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Discussion

In this trial of secondary-fracture prevention, incidence of fractures did not differ between those allocated any calcium versus no calcium, between those allocated any vitamin D3 versus no vitamin D3, or between those allocated combination treatment versus placebo.

As expected, the rate of further low-trauma fracture was high (one in eight). However, there were fewer hip fractures than anticipated, which was related to the tendency for older people to be ineligible because of cognitive impairment (43% of participants in this trial) or because they had already been prescribed bone-active drugs (34%). Both these groups are likely to be at higher risk of further fractures than participants in this trial. Few participants were enrolled after a vertebral fracture, and such patients might be more responsive to treatment." A possible explanation for the findings is that true differences were underestimated because of chance. The trial was large, involving more than 5000 participants with a minimum follow-up of 24 months, and 698 had at least one new low-trauma fracture. At the start of the trial the aim was to identify a 20% relative difference (3% absolute difference). The lower ends of the 95% CI around the HR for the principal analyses were 0.805 for calcium and 0.879 for vitamin D3, indicating that a true effect of that size is very unlikely, on the basis of these results.

As expected, it was difficult to maintain compliance with allocated tablets: participants were elderly, usually taking other medications, and comorbidity was common. By the time data collection had stopped, one in six had died. By 2 years, compliance (defined as a participant who took >80% of tablets) was 60% of those who returned questionnaires. All analyses were based on the intention-to-treat principle, and so effectiveness in this context rather than efficacy was measured. Comparison of compliance in this trial with that of other trials is difficult because rates of compliance with tablets and drop-outs are often not well reported. There were different rates of questionnaire response in the trial groups, especially for comparisons of calcium because of increased rates of possible side-effects in these groups. Although imbalances in the response rate in different groups could introduce bias into comparisons that are based only on questionnaire responses (eg, quality of life), this bias seems unlikely for fractures and deaths because these data were derived from several sources and the pattern of results was similar irrespective of the source of identification.

There was no evidence that supplementation might be especially useful for specific groups (figure 3) or that true differences could have been obscured by poor compliance. A possible mechanism for fracture prevention was a reduced incidence of falls. For pragmatic reasons, we chose to address this issue through one question in every follow-up questionnaire that was sent every 4 months asking about falls during the previous week. Although this method undoubtedly underestimated true rates of falls, there was no evidence of any difference between groups.

The results for participants assigned vitamin D 3 alone and those assigned calcium alone are consistent with an overview of similar trials in that they suggest no significant effect.7,17 However, results of individual trials using vitamin D vary. In a primary-prevention trial of a single dose of 100 000 IU oral vitamin D every 4 months, Trivedi and colleagues18 reported a marginally significant 22% beneficial effect. However, primary-prevention trials19,20 of 400 IU oral vitamin D3 taken every day have shown no significant effect on the incidence of all types of fracture. A UK study21 of 9000 healthy mobile older women and men showed no reduction in fracture risk after three injections of 300 000 IU vitamin D3 per year.

By contrast with Chapuy and colleagues'22-24 and Dawson-Hughes'25 primary-prevention trials, we did not find a significant effect of combined calcium and vitamin D3 on fracture prevention. However, our study population was younger and less frail than were the participants in Chapuy and co-workers' trials, and most were mobile and living in the community. Therefore, the participants in our trial might have been less likely to have vitamin D insufficiency and secondary hyperparathyroidism than those in the trials by Chapuy and colleagues. Our participants were, however, older than were participants in Dawson-Hughes' trial. Concentrations of 25-OH-vitamin D3 achieved with supplementation seem lower in our trial than in these other trials,18,22-25 although differences in analytical techniques make comparisons difficult. We also showed less suppression of parathyroid hormone than did others,22,23,25 but more suppression than in a later trial.25 The amount of vitamin D needed to ensure optimum blood concentrations of 25-OH-vitamin D3 and parathyroid hormone is debatable. As much as 4000 IU per day has been suggested,26 but this amount has yet to be tested in a fracture-prevention trial.

Secondary-fracture prevention is now widely practised. Our trial indicates that routine supplementation with calcium and vitamin D3, either alone or in combination, is not effective in the prevention of further fractures in people who have had a recent low-trauma fracture. Secondary analyses did not identify subgroups that might benefit from supplementation, such as those individuals (17% of those enrolled) who had had a hip fracture before enrolment. These participants were older (mean 79.4 years [SD 6.3] vs 77.0 [5.3]) and twice as likely to die (28% vs 15%) during the trial than those with a non-hip fracture. Policies for secondary prevention should therefore consider other strategies. The main pharmacological intervention is antiresorptive drugs, such as bisphosphonates, which have rarely been assessed in patients who have not been taking calcium or vitamin D.

This trial was not designed to directly address whether supplementation should be used as a primary-prevention measure or in those who live in a care-home environment. Clarification of the role of supplementation in these settings awaits the results of other trials.