from Essential Evidence Evidence Summaries 2009-12-30
Level of evidence = A
Oral vitamin D 700–800 IU/day with calcium supplementation 1200 mg/day or more reduces the risk of hip and nonvertebral fractures in ambulatory or institutionalised elderly people. A vitamin D dose of 400 IU/day seems to be insufficient for fracture prevention.
A Cochrane review 1 (abstract 1 , review 1 ) included 45 randomised or quasi-randomised studies comparing vitamin D or an analogue, alone or with calcium, against placebo, no intervention, or calcium, reporting fracture outcomes, in older people, with a total of over 50 000.
Vitamin D alone showed no statistically significant effect on hip fracture (RR 1.15, 95% CI 0.99 to 1.33; 9 trials, n=24 749), vertebral fracture (RR 0.90, 95% CI 0.42 to 1.95; 5 trials, n=9 138) or any new fracture (RR 1.01, 95% CI 0.93 to 1.09; 10 trials, n=25 016). Vitamin D with calcium marginally reduced hip fractures (RR 0.84, 95% CI 0.73 to 0.96; 8 trials, n=46 658). Although subgroup analysis by residential status showed a significant reduction in hip fractures in people in institutional care, the difference between this and the community-dwelling subgroup was not significant (P = 0.15). Hypercalcaemia was more common when vitamin D or its analogues was given compared with placebo or calcium (RR 2.35, 95% CI 1.59 to 3.47; 18 trials, n=11 346). There was a modest increase in gastrointestinal symptoms (RR 1.04, 95% CI 1.00 to 1.08; 11 trials, 47 042 participants), and a small but significant increase in renal disease (RR 1.16, 95% CI 1.02 to 1.33; 11 trials, 46 537 participants).
A systematic review 3 included 17 trials with a total of 52 625 subjects aged 50 years or older using reported fractures as an outcome. Treatment with vitamin D and calcium was associated with a 12% risk reduction in fractures of all types (RR 0.88, 95% CI 0.83 to 0.95). The fracture risk reduction was significantly greater (24%) in trials in which the compliance rate was high. The treatment effect was better with calcium doses of 1200 mg or more than with doses less than 1200 mg (0.80 vs 0.94, p=0.006) and with vitamin D doses of 800 IU or more than with doses less than 800 IU (0.94 vs 0.87, p=0.03). The NNT for preventing one fracture over 3.5 years was 64.
A systematic review 2 including 7 trials assessing the effectiveness of oral vitamin D supplementation in preventing hip and nonvertebral fractures in older people (mean age of at least 60 years), with a total of 9 820 subjects, was abstracted in DARE. All studies used cholecalciferol; the doses were 400 IU/day (2 studies) and 700 to 800 IU/day (5 studies). Four trials also gave calcium supplementation (500 to 1 200 mg/day). Five trials had placebo control groups, in one trial the control group were given calcium supplementation, and in another trial the control group were given cod liver oil.
There was a statistically significant reduction of hip fractures (RR 0.74, 95% CI 0.61 to 0.88; 3 trials) for patients receiving 700 to 800 IU/day oral vitamin D supplementation, with no significant heterogeneity between studies (P=0.74). The pooled risk difference was 2% (95% CI 1 to 4, P<0.001), therefore the NNT was 45 (95% CI 28 to 114) for a treatment duration of 24 to 60 months. For patients receiving 400 IU/day oral vitamin D supplementation, there was no reduction in the RR of hip fracture (RR 1.15, 95% CI 0.88 to 1.50; 2 trials). When all studies were pooled together, there was no statistically significant reduction in the RR of hip fracture (RR 0.88, 95% CI 0.69 to 1.13; 5 trials) but significant heterogeneity between studies (P=0.09).
For any nonvertebral fracture, there was a statistically significant reduction (RR 0.77, 95% CI 0.68 to 0.87; 5 trials) for patients receiving 700 to 800 IU/day oral vitamin D supplementation, with no significant heterogeneity between studies (P=0.41). The pooled risk difference was 4% (95% CI 2 to 5), therefore the NNT was 27 (95% CI 19 to 49) for a treatment duration of 12 to 60 months. For patients receiving 400 IU/day oral vitamin D supplementation, there was no reduction in the RR of any nonvertebral fracture (RR 1.03, 95% CI 0.86 to 1.24; 2 trials). When all studies were pooled together, there was a statistically significant reduction in the RR of any nonvertebral fracture (RR 0.83, 95% CI 0.70 to 0.98; 7 trials) but significant heterogeneity between studies (P=0.07).
Comment: The quality of evidence is downgraded by inconsistency (heterogeneity in interventions) and upgraded by dose-response relationship. The independent effect of vitamin D can not be determined because in most trials also calcium was administered.
Avenell A, Gillespie WJ, Gillespie LD, O'Connell DL. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev 2009 Apr 15;(2):CD000227.
Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005 May 11;293(18):2257-64.
Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007 Aug 25;370(9588):657-66.
Author: Editors Article ID: evd03421 (022.005) © 2009 Duodecim Medical Publications Ltd