Effect of calcium supplementation on fracture risk: a double-blind randomized controlled trial

BACKGROUND: Calcium supplementation is recommended by several national organizations to achieve optimum bone health.  It is unknown whether this benefit is seen using calcium supplementation without vitamin D.

OBJECTIVE: To assess the efficacy of supplementation with calcium in the reduction in risk of fractures during treatment and follow-up phases.

METHODS: The study design was a randomized, 4-year, double-blind, placebo-controlled trial.  Participants were recruited at 6 sites in the United States between 1988 and 1992.  Eligible patients were <80 years of age, in good health, had at least one histologically confirmed large-bowel adenoma removed within the preceding three months, and the entire large bowel mucosa was judged to be free of polyps.  Patients were excluded if they had a history of familial polyposis, invasive large-bowel cancer, malabsorption syndromes, or any condition that might be worsened by calcium supplementation.  The study began with 1118 individuals in a 3-month single-blind placebo run-in period, of which 930 had taken >80% of their tablets and were deemed eligible for randomization.  Participants were randomly assigned to either the calcium group [3g CaCo3 (600mg elemental Ca)] (n=464) or the placebo group (n=466.  Participants were asked not take any calcium supplements other than those given to them during the treatment period.  The primary outcome of the study looked at the reduction in all fractures and minimal trauma fractures. The intent-to-treat method was used for analyzing the data in the intervention phase.  All treatment comparisons were performed with the use of Cox proportional hazard models to estimate the hazard ratio (HR) for time to first fracture and time to first low-trauma fracture.  Power was not reported in the study.

RESULTS: Overall one or more fractures occurred in 46 of 464 individuals in the calcium group and 54 of 466 in the placebo group (unadjusted HR: 0.86; 95% CI: 0.58-1.28).  During the intervention phase, there were 4 fractures in the calcium group and 14 subjects with fractures in the placebo group, which indicated a reduction in risk (unadjusted HR: 0.28; 95% CI 0.09-0.85).  There were more fractures during the observational, posttreatment follow-up: 42 calcium subjects and 40 placebo subjects had one or more fractures (unadjusted HR: 1.10; 95% CI: 0.71-1.69).  The unadjusted HRs were significantly different after treatment than during treatment (P=0.026).  Of the 930 randomized subjects, 44 experienced at least one minimal trauma fracture (15/464 calcium and 29/466 placebo), 9 of which occurred during the treatment period.  Overall, the risk of one or more minimal trauma fractures was significantly lower in the calcium group (unadjusted HR: 0.52; 95% CI: 0.28-0.97; P=0.04). The authors concluded that there was a marked reduction in the risk of fractures, particularly minimal trauma fractures, during the 4 year treatment period.

STRENGTHS: There were no apparent conflicts of interest in this study.  The rationale behind the study was appropriate due to conflicting evidence in previous studies with calcium supplementation. The design of the study was appropriate and minimized the likelihood of outside factors affecting the observed outcomes. The calcium was dosed appropriately for this study. 

LIMITATIONS: The subjects were chosen based on inclusion criteria for another study and so the study population does not represent the population at risk for osteoporosis.  This study would have been more clinically useful if it had looked at a study population that included older subjects and more women, since that is who is at increased risk of osteoporosis related fractures.  Outcome measures were appropriate for the objective of the study.  There is no way of knowing the risk of Type II error in the all confirmed fractures outcome since this study did not report power.  Since the results showed no significant difference over the entire study between the calcium and placebo groups and power was not reported there is an unknown risk of Type II error.

CONCLUSION:  Although continuous use of a calcium supplement appears to be statistically significant during treatment for the reduction in risk of fractures, it is difficult to say whether it is clinically useful since the study did not mention adverse effects.  There was no statistically significant difference between the two groups in the follow-up phase.  Calcium supplementation may be beneficial in the prevention of fractures among relatively healthy individuals who have close to adequate vitamin D concentrations and who are willing to take the supplements on a continuous basis. Also, since the study population did not represent the population at risk for osteoporosis related fractures, further study is needed to assess the clinical use of calcium supplementation

Bischoff-Ferrari HA, Rees JR, Grau MV, Barry E, Gui J, Baron JA. Effect of calcium supplementation on fracture risk: a double-blind randomized controlled trial. Am J Clin Nutr. 2008 Jun;87(6):1945-51.

Michelle D. Kennedy, PharmD. Candidate