Posts Tagged ‘Clinical trial’

Draft Template for Writing Homeopathic Clinical Trial Protocols – Version-I

[scribd id=172199093 key=key-1dsdm8hzr0syb935lgps mode=scroll]

Calcium supplements boost heart-attack risk: Meta-analysis

Calcium supplements boost heart-attack risk: Meta-analysis


The use of calcium supplements without co-administered Vitamin D is associated with an increased risk of myocardial infarction (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, non-significant 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.”

This study was funded by the Health Research Council of New Zealand and the University of Auckland School of Medicine Foundation. Bolland, Cleland, and Schindler have reported no relevant financial interests. Reid reported financial relationships with Fonterra.


  1. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010; DOI:10.1136/bmj.c3691. Available at: Abstract
  2. Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: Randomised controlled trial. BMJ 2008; 336:262-266. Abstract
  3. Cleland JG, Witte K, Steel S. Calcium supplements in people with osteoporosis. BMJ 2010; 341; DOI:10.1136/bmj.c3856. Available at: Abstract

Additional Resources

The National Institutes of Health has an online fact sheet about calcium supplementation for health professionals.

Clinical Context

Calcium supplements are used to treat osteoporosis among older patients but are only modestly effective in increasing bone density, with a number needed to treat of 39 to 48 patients for 5 years each to prevent 1 fracture. Calcium supplementation has also been associated with adverse effects, including higher mortality rates in patients with renal failure and an increased risk for cardiovascular disease.

This is a meta-analysis of trials examining calcium supplementation to determine the effect on cardiovascular disease outcomes and death.

Study Highlights

  • The investigators searched the databases of MEDLINE, EMBASE, and the Cochrane register for randomized controlled trials of calcium supplements.
  • Included were double-blind randomized controlled trials with calcium supplementation of 500 mg/day or more, participant mean age of at least 40 years, 100 or more participants, and duration of at least 1 year.
  • Excluded were trials that provided both vitamin D and calcium supplementation because vitamin D supplementation has been associated with decreased mortality rates, and trials using dietary modification as calcium addition or in which participants had an indication other than osteoporosis.
  • The researchers considered diagnoses of MI, stroke, and death by using words describing the events or referring to International Classification of Diseases, Ninth Revision, codes.
  • The prespecified primary endpoints were time to first MI; first stroke; and first composite event of MI, stroke, or sudden death.
  • The secondary endpoint was time to death (all-cause mortality).
  • Analysis was performed at the patient level and at the trial level, and random-effects models were used to pool summary data at the trial level.
  • There were 15 eligible trials, of which 5 contributed patient level data with 8151 participants.
  • The median duration of follow-up was 3.6 years in the 5 patient level trials.
  • The HR for MI was 1.31 (95% CI, 1.02 – 1.67; P = .035) in these trials (143 vs 111 MIs for calcium vs no calcium supplementation).
  • The HR for stroke was 1.20 (95% CI, 0.96 – 1.50; P = .11), but the increase was not significant.
  • There was no significant increase in the risk for the composite of MI, stroke, or sudden death for the calcium supplementation group.
  • The number needed to treat for calcium supplementation for 5 years was 69 for MI; 100 for stroke; 61 for the composite of MI, stroke, or sudden death; and 77 for death.
  • Higher calcium intake (> a median of 805 mg/day) was associated with a higher HR (1.85; 95% CI, 1.28 – 2.67) for MI, and intake below the median was not associated with an increased risk for MI.
  • The HRs were 1.18 for an intake of less than 500 mg/day, 0.68 for an intake of 500 to 699 mg/day, 2.28 for an intake of 700 to 899 mg/day, 1.81 for an intake of 900 to 1099 mg/day, and 1.41 for an intake of more than 1100 mg/day.
  • Recurrent cardiovascular disease occurred among 10% to 17% of participants and was more frequent among those who were supplemented with calcium, although this was not statistically significant.
  • Trial level analysis of all 11 trials showed an increased risk for MI with a pooled relative risk for 1.27 (95% CI, 1.01 – 1.59; P = .038) for calcium supplementation but not for stroke, the composite endpoint, or all-cause mortality.
  • The increased risk for MI with calcium was independent of age, sex, and type of supplement.
  • The authors concluded that calcium supplementation without vitamin D added, especially with an intake of more than 805 mg/day, was associated with an increased risk for MI with a trend toward an increased risk for stroke and sudden death but not all-cause death.
  • They recommended a reconsideration of using calcium supplementation to treat osteoporosis in older adults because the risk for MI may be translated into a large disease burden in the population.

%d bloggers like this: