Effect or four monthly oral vitamin [D.sub.3] supplementation on fractures and mortality in men and women - Cholecalciferol - Vitamins and Minerals

Nutrition Research Newsletter, March, 2003

Osteoporotic fractures are projected to increase exponentially worldwide. Most fracture-prevention trials have focused on clinically defined groups such as people with osteoporosis or previous fractures and have mainly been conducted in women. Safe, effective, feasible, and cost effective primary prevention measures are needed in older men and women, in whom most osteoporotic fractures occur. The investigators of the current study report results from a randomized double-blind trial of four monthly supplementation with oral vitamin [D.sub.3] on fractures and mortality in 2,686 men and women aged 65 to 85 years living in the community.

This trial was a pilot to assess the feasibility of a community trial in 20,000 men and women. The researchers recruited men and women aged 65 to 85 years from the British doctors study register at the Clinical Trials Studies Unit, Oxford, and the age-sex register of a general practice in Ipswich, Suffolk. People who were already taking vitamin D supplements and people with conditions that were contraindications to vitamin D supplementation were excluded from the study. Invitations were sent to 11,120 people, and 3,504 (31.5%) of them initially agreed to participate. From June 1996 to March 1997 the researchers randomized 2,686 (77.5%) people to receive either treatment with vitamin D or a placebo. Participants and investigators were blinded to the treatment until the study ended. Participants completed an initial questionnaire. Prevalence of disease was determined with the question "Do you have the following conditions?" followed by a checklist. A modified food frequency questionnaire was used at four years to estimate dietary calcium intake. One capsule containing 100,000 IU vitamin [D.sub.3] (cholecalciferol) or matching placebo was sent by post every four months for five years (15 doses in total). Participants were asked to take the capsule immediately on receipt, complete a form indicating that they had done so, and return the form.

On receiving the capsule, participants filled in a checklist of events (fracture or major illness) and returned the form. All participants were flagged at the Office for National Statistics for mortality and followed until 31 March 2002. Incidences of fracture, cardiovascular disease, and cancer were ascertained by using events identified from questionnaires or death certification by cause.

After four years, 235 participants who had taken at least 10 capsules were invited, to a clinic for measurement of serum vitamin D and parathyroid hormone concentrations. Mean calcium intake at four years was 742 mg/day and did not differ by treatment allocation. Participants in the vitamin D treatment group had a 22% lower rate for first fracture at any site and a 33% lower rate for a fracture occurring in the hip, wrist or forearm, or vertebrae. The differences were consistent when stratified by sex or by doctor versus general practice population. Mean vitamin D concentrations were 40% higher in the active treatment group than in the placebo group (p<0.001). Mean parathyroid concentrations were 6% lower, but this difference was not significant.

This trial was a pilot for a larger trial that was not funded and was, consequently, too small for any decisive effect on fractures to be expected. The results, nevertheless, indicate that isolated vitamin D supplementation prevents fractures. The 22% reduction in fractures in the present study translates to approximately 250 people treated for one year to prevent any fracture. This is particularly important for primary prevention.

DP Trivedi, R Doll, KT Khaw. Effect of four monthly oral vitamin [D.sub.3] (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomized double blind controlled trial. BMJ 326:469-472 (March 2003) [Correspondence: K T Khaw kk101@medschl.cam.ac.uk]