Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials.

BACKGROUND Antifracture efficacy with supplemental vitamin D has been questioned by recent trials. METHODS We performed a meta-analysis on the efficacy of oral supplemental vitamin D in preventing nonvertebral and hip fractures among older individuals (> or =65 years). We included 12 double-blind randomized controlled trials (RCTs) for nonvertebral fractures (n = 42 279) and 8 RCTs for hip fractures (n = 40 886) comparing oral vitamin D, with or without calcium, with calcium or placebo. To incorporate adherence to treatment, we multiplied the dose by the percentage of adherence to estimate the mean received dose (dose x adherence) for each trial. RESULTS The pooled relative risk (RR) was 0.86 (95% confidence interval [CI], 0.77-0.96) for prevention of nonvertebral fractures and 0.91 (95% CI, 0.78-1.05) for the prevention of hip fractures, but with significant heterogeneity for both end points. Including all trials, antifracture efficacy increased significantly with a higher dose and higher achieved blood 25-hydroxyvitamin D levels for both end points. Consistently, pooling trials with a higher received dose of more than 400 IU/d resolved heterogeneity. For the higher dose, the pooled RR was 0.80 (95% CI, 0.72-0.89; n = 33 265 subjects from 9 trials) for nonvertebral fractures and 0.82 (95% CI, 0.69-0.97; n = 31 872 subjects from 5 trials) for hip fractures. The higher dose reduced nonvertebral fractures in community-dwelling individuals (-29%) and institutionalized older individuals (-15%), and its effect was independent of additional calcium supplementation. CONCLUSION Nonvertebral fracture prevention with vitamin D is dose dependent, and a higher dose should reduce fractures by at least 20% for individuals aged 65 years or older.

[1]  S. Fowler,et al.  Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. , 2001, The Journal of clinical endocrinology and metabolism.

[2]  R. Vieth,et al.  Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. , 1998, The American journal of clinical nutrition.

[3]  M. Fukunaga,et al.  A new active vitamin D, ED-71, increases bone mass in osteoporotic patients under vitamin D supplementation: a randomized, double-blind, placebo-controlled clinical trial. , 2005, The Journal of clinical endocrinology and metabolism.

[4]  J. Hopper,et al.  Should Older People in Residential Care Receive Vitamin D to Prevent Falls? Results of a Randomized Trial , 2005, Journal of the American Geriatrics Society.

[5]  L. Bouter,et al.  Vitamin D Supplementation and Fracture Incidence in Elderly Persons , 1996, Annals of Internal Medicine.

[6]  S. Kawai,et al.  Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. , 2004, The American journal of medicine.

[7]  B. Hollis,et al.  Vitamin D2 is much less effective than vitamin D3 in humans. , 2004, The Journal of clinical endocrinology and metabolism.

[8]  R. Vieth,et al.  The case against ergocalciferol (vitamin D2) as a vitamin supplement. , 2006, The American journal of clinical nutrition.

[9]  P. Lips.  Vitamin D deficiency and osteoporosis: the role of vitamin D deficiency and treatment with vitamin D and analogues in the prevention of osteoporosis‐related fractures , 1996, European journal of clinical investigation.

[10]  G. Sigurdsson,et al.  Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. , 2005, JAMA.

[11]  R. Doll,et al.  Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial , 2003, BMJ : British Medical Journal.

[12]  A. Grant.  Oral vitamin D 3 and calcium for secondary prevention of low-trauma fractures in elderly people ( Randomised Evaluation of Calcium Or vitamin D , RECORD ) : a randomised placebo-controlled trial , 2005 .

[13]  F. Hu,et al.  Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged > or =60 y. , 2004, The American journal of clinical nutrition.

[14]  R. Heaney,et al.  Calcium absorptive effects of vitamin D and its major metabolites. , 1997, The Journal of clinical endocrinology and metabolism.

[15]  M. Holick,et al.  Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. , 2008, The Journal of clinical endocrinology and metabolism.

