Abstract:
Aim: In view of the association of calcium supplements with myocardial infarction and stroke, we sought to understand whether this effect persisted after their discontinuation and whether this risk varied across different patient subgroups. We also sought to understand what effect calcium supplements might exert in a mouse model of accentuated inflammation. Method: We continued follow-up of the Auckland Calcium study participants for a further 5 years to understand the persistence of the harmful effects of calcium supplements in the context of bone protective actions. We re-analysed the Women's Health Initiative Calcium and Vitamin D (WHI CaD) study and performed similar analyses in our pooled, patient-level metaanalysis dataset to detect if calcium supplements conferred a differential cardiovascular risk across various patient groups. Finally, we investigated whether calcium supplements increased vascular calcification, altered the serum mineral profile and produced changes in gene expression of vascular cells in a mouse model of accentuated inflammation. We were also interested as to whether providing calcium over 24 hours would mitigate any negative effects of a single calcium bolus. Findings: Post-trial follow-up of the Auckland Calcium study showed that allocation to calcium reduced forearm and vertebral fractures over the entire follow up period, but did not influence the risk for myocardial infarction, stroke, transient ischaemic attacks, or death. In the bone mineral density sub-study, there were no between-group differences in the percentage change from baseline at any site, at 10 years. Results from the meta-analysis of calcium monotherapy and the re-analysis of the WHI CaD were strikingly similar in terms of risk for myocardial infarction and stroke, however, we found no evidence for an interaction between allocation to calcium and important baseline characteristics. In adiponectin knockout mice, a once daily bolus dose of calcium altered serum mineral profile and genes implicated in vascular calcification. Conclusion: The harmful effects of calcium supplements do not differ across differing patient subgroups and do not persist once discontinued. At the cell level, calcium supplements may play a role in the phenotypic change of vascular smooth muscle cells promoting vascular disease, but this will need to be confirmed in targeted experiments.