Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysisBMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d2040 (Published 19 April 2011) Cite this as: BMJ 2011;342:d2040
- Mark J Bolland, senior research fellow1,
- Andrew Grey, associate professor1,
- Alison Avenell, clinical research fellow2,
- Greg D Gamble, research fellow1,
- Ian R Reid, professor of medicine and endocrinology1
- 1Department of Medicine, University of Auckland, Private Bag 92 019, Auckland 1142, New Zealand
- 2Health Services Research Unit, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland
- Correspondence to: I R Reid
- Accepted 18 February 2011
Objectives To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.
Design Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with eight other studies.
Data source WHI CaD Study, a seven year, randomised, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36 282 community dwelling postmenopausal women.
Main outcome measures Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data.
Results In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16 718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P=0.05 for clinical myocardial infarction or stroke, P=0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), P=0.04), stroke (1.20 (1.00 to 1.43), P=0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), P=0.02). In meta-analyses of placebo controlled trials of calcium or calcium and vitamin D, complete trial-level data were available for 28 072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P=0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P=0.009).
Conclusions Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.
The Women’s Health Initiative is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the WHI Study Investigators. This manuscript was prepared using a limited access dataset obtained from the NHLBI and does not necessarily reflect the opinions or views of the WHI or the NHLBI.
We thank Professor John Baron who provided patient-level data on cardiovascular events from his study, Professor Joan Lappe who provided trial-level data on her study, and Graeme MacLennan from the RECORD trial.
Contributors: MJB, AG, and IRR drafted the study protocol. All authors provided individual patient data from their studies. MJB and GDG performed the analyses. MJB drafted the paper. All authors critically reviewed the paper. MJB had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. MJB is the guarantor of the paper.
Funding: Funded by the Health Research Council of New Zealand, and the University of Auckland School of Medicine Foundation. AA is funded by a Career Scientist award of the Chief Scientist Office of the Scottish Government Health Directorates. The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Government Health Directorates.
The study sponsors had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript. The authors are independent from the funders.
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that no author has support from companies for the submitted work; IRR has received research support from and acted as a consultant for Fonterra and had study medications for clinical trials of calcium supplementation supplied by Mission Pharmacal, and AA had study medications for clinical trials of calcium supplementation supplied by Shire Pharmaceuticals and Nycomed; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: Not required.
Data sharing: No additional data available.
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