[16]  H. Orimo,et al.  Effects of 2 years' treatment of osteoporosis with 1 alpha-hydroxy vitamin D3 on bone mineral density and incidence of fracture: a placebo-controlled, double-blind prospective study. , 1996, Endocrine journal.

[17]  G E Dallal,et al.  Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. , 1997, The New England journal of medicine.

[18]  R. Steinberg,et al.  Alfacalcidol (alpha D3) and calcium in osteoporosis. , 1994, Clinical orthopaedics and related research.

[19]  H. Minne,et al.  Effects of a Short‐Term Vitamin D and Calcium Supplementation on Body Sway and Secondary Hyperparathyroidism in Elderly Women , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[20]  S. Boonen,et al.  NEED FOR ADDITIONAL CALCIUM TO REDUCE THE RISK OF HIP OR ANY NONVERTEBRAL FRACTURE WITH VITAMIN D SUPPLEMENTATION: EVIDENCE FROM A COMPARATIVE META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS , 2009 .

[21]  C. Cooper,et al.  Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial , 2005, The Lancet.

[22]  S. Thompson,et al.  How should meta‐regression analyses be undertaken and interpreted? , 2002, Statistics in medicine.

[23]  R. Harwood,et al.  A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study. , 2004, Age and ageing.

[24]  L. Mosekilde,et al.  Vitamin D and Calcium Supplementation Prevents Osteoporotic Fractures in Elderly Community Dwelling Residents: A Pragmatic Population‐Based 3‐Year Intervention Study , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[25]  H. Minne,et al.  Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals , 2009, Osteoporosis International.

[26]  S. Ott,et al.  Calcitriol treatment is not effective in postmenopausal osteoporosis. , 1989, Annals of internal medicine.

[27]  H. Bischoff-Ferrari,et al.  Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. , 2004, The American journal of medicine.

[28]  M. Chapuy,et al.  Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women , 1994, BMJ.

[29]  Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials. , 2007, The Journal of clinical endocrinology and metabolism.

[30]  M. Law,et al.  Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation. , 2006, Age and ageing.

[31]  J. I. Pedersen,et al.  Can Vitamin D Supplementation Reduce the Risk of Fracture in the Elderly? A Randomized Controlled Trial , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[32]  M. Schlichting,et al.  Combined Calcium and Vitamin D3 Supplementation in Elderly Women: Confirmation of Reversal of Secondary Hyperparathyroidism and Hip Fracture Risk: The Decalyos II Study , 2002, Osteoporosis International.

[33]  S. Sharp,et al.  Explaining heterogeneity in meta-analysis: a comparison of methods. , 1999 .

[34]  J. Manson,et al.  Calcium plus vitamin D supplementation and the risk of fractures. , 2006, The New England journal of medicine.

[35]  David Moher,et al.  Effectiveness and safety of vitamin D in relation to bone health. , 2007, Evidence report/technology assessment.

[36]  Douglas G. Altman,et al.  Systematic reviews in health care : meta-analysis in context , 2008 .

[37]  D. Kiel,et al.  Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials. , 2007, The American journal of clinical nutrition.

[38]  Bess Dawson-Hughes,et al.  Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. , 2005, JAMA.

[39]  S. Boonen,et al.  Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials. , 2007, The Journal of clinical endocrinology and metabolism.

[40]  D. Knol,et al.  Vitamin D status predicts physical performance and its decline in older persons. , 2007, The Journal of clinical endocrinology and metabolism.

[41]  G. Spears,et al.  Treatment of postmenopausal osteoporosis with calcitriol or calcium , 1992 .

[42]  R. Newcombe,et al.  Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation , 2007, Osteoporosis International.

[43]  S Duval,et al.  Trim and Fill: A Simple Funnel‐Plot–Based Method of Testing and Adjusting for Publication Bias in Meta‐Analysis , 2000, Biometrics.

[44]  David J Torgerson,et al.  Primary care Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D 3 ) for prevention of fractures in primary care , 2005 .

[45]  Alan Bensoussan,et al.  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 , 2007, The Lancet.