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Cardiovascular risks of calcium supplements in women
Editorials
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Increased risk of myocardial infarction outweighs the reduction in fractures
BMJ (published 17 January 2008)
Calcium is an important component of bone, and a sufficient intake of calcium is needed for bone homoeostasis. Calcium supplements can reduce the risk of fractures in elderly women who are deficient in calcium and vitamin D, but data on the risk of adverse effects on cardiovascular outcomes have so far been inconclusive. In their accompanying paper, Bolland and colleagues report a preplanned secondary analysis of their randomised controlled trial of calcium supplements in 1471 postmenopausal women. They analysed the effect of calcium supplements on myocardial infarction, stroke, and sudden death.1
Calcium and vitamin D supplements have been shown to reduce the risk of hip fractures in elderly institutionalised women who are deficient in calcium and vitamin D.2 More recent large trials based in the community have been negative, but this may have been the result of poor adherence,3 which is particularly important for calcium to be effective. Benefit has been shown only in analyses restricted to women who adhered to treatment for total fractures,4 hip fractures,5 and forearm fractures.6 A recent meta-analysis suggested an overall 12% decrease in the relative risk of fracture.3 If we assume that the average incidence of fracture in women aged 80-84 years is 4% each year, then the number needed to treat (NNT) for five years to prevent one fracture is 42.7
Calcium supplements have generally been thought not to be harmful. Patients often complain of constipation,6 and the risk of renal calculi is slightly increased.5 Possible positive effects on obesity and cholesterol have implied a protective effect on cardiovascular outcomes. However, calcium based phosphate binders are associated with increased vascular calcification in patients about to undergo dialysis.8 The potential mechanisms of arterial calcification are many and complex,9 but biologically plausible mechanisms support the role of calcium. Under certain stimuli, vascular smooth muscle cells may undergo a phenotypic switch to bone-like cells,9 and in the presence of high amounts of calcium these may be capable of producing vascular calcification.
So what does the analysis by Bolland and colleagues tell us? The data were not totally consistent, but if most weight is placed on the verified events (from medical records alone as well as a search of a national database of hospital admissions), women taking calcium had a significantly higher risk of cardiovascular disease (relative risk 2.12, 95% confidence interval 1.01 to 4.47, P=0.047), especially myocardial infarction (1.49, 0.86 to 2.57, P=0.16). The equivalent risks for stroke were 1.42 (0.83 to 2.43, P=0.21) and 1.37 (0.83 to 2.28, P=0.23), respectively. The survival curves started to diverge after about two years, indicating a slow onset of effect.
When directly comparable incidence rates for myocardial infarction and stroke are used in 80-84 year old women, the number needed to harm (NNH) for five years is 10-17 and 26-28, respectively.10 Both are considerably less than the NNT, which indicates that the risks greatly outweigh the benefits in an elderly population. Indeed, the absolute risk of fracture would have to be four times that of cardiovascular disease for the NNT to be less than the NNH. This would be met only in women with a very high risk of fracture, in whom guidelines recommend more effective treatment anyway. These estimates are subject to wide confidence intervals and they contrast with the absence of increased cardiovascular risk in the women's health initiative study in younger postmenopausal women, although poor adherence in that study may contribute to this.5
These adverse findings need to be replicated by re-examining the databases of other large trials for cardiovascular endpoints, especially in people with good long term adherence. Until then, the use of calcium supplements as monotherapy in elderly people does not seem to be justified, except possibly in women with very low calcium intakes. Data suggest that it may be safe to use supplements to prevent osteoporosis in younger postmenopausal women. Caution is necessary, however, given the need for long term use to maintain the benefit on bones and the likely time lag between treatment with calcium and adverse cardiovascular events.
The place of calcium as co-therapy with other treatments for osteoporosis-such as bisphosphonates and strontium-is less clear. None of these agents has been shown to be effective without co-administration of calcium and vitamin D. The literature on dialysis provides a rationale for the use of bisphosphonates to prevent arterial calcification,11 so these agents may offset one of the harmful effects of calcium. The recent report of decreased mortality caused by cardiovascular disease starting about 18 months after treatment with zoledronic acid is consistent with this hypothesis.12 Furthermore, these patients are at much higher risk of fracture, so the NNT would be lower. It therefore seems reasonable to continue supplementation in people taking bisphosphonates.
Graeme Jones, professor of rheumatology and epidemiology, Tania Winzenberg, postdoctoral research fellow
1 Menzies Research Institute, Hobart, Tas, Australia 7000
Competing interests: None declared.
Provenance and peer review: Commissioned; not externally peer reviewed.
References
1. Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, Ames R, et al Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ 2008 doi: 10.1136/bmj.39440.525752.BE.[Abstract/Free Full Text]
2. Chapuy MC, Arlot ME, Doboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992;327:1637-42.[Abstract]
3. Tang BMP, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007;370:657-66.[CrossRef][ISI][Medline]
4. Prince RL, Devine A, Dhaliwal SS, Dick IM. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med 2006;166:869-75.[Abstract/Free Full Text]
5. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-83.[Abstract/Free Full Text]
6. Reid IR, Mason B, Horne A, Ames R, Reid HE, Bava U, et al. Randomized controlled trial of calcium in healthy older women. Am J Med 2006;119:777-85.[CrossRef][ISI][Medline]
7. Cooley H, Jones G. A population based study of fracture incidence in southern Tasmania: lifetime fracture risk and evidence for geographic variations within the same country. Osteoporos Int 2001;12:124-30.[CrossRef][ISI][Medline]
8. Russo D, Miranda I, Ruocco C, Battaglia Y, Buonanno E, Manzi S, et al. The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer. Kidney Int 2007;72:1255-61.[CrossRef][ISI][Medline]
9. Wallin R, Wajih N, Greenwood GT, Sane DC. Arterial calcification: a review of mechanisms, animal models, and the prospects for therapy. Med Res Rev 2001;21:274-301.[CrossRef][ISI][Medline]
10. Simons LA, Simons J, Friedlander Y, McCallum J, Palaniappan L. Risk functions for prediction of cardiovascular disease in elderly Australians: the Dubbo study. Med J Aust 2003;178: 113-6.
11. Ariyoshi T, Eishi K, Sakamoto I, Matsukuma1 S, Odate T. Effect of etidronic acid on arterial calcification in dialysis patients. Clin Drug Invest 2006;26:215-22.[CrossRef]
12. Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357:1799-809.[Abstract/Free Full Text]
Related Article
Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial
Mark J Bolland, P Alan Barber, Robert N Doughty, Barbara Mason, Anne Horne, Ruth Ames, Gregory D Gamble, Andrew Grey, and Ian R Reid
BMJ 2008 0: 394405257.
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