Who Should Receive Calcium and Vitamin D Supplementation?
Who Should Receive Calcium and Vitamin D Supplementation?
A trial by Bolland et al. suggested that calcium supplements might be associated with cardiovascular complications. The Auckland Calcium Study was a randomised, placebo-controlled trial in which almost 1,500 post-menopausal women were followed for 5 years. Exclusion criteria were osteoporosis medication, co-morbidity and low serum levels of vitamin D. Participants received 1,000 mg calciumcitrate or placebo. The analysis was set up to determine whether calcium supplements protect against cardiovascular diseases. After all, other trials showed favourable effects of calcium on lipid metabolism and blood pressure. Moreover, observational research suggested an inverse correlation between dietary calcium intake and cardiovascular risk. Unexpectedly, an increased cardiovascular risk was seen in the group that received calcium. In this group, the relative risk (RR) for myocardial infarction and stroke was 2.12 [95% confidence interval (CI) 1.01–4.47] and 1.42 (95% CI 0.83–2.43), respectively.
Since these results were based on small absolute numbers of events (34 myocardial infarctions and 57 strokes) which affected the study power, a meta-analysis was performed by the same authors. This meta-analysis included more than 12,000 individuals from 15 randomised placebo–controlled trials of calcium supplements (≥ 500 mg daily). An increase in the incidence of myocardial infarction of about 30% was seen in the calcium group when compared with the placebo group [hazard ratio (HR) 1.31, 95% CI 1.02–1.67]. No significant increases were observed in the incidence of stroke and the combined endpoint of myocardial infarction, stroke and sudden death.
Two studies dominated the meta-analysis: the aforementioned Auckland Calcium Study (relative contribution 17%) and the RECORD trial (relative contribution 55%). The RECORD trial is a randomised placebo-controlled trial that failed to show a protection against osteoporotic fractures with calcium and vitamin D supplements. However, the result of this trial is inconclusive because of the low compliance with calcium and vitamin D (<40% after 24 months) and the fact that supplementation was not targeted on vulnerable people with calcium needs. In this trial, the incidence of death (17.7 versus 16.2%), myocardial infarction (3.4 versus 2.7%) and stroke (4.4 versus 3.9%) were comparable between the calcium and placebo group.
In a second meta-analysis of Bolland et al., the cardiovascular risk of combined calcium and vitamin D supplementation was examined. This meta-analysis, which included three randomised placebo-controlled trials, showed that calcium and vitamin D significantly increased the risk of myocardial infarction (RR 1.21, 95% CI 1.01–1.44) and the composite endpoint of myocardial infarction and stroke (RR 1.16, 95% CI 1.02–1.32). The results of this meta-analysis are dominated by a re-analysis of the Women's health Initiative (WHI) clinical trial. The original analysis of the WHI showed no adverse cardiovascular effect of combined calcium and vitamin D supplementation. However, in the re-analysis that grouped participants according to whether or not non-protocol calcium supplements were used, calcium and vitamin D increased the risk of myocardial infarction or coronary revascularisation by 16% (RR 1.16, 95% CI 1.01–1.43) in the group without non-protocol use of calcium supplements. The risk of myocardial infarction (RR 1.22, 95% CI 1.00–1.50) and the combined endpoint of myocardial infarction and stroke (RR 1.16, 95% CI 1.00–1.35) increased non-significantly (P = 0.05). When the results of the two meta-analyses were combined, Bolland et al. [16] found that calcium alone or calcium and vitamin D increased the risk of myocardial infarction (RR 1.24, 95% CI 1.07–1.45) and the composite endpoint of myocardial infarction and stroke (RR 1.15, 95% CI 1.03–1.27).
The mechanisms by which calcium supplements might increase the cardiovascular risk remain speculative. Since high dietary calcium intake, which hardly affects serum levels of calcium, was not associated with an increased risk, the negative effect of calcium supplements might be explained by the fact that supplements acutely elevate serum calcium, which may enhance vascular calcification. Vascular calcification has been associated with an increased risk of cardiovascular events in trials when calcium supplements were used as oral phosphate binders in chronic renal insufficiency as well as in the case of chronic hypercalcaemia caused by hyperparathyroidism. High serum calcium might also be associated with increased coagulability and arterial stiffness.
