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Calcium supplements boost heart-attack risk: Meta-analysis
  "Schindler also said that the real risk of MI appeared to be in people who took calcium supplements on top of high levels of dietary calcium" see BMJ full Editorial below
AUGUST 3, 2010 | Fran Lowry,
Auckland, NZ - The use of calcium supplements without coadministered vitamin D is associated with an increased risk of MI [1]. The finding, from a meta-analysis encompassing 15 randomized trials and up to 11 921 participants, warrants a reassessment of the role of calcium supplements in the management of osteoporosis, researchers report online July 29, 2010 in BMJ. Most guidelines for the prevention or treatment of osteoporosis recommend the use of calcium supplements, despite the fact that they reduce the risk of fracture only marginally, write Dr Mark J Bolland(University of Auckland, New Zealand) and colleagues.
Studies have yielded conflicting results about their use, with some observational studies suggesting that high calcium intake is protective against vascular disease, and others showing that calcium supplements speed vascular calcification and increase mortality in patients with kidney failure and increase cardiovascular events and MI in women.
Senior author Dr Ian R Reid (University of Auckland) told heartwire that women should discuss the finding from his study with their doctors, but that in most cases, "discontinuation of calcium would seem appropriate."
The researchers had previously found an adverse effect from calcium supplements in a clinical trial, which they published in BMJ in 2008 [2], Reid explained. They repeated electronic database searches in March of this year to consolidate those findings.
Their current meta-analysis looked at randomized trials of calcium supplements that supplied at least 500 mg/day of elemental calcium vs placebo. Each of the trials lasted for at least a year and had at least 100 participants with a mean age of 40 years or older. Cardiovascular outcomes were obtained from self-reports, hospital admissions, and death certificates.
In a combined analysis of the five studies that had contributed patient-level data, the investigators found that calcium supplements were associated with about a 30% increase in the incidence of MI (hazard ratio 1.31; 95% CI 1.02-1.67; p=0.035) and smaller, nonsignificant increases in the risk of stroke and mortality.
The findings were consistent across trials, and the risk of MI with calcium supplements tended to be greater in those with higher dietary calcium intake. The MI risk was independent of age, sex, and type of supplement.
A similar analysis of 11 trials that contributed trial-level data showed a 1.27 relative risk of MI (95% CI 1.01-1.59; p=0.038) associated with calcium supplements.
"Clinicians should tell their patients that, for most older people, the risks of calcium supplements outweigh the benefits. Changing to calcium-rich foods may be appropriate," Reid said.
Calcium supplements causing heartburn, not MI?
In an editorial accompanying the article [3], Dr John Cleland (Castle Hill Hospital, Kingston upon Hull, UK) and colleagues wonder why calcium supplements should increase cardiovascular risk, as found in this meta-analysis. "Accumulation of calcium in the arterial wall leading to reduced compliance would be expected to take years, but the increased risk of myocardial infarction reported by Bolland and colleagues occurred early after calcium supplementation (median follow-up of 3.6 years)."
Cleland et al suggest that the increased risk of MI may not be a true effect, because the increased risk of MI was not accompanied by an increase in mortality. "Calcium supplements could simply be causing gastrointestinal symptoms that could be misdiagnosed as cardiac chest pain," they write, adding that even if the supplements are safe, the neutral effect on mortality "casts doubt on whether they are effective prophylaxis for fractures."
Until more becomes known about the best way to prevent osteoporotic fractures, the editorialists conclude that "patients with osteoporosis should generally not be treated with calcium supplements, either alone or with vitamin D, unless they are also receiving an effective treatment for osteoporosis for a recognized indication." They add that research on whether such supplements are needed in addition to effective osteoporosis treatment is "urgently required."
Dr John Schindler (University of Pittsburgh Medical Center, PA), who isn't a coauthor of the study from Bolland et al, told heartwire that the increased MI risk in the study, although quite modest, is concerning because of the large numbers of people who take calcium supplements. He also questioned whether vascular calcifications could be the cause, because of the trials' relatively short follow-up times.
