, observational studies may be limited by several factors, particularly residual confounding; for example, frail subjects at risk for bone loss may be more likely to take calcium supplements than individuals who are not frail. Therefore, the best evidence should be gleamed from RCTs of calcium supplementation. To date, trial evidence for calcium supplementation and cardiovascular risk has been mixed, and no trial to date of calcium supplementation has been a designated cardiovascular outcome trial. Although the original WHI trial did not find that calcium (1,000 mg/day) combined with vitamin D3 (400 IU/day) supplementation increased or decreased CVD risk, a subsequent reanalysis of WHI that excluded participants with personal use of calcium supplements outside of that trial, pooled with trial results from 8 other studies, did report an increase in the risk for MI (HR: 1.24; 95% CI: 1.07 to 1.45) and for MI plus stroke (HR: 1.15; 95% CI: 1.03 to 1.27) with calcium supplement use compared with placebo (23). However, this analysis was controversial given its somewhat unusual methodology (81). In contrast, an earlier meta-analysis did not find a dose-response relationship, neither benefit nor harm, of calcium intake with CVD (17).

Additional meta-analyses have been completed. A 2018 meta-analysis of RCTs of calcium supplementation demonstrated a trend toward cardiovascular harm, with all CVD outcomes showing RRs >1.0, although findings were not statistically significant for any cardiovascular outcome (82), while another 2019 meta-analysis of RCTs found an increased risk for stroke when calcium supplements were combined with vitamin D supplements (79). Furthermore, a 2020 meta-analysis of 26 cohort studies and 16 RCTs concluded that calcium intake from food sources did not increase CVD risk, but calcium supplements might increase CVD risk, particularly for MI. In that meta-analysis, the pooled RR from RCTs showed increased risk for CHD events due to any calcium supplement (RR: 1.08; 95% CI: 1.02 to 1.22) and calcium supplements alone (RR: 1.20; 95% CI: 1.08 to 1.33), with a stronger association for MI specifically for any calcium supplement (RR: 1.14; 95% CI: 1.05 to 1.25) and calcium supplements alone (RR: 1.21; 95% CI: 1.08 to 1.35) (24). Combining with vitamin D may offset some of the risk for calcium alone (24), as vitamin D facilitates calcium absorption. Supplementation doses ≥1,000 mg/day were associated with higher risk in that meta-analysis, and men seem to be more adversely affected with calcium supplementation than women (24,83).

Potential mechanisms

Hypothesized mechanisms for increased vascular risk with calcium supplementation include transient rise in serum calcium levels (hypercalcemia) after ingestion of a single large dose, which can trigger coagulation cascade or vascular deposition of calcium, altering endothelial function and conferring arterial stiffening (84) (Figure 2). This is in line with Mendelian randomization studies that have shown that genetically determined elevations in serum calcium levels are associated with increased CHD and MI risk (85). In observational studies, higher serum and plasma levels of calcium have been associated with increased risk for CHD, heart failure, stroke, and type 2 diabetes (86–89). Previously it was reported that hypercalcemia and hypercalciuria occurred in 8.8% and 30.6% of participants, respectively, taking 1,200 mg/day of calcium supplementation (90). Thus, it is possible that even at recommended levels of calcium supplementation, persons may be at risk for the adverse effects of high calcium levels, either transient or sustained.

Figure 2
Figure 2

Calcium Supplements and Cardiovascular Disease: Proposed Mechanisms

Potential mechanisms linking calcium supplements and transient or sustained elevated calcium levels with increased cardiovascular risk. Abbreviations as in Figure 1.

Calcium Supplements: Implications for Clinical Practice

Certain subgroups, particularly those with very low calcium dietary intake and persons with increased calcium needs, may indeed benefit from supplementation. For example, among pregnant women with low calcium diets, calcium supplementation may reduce the risk for pre-eclampsia (91). In persons at risk for osteoporosis, moderate calcium intake (1,000 to 1,200 mg/day) in combination with vitamin D can reduce the risk for fractures (71); thus calcium supplementation may be considered to make up any gaps in intake not achieved from food sources. Nevertheless, the potential for harm with calcium supplements, particularly at higher doses, should give practitioners pause before prescribing, and benefits should be carefully considered against risks. Shared decision making should be undertaken with the patient, pointing out that some patients may benefit from calcium supplementation but at the same time be exposed to a potentially slightly elevated risk for CVD events. In RCTs, calcium supplements were also linked to an increased risk for kidney stones (25) and colon polyps (92), the latter likely through decreased gut motility, as constipation is also a side effect of calcium supplementation. Therefore, even if the cardiovascular effects were neutral, calcium supplements are not without risk for other adverse side effects.

Calcium Supplements: Evidence Gaps and Future Directions

Designated RCT with pre-specified cardiovascular outcomes and appropriate ascertainment procedures are ultimately needed to clarify the potential dangers of calcium supplementation. However, given the over-the-counter availability of calcium supplements and their widespread use, it is unlikely that such trials will ever be undertaken. Furthermore, trials are not conducted to confirm harm. Other research should evaluate the effects of different dosing strategies of calcium supplements and types of calcium supplement formulations. Additional research is also needed to further understand the effect of combined calcium plus vitamin D supplementation on cardiovascular outcomes.

Conclusions

Although vitamin D does not appear to be harmful to cardiovascular health, the lack of a demonstrable benefit of supplementation in RCTs should discourage its use for this purpose, favoring optimizing vitamin D status through dietary intake and modest sunlight exposure instead (Figure 3) and reserving vitamin D supplements only for documented 25(OH)D deficiency. Calcium supplements are widely used for optimizing bone health; however, studies have emerged that suggest potential for cardiovascular harm. Therefore, calcium supplementation should be used cautiously and judiciously, and achievement of recommended daily allowances of calcium from dietary food sources should be encouraged (Figure 3).

Figure 3
Figure 3

Vitamin and Calcium Supplements and Cardiovascular Health

Proposed clinical recommendations for vitamin D and calcium supplements for cardiovascular health and safety. CV = cardiovascular; CVD = cardiovascular disease.

Hopefully, future studies can shed further light on the safety of different calcium supplement dosing strategies. In the meantime, we are left weighing the aforementioned evidence from secondary analyses and meta-analyses of already completed non-CVD trials to guide risk discussions with patients regarding calcium supplementation alone or in combination with vitamin D. Shared decision making is clearly warranted given the potential for both harm and benefit. For patients with nutrient deficiencies that cannot be fulfilled with dietary changes, supplementation plays an important role in correcting those gaps. However, many persons who do not have any clear nutrient deficiency also take supplements in the misguided belief that they are optimizing their health through “natural” means. One should capitalize on such patient motivation for nonpharmacological health promotion by encouraging “natural” lifestyles: being physically active, eating a heart-healthy diet, abstaining from tobacco products and excess alcohol, and maintaining an optimal weight.

Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Abbreviations and Acronyms

1,25(OH)2D

1,25-dihydroxyvitamin D

25(OH)D

25-hydroxyvitamin D

CHD

coronary heart disease

CI

confidence interval

CVD

cardiovascular disease

HR

hazard ratio

MI

myocardial infarction

NAM

National Academy of Medicine

RCT

randomized controlled trial

RR

relative risk

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Footnotes

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