Table 2.

Meta-analyses assessing the association between DCSs or CSs intake (with or without Vitamin D) and cardiovascular events.

Authors, Year	Meta-analysis for CHD, MI, CVD, and all-cause mortality	Total number of subjects	Ethnicity – Sex (age)	Follow –up (average or range of years)	Outcome	Ref.
Bolland et al., 2010	15 studies	8151 (in 15 trials eligible for inclusion); plus 11,921 participants (in 11 trial level data)	Different ethnicity; males and females (from 51 to 77 years old)	Average of 3.6 years (15 trials for inclusion) and 4 years (11 trials level data)	In five studies contributing patient level data (5 studies), 143 participants allocated to calcium had an MI compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, p = 0.035); composite endpoint of MI, stroke, or sudden death (hazard ratio 1.18, 95% confidence interval 1.00 to 1.39, p = 0.057), and death (1.09, 0.96 to 1.23, p = 0.18). The meta-analysis of trial level data (11 studies) yielded similar results: 296 participants had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, p = 0.038).	14
Bolland et al., 2011	2 trials of co-administered calcium and vitamin D with CVD outcome data (WHI CaD Study), a small 1-year trial of 191 participants, plus previously unpublishe d data from two studies	28,072	Different ethnicity; only females (post-menopausal women)	Average 5.9 years	CSs with or without vitamin D modestly increase the risk of CVD events, especially MI. In meta-analyses of three placebo-controlled trials, calcium and vitamin D increased the risk of MI (relative risk 1.21 (95% confidence interval 1.01 to 1.44), p = 0.04), and the composite of MI or stroke (1.16 (1.02–1.32), p = 0.02). Meta-analyses of calcium or calcium and vitamin D complete trial-level data were available for 28,072 participants from eight trials of CSs and the WHI CaD participants not taking personal CSs. In total 1384 individuals had an incident MI or stroke. Calcium or calcium and vitamin D increased the risk of MI (relative risk 1.24 (1.07–1.45), p = 0.004) and the composite of myocardial infarction or stroke (1.15 (1.03–1.27), p = 0.009).	15
Rejnmark et al., 2012	8 studies for individual patient data; 24 studies for trial level data	70,528 in the individual patient data; 88,097 in the trial data	Different ethnicity; males and females equal to 86.8% (with a median age of 70 years old, range, 62–77 years old)	Over 3 years	In participants randomized to treatment with vitamin D with or without calcium (OR, 0.95; 95% CI, 0.91–1.00) mortality was significantly reduced (p = 0.04). Stratification by coadministration of calcium showed reduced mortality in participants randomized to CaD (OR, 0.94; 95% CI, 0.88–0.99), but not in participants treated with vitamin D supplement alone. Influence analyses with the removal of studies one by one did not change risk estimates to any major degree. Restricting the trial level analysis to include only individually randomized doubleblind studies, mortality was reduced overall (OR, 0.94; 95% CI, 0.89–0.99). Stratification by coadministration of calcium showed a significantly (p < 0.05) reduced mortality in response to CaD (OR, 0.93; 95% CI, 0.86–1.00), but not with vitamin D alone (OR, 0.95; 95% CI, 0.89–1.03).	16
Wang et al., 2014	11 prospective studies with 12 independent cohorts assessing the association between DCIs and risk of mortality for CVD and all causes	For CVD study: 709,499; for all-cause mortality study: 225,189	Different ethnicity; males and females (from 4 to 79 years old)	Large range: from 5.5 years to 28 years	Intakes around 800 mg/day conferred the lowest risk of cardiovascular mortality years Compared to individuals with 800 mg/day of DCIs, the predicted RRs for cardiovascular mortality were 1.08 (95% CI: 0.98 to 1.20) for individuals with 500 mg/day of calcium intake; 1.01 (95% CI: 0.98 to 1.04) for 1000 mg/day; 1.05 (95% CI: 1.01 to 1.09) for 1200 mg/day; and 1.10 (95% CI: 1.02 to 1.18) for 1400 mg/day years Compared to intakes of 900 mg/day, the risks of all-cause mortality comparing the highest and lowest level of dietary calcium intake was 0.83 (95% CI: 0.70 to 1.00; p = 0.05), with significant heterogeneity among the studies (I [2] = 74.9%; p = 0.003).	17
