Annual High-Dose Oral Vitamin D and Falls and Fractures in Older Women: A Randomized Controlled Trial | Geriatrics | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Jackson R, LaCroix A, Gass M,  et al; Women's Health Initiative Investigators.  Calcium plus vitamin D supplementation and the risk of fractures.  N Engl J Med. 2006;354(7):669-68316481635PubMedGoogle ScholarCrossref
Grant A, Anderson F, Avenell A,  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).  Lancet. 2005;365(9471):1621-162815885294PubMedGoogle ScholarCrossref
Trivedi D, Doll R, Khaw K. Effect of four monthly oral vitamin D supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.  BMJ. 2003;326(7387):469-47512609940PubMedGoogle ScholarCrossref
Chapuy MC, Arlot ME, Delmas PD, Meunier P. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women.  BMJ. 1994;308(6936):1081-10828173430PubMedGoogle ScholarCrossref
Chapuy MC, Arlot ME, Duboeuf F,  et al.  Vitamin D3 and calcium to prevent hip fractures in elderly women.  N Engl J Med. 1992;327(23):1637-16421331788PubMedGoogle ScholarCrossref
Porthouse J, Cockayne S, King C,  et al.  Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.  BMJ. 2005;330(7498):100315860827PubMedGoogle ScholarCrossref
Heikinheimo R, Inkovaara JA, Harju EJ,  et al.  Annual injection of vitamin D and fractures of aged bones.  Calcif Tissue Int. 1992;51(2):105-1101422948PubMedGoogle ScholarCrossref
Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C. Effect of annual intramuscular vitamin D on fracture risk in elderly men and women: a population-based, randomized, double-blind, placebo-controlled trial.  Rheumatology (Oxford). 2007;46(12):1852-185717998225PubMedGoogle ScholarCrossref
Larsen E, Mosekilde L, Foldspang A. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study.  J Bone Miner Res. 2004;19(3):370-37815040824PubMedGoogle ScholarCrossref
Dawson-Hughes B, Harris S, Krall E, Dallal G. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.  N Engl J Med. 1997;337(10):670-6769278463PubMedGoogle ScholarCrossref
Lyons R, Johansen A, Brophy S,  et al.  Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation.  Osteoporos Int. 2007;18(6):811-81817473911PubMedGoogle ScholarCrossref
Prince R, Austin N, Devine A, Dick I, Bruce D, Zhu K. Effects of ergocalciferol added to calcium on the risk of falls in elderly high-risk women.  Arch Intern Med. 2008;168(1):103-10818195202PubMedGoogle ScholarCrossref
Law MR, Wald NJ, Meade TW. Strategies for prevention of osteoporosis and hip fracture.  BMJ. 1991;303(6800):453-4591912840PubMedGoogle ScholarCrossref
Bischoff-Ferrari H, Willett W, Wong J, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials.  JAMA. 2005;293(18):2257-226415886381PubMedGoogle ScholarCrossref
Bischoff-Ferrari H, Willett W, Wong J,  et al.  Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials.  Arch Intern Med. 2009;169(6):551-56119307517PubMedGoogle ScholarCrossref
Tang B, Eslick G, 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;370(9588):657-66617720017PubMedGoogle ScholarCrossref
Reid I, Bolland M, Grey A. Effect of calcium supplementation on hip fractures.  Osteoporos Int. 2008;19(8):1119-112318286218PubMedGoogle ScholarCrossref
Cranney A, Weiler H, O'Donnell S, Puil L. Summary of evidence-based review on vitamin D efficacy and safety in relation to bone health.  Am J Clin Nutr. 2008;88(2):513S-519S18689393PubMedGoogle Scholar
Jackson C, Gaugris S, Sen S, Hosking D. The effect of cholecalciferol (vitamin D3) on the risk of fall and fracture: a meta-analysis.  QJM. 2007;100(4):185-19217308327PubMedGoogle ScholarCrossref
Avenell A, Gillespie W, Gillespie L, O'Connell D. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis.  Cochrane Database Syst Rev. 2009;2(2):CD00022719370554PubMedGoogle Scholar
DIPART group.  Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe.  BMJ. 2010;340:b546320068257PubMedGoogle ScholarCrossref
Izaks G. Fracture prevention with vitamin D supplementation: considering the inconsistent results.  BMC Musculoskelet Disord. 2007;8:2617349055PubMedGoogle ScholarCrossref
Bischoff-Ferrari H, Dawson-Hughes B, Staehelin H,  et al.  Falls prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised trials.  BMJ. 2009;339:b369219797342PubMedGoogle ScholarCrossref
Wu F, Staykova T, Horne A,  et al.  Efficacy of an oral, 10-day course of high dose calciferol in correcting vitamin D deficiency.  N Z Med J. 2003;116(1179):U53614513083PubMedGoogle Scholar
Pasco J, Henry M, Nicholson G, Sanders K, Kotowicz M. Vitamin D status of women in the Geelong Osteoporosis Study: association with diet and casual exposure to sunlight.  Med J Aust. 2001;175(8):401-40511700831PubMedGoogle Scholar
