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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;293:2257-2264.

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.

Author Affiliations: Department of Nutrition, Harvard School of Public Health (Drs Bischoff-Ferrari, Willett, and Giovannucci); Division of Rheumatology, Immunology, and Allergy, The Robert B. Brigham Arthritis and Musculoskeletal Diseases Clinical Research Center, and Division of Aging, Brigham and Women’s Hospital (Dr Bischoff-Ferrari); Department of Epidemiology and Channing Laboratory, Brigham and Women’s Hospital (Drs Willett and Giovannucci); Department of Medicine, Tufts-New England Medical Center (Dr Wong); Department of Health Policy and Health Services Research, Boston University Goldman School of Dental Medicine (Mr Dietrich); and Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University (Dr Dawson-Hughes), Boston, Mass.

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