Gender differences may be important
For Schindler, research into gender differences may yield answers to the increased risk of MI seen in this meta-analysis.
"In this analysis, 88% of the participants were women, and we know that cardiovascular disease in women is radically different from cardiovascular disease in men. The same holds true for cerebrovascular disease. There is something we need to get at, and at this point, no one has really been able to do so."
Schindler also said that the real risk of MI appeared to be in people who took calcium supplements on top of high levels of dietary calcium. "I think the safest thing to tell your patients right now is if you can get your dietary calcium from good dietary sources, such as yogurt, sardines, and skim milk, that potentially might be all you need to ward off the risk of osteoporosis. Then we don't have to deal with this increased cardiovascular risk."
He added that it is important to consider the potential safety concerns along with the benefits of bone health. "The benefits of calcium supplementation in older women with a low risk of fracture may not outweigh the potential cardiovascular risk."
Finally, Schindler noted the absence in the meta-analysis of the Women's Health Initiative, a large study that looked at the role of calcium supplementation with vitamin D in reducing osteoporotic fracture. "There are a lot of data that show that vitamin D is protective from a cardiovascular standpoint. They excluded studies with vitamin D probably because they are trying to isolate one ----variable. They didn't want to cloud the picture."
Published 29 July 2010, Cite this as: BMJ 2010;341:c3856
Calcium supplements in people with osteoporosis
Should not be given without concomitant treatment for osteoporosis

In the linked systematic review (doi:10.1136/bmj.c3691), Bolland and colleagues assessed whether calcium supplements increase the risk of cardiovascular events in people with, or at risk of, osteoporosis.1 They found that calcium supplements increased the risk of myocardial infarction (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67), but they found no significant difference in the risk of stroke, death, or the composite end point of myocardial infarction, stroke, or sudden death.
The effort spent on detecting and treating osteoporosis is only worthwhile if it translates into a health benefit for patients. The most common argument for detecting and treating osteoporosis is a reduction in bone fractures that are either subtle and progressive (for example, those that cause loss of vertebral height) or overt (for example, fractures of the hip and wrist). Bone mineral density, which is often used as a measure of treatment success, is a surrogate measure for real clinical benefit.
Surrogate measures may be useful in pilot studies but become problematic when they become the goal of treatment. 2 3 Bone fractures in older people are an important cause of disability, and more than 20% of patients will die within one year of a low trauma hip fracture.4 5 Accordingly, a safe and effective treatment that can prevent fractures should reduce mortality if given to a large enough population at sufficient risk.
Calcium supplements, given alone, improve bone mineral density,4 but they are ineffective in reducing the risk of fractures and might even increase risk,4 5 they might increase the risk of cardiovascular events,1 and they do not reduce mortality.1 They seem to be unnecessary in adults with an adequate diet. Given the uncertain benefits of calcium supplements, any level of risk is unwarranted.
Why should calcium supplements increase cardiovascular risk? Calcium supplements may improve some conventional cardiovascular risk factors including blood pressure and lipids.6 Accumulation of calcium in the arterial wall leading to reduced compliance would be expected to take years, but the increased risk of myocardial infarction reported by Bolland and colleagues occurred early after calcium supplementation (median follow-up of 3.6 years).
An alternative possibility is that the increased risk of myocardial infarction is not a true effect. If an intervention changes the rate of vascular events but is not associated with a commensurate change in mortality, the intervention may be changing the presentation rather than the incidence. Flecainide reduces the risk of non-fatal myocardial infarction by about 30% because infarctions are more likely to be fatal before patients reach hospital.7 Similarly, long term treatment with aspirin seems to modify the presentation of vascular events with no effect on mortality and, possibly, with acceleration of the progression of vascular disease.8 Although the risk of myocardial infarction seemed to increase substantially (by about 25%) with calcium supplementation this was not accompanied by an increase in mortality. Calcium supplements could simply be causing gastrointestinal symptoms that could be misdiagnosed as cardiac chest pain. However, even if calcium supplements really are safe, a neutral effect on mortality casts doubt on whether they are effective prophylaxis for fractures.