Sanders K, Stuart A, Merriman E,  et al.  Trials and tribulations of recruiting 2,000 older women onto a clinical trial investigating falls and fractures: Vital D study.  BMC Med Res Methodol. 2009;9(1):7819930724PubMedGoogle ScholarCrossref
Cummings S, Nevitt M, Browner W,  et al; Study of Osteoporotic Fractures Research Group.  Risk factors for hip fractures in white women.  N Engl J Med. 1995;332(12):767-7737862179PubMedGoogle ScholarCrossref
Rubenstein L, Robbins A, Josephson K, Schulman B, Osterweil D. The value of assessing falls in an elderly population: a randomised clinical trial.  Ann Intern Med. 1990;113(4):308-3162115755PubMedGoogle ScholarCrossref
Cumming R. Injury epidemiology and older people: counting and analysing data on falls.  Australasian Epidemiologist. 2000;7(1):10-12Google Scholar
Angus RM, Sambrook PN, Pocock NA, Eisman JA. A simple method for assessing calcium intake in Caucasian women.  J Am Diet Assoc. 1989;89(2):209-2142915093PubMedGoogle Scholar
Sanders K, Seeman E, Ugoni A,  et al.  Age- and gender-specific rate of fractures in Australia: a population based study.  Osteoporos Int. 1999;10(3):240-24710525717PubMedGoogle ScholarCrossref
Pasco J, Henry M, Kotowicz M,  et al.  Seasonal periodicity of serum vitamin D and parathyroid hormone, bone resorption, and fractures: the Geelong Osteoporosis Study.  J Bone Miner Res. 2004;19(5):752-75815068498PubMedGoogle ScholarCrossref
Mithal A, Wahl D, Bonjour J,  et al; IOF Committee of Scientific Advisors (CSA) Nutrition Working Group.  Global vitamin D status and determinants of hypovitaminosis D.  Osteoporos Int. 2009;20(11):1807-182019543765PubMedGoogle ScholarCrossref
Bacon C, Gamble G, Horne A, Scott M, Reid I. High-dose vitamin D3 supplementation in the elderly.  Osteoporos Int. 2009;20(8):1407-141519101755PubMedGoogle ScholarCrossref
Law M, Withers H, Morris J, Anderson F. Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation.  Age Ageing. 2006;35(5):482-48616641143PubMedGoogle ScholarCrossref
Latham N, Anderson C, Reid I. Effects of vitamin D supplementation on strength, physical performance, and falls in older persons: a systematic review.  J Am Geriatr Soc. 2003;51(9):1219-122612919233PubMedGoogle ScholarCrossref
Health Canada.  Vitamin D: recommendations and review status. Updated July 23, 2009. Accessed April 2010
Office of Dietary Supplements, National Institutes of Health.  Dietary Supplement Fact Sheet: Vitamin D Health Professional Fact Sheet. Accessed April 2010
Lord S, Sherrington C, Menz H. Falls in older people: methodological considerations.  Australasian Epidemiologist. 2000;7(1):13-17Google Scholar
Jones G. Pharmokinetics of vitamin D toxicity.  Am J Clin Nutr. 2008;88(2):(suppl)  582s-586s18689406PubMedGoogle Scholar
Ilahi M, Armas L, Heaney R. Pharmokinetics of a single, large dose of cholecalciferol.  Am J Clin Nutr. 2008;87(3):688-69118326608PubMedGoogle Scholar
Pietras S, Obayan B, Cai M, Holick M. Vitamin D2 treatment for vitamin D deficiency and insufficiency for up to 6 years.  Arch Intern Med. 2009;169(19):1806-180819858440PubMedGoogle ScholarCrossref
Heaney R. Vitamin D: criteria for safety and efficacy.  Nutr Rev. 2008;66(10):(suppl 2)  s178-s18118844846PubMedGoogle ScholarCrossref
Original Contribution
May 12, 2010

Annual High-Dose Oral Vitamin D and Falls and Fractures in Older Women: A Randomized Controlled Trial

Author Affiliations

Author Affiliations: Department of Clinical and Biomedical Sciences, Barwon Health, University of Melbourne, Geelong (Drs Sanders, Kotowicz, and Nicholson and Ms Stuart); Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, University of Melbourne, Carlton (Drs Williamson and Simpson); Murdoch Children's Research Institute, and Royal Children's Hospital (Dr Williamson); and Department of General Practice, University of Melbourne, Parkville, Victoria (Dr Young), Australia.

JAMA. 2010;303(18):1815-1822. doi:10.1001/jama.2010.594

Context Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.

Objective To determine whether a single annual dose of 500 000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.

Design, Setting, and Participants A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.

Intervention 500 000 IU of cholecalciferol or placebo.

Main Outcome Measures Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.

Results Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.

Conclusion Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.

Trial Registration Identifier: ACTRN12605000658617; Identifier: ISRCTN83409867