Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ Online First doi:10.1136/bmj.39440.525752.BE (published 15 January 2008)
What is the background to this? – Postmenopausal women have a high incidence of vascular disease and it has been suggested that calcium supplements might be beneficial for vascular health, as well as bone health, in these women. This New Zealand study aimed to determine the effect of calcium supplementation on myocardial infarction (MI), stroke and sudden death in healthy postmenopausal women.
What does this study claim? – MI was more commonly reported in women receiving 1g/day of calcium, compared with placebo (45 events in 31 women vs. 19 events in 14 women; relative risk [RR] 2.24 [95%CI 1.20 to 4.17]; P=0.01). The composite endpoint of MI, stroke or sudden death also occurred significantly more often in the women taking calcium supplementation (101 events in 69 women vs. 54 events in 42 women; RR 1.66 [95%CI 1.15 to 2.40]; P=0.008). There was no significant difference between the groups for the other outcomes that were assessed.
When the reported results were re-assessed following confirmation of CV events by a cardiologist (MI and sudden death) or neurologist (stroke and transient ischaemic attack [TIA]) who was blinded to the participants’ treatment group, a statistically significant increase in MI remained in the calcium group (24 events in 21 women vs. 10 events in 10 women; RR 2.12 [95%CI 1.01 to 4.47]; P=0.047). However, there was no significant increase in the composite endpoint.
When unreported events from the national database of hospital admissions in New Zealand were added to the reported events there were no longer statistically significant differences between the groups for any of the endpoints.
How does this relate to other studies? – Calcium supplementation has been shown to produce changes in cholesterol levels that might be expected to reduce cardiovascular (CV) risk. Similarly, results from observational data have suggested that a high calcium intake might protect against vascular disease. However, contrary to the authors’ expectations, this study found that healthy postmenopausal women who were randomised to calcium supplementation had a higher risk of MI not a lower one. Although calcium appears to have beneficial effects on cholesterol, this does not seem to translate into a reduced CV risk, particularly the risk of MI.
The study has some limitations – in particular it was was not designed to look at cardiovascular outcomes and the n umber of events seen was relatively small. Definitive conclusions cannot be drawn, as the authors conclude, “this potentially detrimental effect should be balanced against the likely benefits of calcium on bone, particularly in elderly women”. An editorial makes similar comments.
In addition, monotherapy with calcium, as used in this study, has not been shown to reduce fractures in postmenopausal women, so it is not generally recommended. [1,2] Combined calcium and vitamin D may reduce vertebral and non-vertebral fractures, but the results from controlled studies are inconclusive. The Clinical Knowledge Summaries guideline on osteoporosis recommends that calcium and vitamin D supplements should be prescribed for all women who are receiving treatment for osteoporosis (e.g. bisphosphonates) unless dietary intake is thought to be adequate. It is unclear whether calcium plus vitamin D could carry the same risk of MI.
So what? – Postmenopausal women already have an increased risk of CV disease. Those who are at particularly high risk for falls and osteoporotic fracture (e.g. the elderly) may also be at particularly high risk for CV disease. It is worrying that any benefit of calcium supplementation on bone health could potentially be cancelled out by an increase in the risk of MI. In this study the number of women needed to treat for five years to cause one MI was 44. By comparison the number needed to treat to prevent one symptomatic fracture was 50.
Action – Calcium supplementation alone should not generally be prescribed to postmenopausal women for fracture prevention. Clinicians should weigh up the pros and cons of calcium and vitamin D supplementation on an individual basis, taking into account the patient’s risk of CV disease and osteoporosis.
There is a whole suite of educational materials on osteoporosis available on NPC.
Study details –
Design: This was a secondary pre-planned analysis of a randomised controlled trial of calcium supplementation in healthy postmenopausal women in New Zealand. The study was originally designed to assess the effects of calcium on bone density and fracture risk over five years.
Patients: The study included 1,471 women aged 55 years or more (mean 74 years) who had been postmenopausal for over five years and had a life expectancy of over five years.
Intervention: 732 women were randomised to calcium supplementation (1g elemental calcium as citrate).
Comparison: 739 women were randomised to an identical placebo.
Outcomes: Adverse cardiac events (death, sudden death, MI, angina, other chest pain, stroke, TIA, and a composite endpoint of MI, stroke or sudden death) were recorded every six months for 5 years. Events were self-reported by the women or their familes. However, the national database of hospital admissions for CV events was also searched after study completion to identify events which had not been reported.
Results: The main results of the study are outlined above.
Sponsorship: The study was supported by the Health Research Council of New Zealand. Mission Pharmacal supplied the calcium citrate tablets and placebo. One author has received research support from and acted as a consultant for Fonterra and Mission Pharmacal.
Mosekilde L, Vestergaard P, Langdahl B. Fracture prevention in postmenopausal women. BMJ Clinical Evidence 2007. Accessed from www.clinicalevidence.com on 17/01/08
CKS. Osteoporosis — treatment and prevention of fragility fractures (Topic Review). Clinical Knowledge Summaries Service. Accessed from www.cks.library.nhs.uk/osteoporosis_treatment on 16/01/08