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Fracture Prevention With Vitamin D Supplementation:  A Meta-analysis of Randomized Controlled Trials

Heike A. Bischoff-Ferrari, MD, MPH; Walter C. Willett, DrPH; John B. Wong, MD; Edward Giovannucci, ScD; Thomas Dietrich, MPH; Bess Dawson-Hughes, MD
JAMA. 2005;293(18):2257-2264. doi:10.1001/jama.293.18.2257.
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Context The role and dose of oral vitamin D supplementation in nonvertebral fracture prevention have not been well established.

Objective To estimate the effectiveness of vitamin D supplementation in preventing hip and nonvertebral fractures in older persons.

Data Sources A systematic review of English and non-English articles using MEDLINE and the Cochrane Controlled Trials Register (1960-2005), and EMBASE (1991-2005). Additional studies were identified by contacting clinical experts and searching bibliographies and abstracts presented at the American Society for Bone and Mineral Research (1995-2004). Search terms included randomized controlled trial (RCT), controlled clinical trial, random allocation,double-blind method, cholecalciferol,ergocalciferol,25-hydroxyvitamin D, fractures, humans, elderly, falls, and bone density.

Study Selection Only double-blind RCTs of oral vitamin D supplementation (cholecalciferol, ergocalciferol) with or without calcium supplementation vs calcium supplementation or placebo in older persons (≥60 years) that examined hip or nonvertebral fractures were included.

Data Extraction Independent extraction of articles by 2 authors using predefined data fields, including study quality indicators.

Data Synthesis All pooled analyses were based on random-effects models. Five RCTs for hip fracture (n = 9294) and 7 RCTs for nonvertebral fracture risk (n = 9820) met our inclusion criteria. All trials used cholecalciferol. Heterogeneity among studies for both hip and nonvertebral fracture prevention was observed, which disappeared after pooling RCTs with low-dose (400 IU/d) and higher-dose vitamin D (700-800 IU/d), separately. A vitamin D dose of 700 to 800 IU/d reduced the relative risk (RR) of hip fracture by 26% (3 RCTs with 5572 persons; pooled RR, 0.74; 95% confidence interval [CI], 0.61-0.88) and any nonvertebral fracture by 23% (5 RCTs with 6098 persons; pooled RR, 0.77; 95% CI, 0.68-0.87) vs calcium or placebo. No significant benefit was observed for RCTs with 400 IU/d vitamin D (2 RCTs with 3722 persons; pooled RR for hip fracture, 1.15; 95% CI, 0.88-1.50; and pooled RR for any nonvertebral fracture, 1.03; 95% CI, 0.86-1.24).

Conclusions Oral vitamin D supplementation between 700 to 800 IU/d appears to reduce the risk of hip and any nonvertebral fractures in ambulatory or institutionalized elderly persons. An oral vitamin D dose of 400 IU/d is not sufficient for fracture prevention.

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Figure 1. QUOROM Flow Diagram
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QUOROM indicates Quality of Reporting of Meta-analyses; RCTs, randomized controlled trials.
*Vitamin D or active vitamin D compared with treatments other than calcium or placebo.

Figure 2. Forest Plots Comparing the Risk of Hip and Nonvertebral Fractures Between Vitamin D (700-800 IU/d and 400 IU/d) and Control Groups
Graphic Jump Location

Squares represent relative risks (RRs) and size of squares is proportional to the size of the trials. Error bars represent 95% confidence intervals (CIs). Trials are sorted by trial duration ranging from 24 to 60 months for hip fracture and 12 to 60 months for nonvertebral fracture. For 3 trials with hip fractures,12,17,18 which included 5572 individuals with a vitamin D dose of 700 to 800 IU/d, the pooled RR was 0.74 (95% CI, 0.61-0.88; Q test P = .74). For 5 trials with nonvertebral fractures,12,14,15,17,18 which included 6098 individuals with a vitamin D dose of 700 to 800 IU/d, the pooled RR was 0.77 (95% CI, 0.68-0.87; Q test P = .41). For the 2 trials,13,16 with a vitamin D dose of 400 IU/d, trial duration ranged from 24 months to 36 to 41 months.

Figure 3. Hip and Nonvertebral Fracture Efficacies by Achieved 25-Hydroxyvitamin D Levels in 400 IU/d and 700-800 IU/d Vitamin D–Treated Groups
Graphic Jump Location

Circles and squares represent relative risks (RRs) and error bars represent 95% confidence intervals. Trendline is based on series of effect sizes (open circles and squares). All trials identified for the primary analyses for both fractures are shown as a reference number outside each circle or square. A meta-regression, which included 9294 individuals, indicated a significant inverse relationship between higher achieved 25-hydroxyvitamin D levels in the treatment group and hip fracture risk (β = –0.009; P = .02; log RR of hip fracture is estimated to decrease by 0.009 per 1-nmol/L increase in 25-hydroxyvitamin D). A meta-regression, which included 9820 individuals, indicated a significant inverse relationship between higher achieved 25-hydroxyvitamin D levels in the treatment group and nonvertebral fracture risk (β = −0.006; P = .03; log RR of nonvertebral fracture is estimated to decrease by 0.006 per 1-nmol/L of 25-hydroxyvitamin D achieved in the treatment group). To convert 25-hydroxyvitamin D to ng/mL, divide values by 2.496.

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