A combination of calcium and vitamin D is commonly used to treat osteoporosis. Vitamin D supplements might reduce the risk of falls, might have important clinical effects on cardiovascular function, do not increase mortality, and may mitigate the trend to excess mortality seen with calcium supplements alone.9 However, no conclusive data are available to show that current doses of vitamin D supplements with or without calcium supplements reduce the rates of fracture, and meta-analyses found evidence of substantial reporting bias.4 5 9
Several agents that are, or might be, used to treat osteoporosis do reduce mortality, including bisphosphonates,10 11 raloxifene,10 and thiazides.12 However, biphosphonates and raloxifene were generally given in addition to calcium and vitamin D supplements. Other methods of reducing fractures should also be subject to scientific scrutiny. Reducing falls and bone trauma is, probably, the most effective method of reducing fractures, but if it leads to a sedentary lifestyle it might impair both quality of life and longevity. Exercise might be a good way to increase bone strength, although it also carries risk.12
Requiring companies to show before licensing that treatments for chronic diseases such as osteoporosis, diabetes, and hypertension reduce long term disability and death could lead to a cessation of research in these areas. The cost and commercial risk would be too high. However, we do need to know whether treatments are safe, effective, and value for money. Extending the patent life of drugs to that of the copyright on a song (50 years according to the Berne Convention) would have many benefits and few drawbacks if properly managed. Regulators could insist that drugs show benefits on symptoms, disability, and mortality rather than surrogate outcomes, which would give doctors and patients greater certainty about the benefits and risks. Regulators could also insist that more trials examine the added value of new compared with old drugs. Lower prices for innovative drugs could be negotiated. Companies could plan a more comprehensive research programme with the knowledge that their income streams were more reliable, although still vulnerable to price competition from other companies and to being superseded by more innovative drugs. There would be fewer impediments to the adoption of innovations on financial grounds and less reason to persist with low cost generic drugs if they are inferior.
In the meantime, on the basis of the limited evidence available, patients with osteoporosis should generally not be treated with calcium supplements, either alone or combined with vitamin D, unless they are also receiving an effective treatment for osteoporosis for a recognised indication. Research on whether such supplements are needed as an adjunct to effective agents is urgently required.
Cite this as: BMJ 2010;341:c3856
John G F Cleland, professor1, Klaus Witte, senior lecturer and honorary consultant cardiologist2, Sue Steel, consultant physicist1
1 Department of Cardiology, Castle Hill Hospital, Hull York Medical School, University of Hull, Kingston upon Hull HU16 5JQ, 2 Division of Diabetes and Cardiovascular Research, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds LS2 9JT
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2. Freemantle N, Calvert M. Composite and surrogate outcomes in randomised controlled trials. BMJ 2007;334:756-7.
3. Cleland JGF, Atkin SL. Thiazolidinediones, deadly sins, surrogates and elephants. Lancet 2007;370:1103-4.[CrossRef][Web of Science][Medline]
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5. Reid IR, Bolland MJ, Grey A. Effect of calcium supplementation on hip fractures. Osteoporos Int 2008;19:1119-23.[CrossRef][Web of Science]
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7. Greenberg HM, Dwyer EM Jr, Hochman JS, Steinberg JS, Echt DS, Peters RW. Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST I. Br Heart J 1995;74:631-5.
8. Cleland JGF. For debate: preventing atherosclerotic events with aspirin. BMJ 2002;324:103-5.
9. Sahota O. Reducing the risk of fractures with calcium and vitamin D. BMJ 2010;340:b5492.
10. Stevenson M, Jones ML, De NE, Brewer N, Davis S, Oakley J. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis. Health Technol Assess 2005;9:1-160.
11. Bolland MJ, Grey AB, Gamble GD, Reid IR. Effect of osteoporosis treatment on mortality: a meta-analysis. J Clin Endocrinol Metab 2010;95:1174-81.
12. Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd JM. Treatment of established osteoporosis: a systematic review and cost-utility analysis. Health Technol Assess 2002;6:1-146.
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