Asemi et al., 2015	21 prospective cohort studies and 1 nested casecontrol study	2,346,368	Different ethnicity; males and females (from 25 to 79 years old)	Large range: from 4.6 to 28 years	The studies revealed no significant association between total and dietary calcium intake and mortality from all-causes. Subgroup analysis by the duration of follow-up revealed a significant positive association between total calcium intake and CVD mortality for cohort studies with a mean follow-up duration of >10 years (relative risk (RR): 1.35; 95% confidence interval (CI): 1.09–1.68). A significant inverse association was seen between dietary calcium intake and all-cause (RR: 0.84; 95% CI: 0.70–1.00) and CVD mortality (RR: 0.88; 95% CI: 0.78–0.99) for studies with a mean follow-up duration of ≤10 years. Although supplemental calcium intake was not associated with CVD (RR: 0.95; 95% CI: 0.82–1.10), it was inversely associated with the risk of all-cause mortality (RR: 0.91; 95% CI: 0.88–0.94).	18
Lewis et al., 2015	18 studies including 13 trials providing published data, and 5 trials providing unpublished data	63,564 (3390 CHD events and 4157 deaths)	Different ethnicity; only females (post-menopausal women)	Large range: from 1 to 42 years	No analyses reached nominal levels of significance (p < 0.05) for any CHD outcomes. Five studies contributed data on CHD hospitalization and death in 48,460 women. 7.1% CHD events in the calcium with or without vitamin D group compared with 6.9% in the control group (pooled RR = 1.02, 95% confidence interval [CI], 0.96–1.09; p = 0.51). No heterogeneity between studies (I [2] = 0%). For CHD deaths were 1.3% in the CSs with or without vitamin D group compared with 21.2% in the control group (pooled RR = 1.04, 95% CI, 0.88–1.21; p = 0.67 with no heterogeneity [I2 = 0%]). No increased risk in CSs-treated patients for any secondary outcome (MI: RR = 1.08 [95% CI, 0.93–1.25; p = 0.32]; angina pectoris: RR = 1.09 [95% CI, 0.95–1.24; p = 0.22]; chronic CHD: RR = 0.92 [95% CI, 0.73–1.15; p = 0.46]). Little heterogeneity between studies for MI or angina pectoris (I [2] statistic = 8% and 0%, respectively). For CHD low heterogeneity (I [2] = 38%).	19
Chung et al., 2016	4 randomized trials, 26 prospective cohorts, and 1 nested case-control study examining the risk for CVD events or mortality in groups receiving placebo, CSs alone, or CSs plus vitamin D	36,282 post-menopausal women, plus 1460 elderly women	Different ethnicity; only females (post-menopausal and elderly)	Large range: from 3 years to 30 years	The assessments of internal validity, precision of risk estimates, and consistency of results from studies, show that calcium intakes (from either food or supplement sources) at levels 2000–2500 mg/day are not associated with CVD risks in generally healthy adults. The analysis found a lower risk of HF with calcium and vitamin D supplementation in postmenopausal women without preexisting HF precursors at baseline (hazard ratio, 0.63 [CI, 0.46 to 0.87]) but no statistically significant effect of supplementation in those with HF precursors and conditions (hazard ratio, 1.06 [CI, 0.90 to 1.24]). Calcium plus vitamin D had no statistically significant effect on all vascular disease deaths compared with placebo (risk ratio, 0.99 [CI, 0.82 to 1.20]). No studies with significant effects of CSs alone on CVD outcomes (hazard ratios, 0.82 to 1.43).	20
Yang et al., 2019	42 studies including prospective cohort studies examining the association between DCIs/CSs and CVD, CHD, and MI	1,222,041	Different ethnicity; males and females (from 34 to 79 years old)	Average 9,9 years	Inverse relationship DCIs and CVD risk for duration ≤10 y (RR = 0.84; 95% CI, 0.72–0.98). No significant associations DCIs with CHD mortality or incidence (incidence: RR = 0.93, 95% CI, 0.83–1.05, I2 = 0.0%; for mortality: RR = 1.00, 95% CI, 0.91–1.11, I2 = 42.5%, P = 0.36). No association between CSs and risk of CVD (RR = 0.99; 95% CI, 0.93–1.05; p = 0.74) with a mild heterogeneity (I2 = 41.1%; p = 0.12). CSs with vitamin D did not increase the risk of CVD (RRco-supplementation = 0.99; 95% CI, 0.93–1.15; p = 0.77, I2 = 0). RCTs showed a risk of CHD due to CSs increased 8% (RR = 1.08; 95% CI; 1.02–1.22; I2 = 0.0%). Increased 20% due to CS alone (RR = 1.20, 95% CI, 1.08–1.33; I2 = 0.0%). Association between CSs and MI risk (RR = 1.14, 95% CI, 1.05–1.25; I2 = 0.0%). MI risk increased 21% with taking CSs alone (RR = 1.21, 95% CI, 1.08–1.35; I2 = 0.0%)	21

CHD: Coronary Heart Disease, CSs: Calcium Supplements, DCSs: Dietary Calcium Supplements, CVD: Cardiovascular Disease, MI: Myocardial Infarction, WHI/CaD: Women’s Health Initiative calcium-vitamin D supplementation.