Calcium Supplements and Risk for Myocardial Infarction
A trial by Bolland et al. suggested that calcium supplements might be associated with cardiovascular complications. The Auckland Calcium Study was a randomised, placebo-controlled trial in which almost 1,500 post-menopausal women were followed for 5 years. Exclusion criteria were osteoporosis medication, co-morbidity and low serum levels of vitamin D. Participants received 1,000 mg calciumcitrate or placebo. The analysis was set up to determine whether calcium supplements protect against cardiovascular diseases. After all, other trials showed favourable effects of calcium on lipid metabolism and blood pressure. Moreover, observational research suggested an inverse correlation between dietary calcium intake and cardiovascular risk. Unexpectedly, an increased cardiovascular risk was seen in the group that received calcium. In this group, the relative risk (RR) for myocardial infarction and stroke was 2.12 [95% confidence interval (CI) 1.01–4.47] and 1.42 (95% CI 0.83–2.43), respectively.
Since these results were based on small absolute numbers of events (34 myocardial infarctions and 57 strokes) which affected the study power, a meta-analysis was performed by the same authors. This meta-analysis included more than 12,000 individuals from 15 randomised placebo–controlled trials of calcium supplements (≥ 500 mg daily). An increase in the incidence of myocardial infarction of about 30% was seen in the calcium group when compared with the placebo group [hazard ratio (HR) 1.31, 95% CI 1.02–1.67]. No significant increases were observed in the incidence of stroke and the combined endpoint of myocardial infarction, stroke and sudden death.
Two studies dominated the meta-analysis: the aforementioned Auckland Calcium Study (relative contribution 17%) and the RECORD trial (relative contribution 55%). The RECORD trial is a randomised placebo-controlled trial that failed to show a protection against osteoporotic fractures with calcium and vitamin D supplements. However, the result of this trial is inconclusive because of the low compliance with calcium and vitamin D (<40% after 24 months) and the fact that supplementation was not targeted on vulnerable people with calcium needs. In this trial, the incidence of death (17.7 versus 16.2%), myocardial infarction (3.4 versus 2.7%) and stroke (4.4 versus 3.9%) were comparable between the calcium and placebo group.
In a second meta-analysis of Bolland et al., the cardiovascular risk of combined calcium and vitamin D supplementation was examined. This meta-analysis, which included three randomised placebo-controlled trials, showed that calcium and vitamin D significantly increased the risk of myocardial infarction (RR 1.21, 95% CI 1.01–1.44) and the composite endpoint of myocardial infarction and stroke (RR 1.16, 95% CI 1.02–1.32). The results of this meta-analysis are dominated by a re-analysis of the Women's health Initiative (WHI) clinical trial. The original analysis of the WHI showed no adverse cardiovascular effect of combined calcium and vitamin D supplementation. However, in the re-analysis that grouped participants according to whether or not non-protocol calcium supplements were used, calcium and vitamin D increased the risk of myocardial infarction or coronary revascularisation by 16% (RR 1.16, 95% CI 1.01–1.43) in the group without non-protocol use of calcium supplements. The risk of myocardial infarction (RR 1.22, 95% CI 1.00–1.50) and the combined endpoint of myocardial infarction and stroke (RR 1.16, 95% CI 1.00–1.35) increased non-significantly (P = 0.05). When the results of the two meta-analyses were combined, Bolland et al. [16] found that calcium alone or calcium and vitamin D increased the risk of myocardial infarction (RR 1.24, 95% CI 1.07–1.45) and the composite endpoint of myocardial infarction and stroke (RR 1.15, 95% CI 1.03–1.27).
The mechanisms by which calcium supplements might increase the cardiovascular risk remain speculative. Since high dietary calcium intake, which hardly affects serum levels of calcium, was not associated with an increased risk, the negative effect of calcium supplements might be explained by the fact that supplements acutely elevate serum calcium, which may enhance vascular calcification. Vascular calcification has been associated with an increased risk of cardiovascular events in trials when calcium supplements were used as oral phosphate binders in chronic renal insufficiency as well as in the case of chronic hypercalcaemia caused by hyperparathyroidism. High serum calcium might also be associated with increased coagulability and arterial stiffness.
Source...