Benefits of Calcium Supplements Are Too Small for Clinical Equipoise to Exist

Abstract

In his article “The Calcium Supplement Controversy: Now What?” Dr Bauer suggests that there is clinical equipoise regarding the use of calcium supplements and that more clinical trials are needed.1 We think both these views are questionable. Clinical equipoise implies uncertainty as to whether the benefits of calcium outweigh the risks. The benefits of calcium have been clearly defined in a number of large clinical trials with fracture as a primary endpoint. Pooled analyses of these trials suggest a 12% reduction in total fractures with calcium2 but no reduction, and possibly an increase, in hip fracture risk in community-dwelling individuals.3, 4 A 12% reduction in relative risk translates into a very small absolute benefit for people at low-moderate risk of fracture. For a population with an average 10-year fracture risk of 20%, 10 in 100 people would sustain a fracture within 5 years. By taking calcium supplements for 5 years, the proportion with fracture would reduce to 8.8 in 100 people, so that about 1 in 100 people benefit from taking calcium. If the average 10-year fracture risk is 10%, about 1 in 200 people benefit from taking calcium for 5 years. Because the absolute benefit of calcium in preventing fractures is so small, the risks must also be very small for clinical equipoise to exist. However, many people experience adverse effects from taking calcium. At least 10% to 20% experience gastrointestinal side effects, such as constipation, which cause a significant number to stop the supplements. Less common side effects include hospital admissions for acute gastrointestinal symptoms,5 renal stones,6 myocardial infarction (MI),7, 8 stroke,8 and, rarely, hypercalcemia.9 In the study by Prince and colleagues, there were 24 more women with a hospitalization for acute gastrointestinal symptoms in the calcium group than in the placebo group, and 16 fewer women with a fracture.5, 10 In the Women's Health Initiative, there were 68 more women with a kidney stone in the calcium group, and 56 fewer women with a fracture.6 In our two meta-analyses, the cardiovascular risks of calcium were similar to7 or exceeded8 the benefits of calcium on fracture prevention. Thus, available evidence suggests that the small risk of significant side effects coupled with the moderate risk of minor side effects outweighs any small benefits on fracture prevention. Even if clinical equipoise does exist, further clinical trials are both difficult to justify and unlikely to be feasible. The effect on fracture risk is already known, so the main purpose of future trials would be to define the risk of adverse events such as cardiovascular events. Based on the incidence of events in our previous individual patient data meta-analyses (mean age 74 years, 77% female),7 a 5-year study with 90% power to detect a 20% increase in MI, allowing for 20% loss to follow-up, would need about 27,000 participants and 45,000 participants to detect a 15% increase in stroke. Using data from a younger cohort at lower risk (mean age 67 years, 93% female),8 the respective numbers would be 56,000 for MI and 108,000 for stroke. Depending on the study design, these numbers are likely conservative estimates. Such trials would be extremely expensive and logistically challenging. Furthermore, obtaining ethical approval and recruiting participants is likely to be difficult given that the primary purpose would be to define the risks of an intervention with very small absolute benefits. For these reasons, we think that further large clinical trials of calcium supplements are unlikely to be undertaken. Clinical practice must, therefore, be guided by the data from existing clinical trials, with all their limitations. All authors state that they have no conflicts of interest.