Therapeutics
A single, annual, high dose of oral vitamin
D increased falls and fractures in older
women
Clinical impact ratings: F ★★★★★★✩ G ★★★★★★✩ R ★★★★★★✩
Question
Does a single, annual, high dose of oral cholecalciferol (vitamin D)
reduce risk for falls and fractures in older women?
Methods
Design: Randomized, placebo-controlled trial (Vital D study).
ACTR12605000658617; ISRCTN83409867.
Allocation: Concealed.*
Blinding: Blinded (participants, clinicians, {data collectors, and
outcome assessors}†).*
Follow-up period: 12 months after last dose of study medication.
Setting: Southern Victoria, Australia.
Participants: 2258 women ≥ 70 years of age (median age 76 y)
who were at high risk for hip fracture (e.g., maternal hip fracture,
previous fracture, or self-reported faller). Exclusion criteria were
inability to provide information about falls or fractures; permanent
residence in a high-level care facility; albumin-corrected calcium
level > 2.65 mmol/L (10.6 mg/dL); creatinine level > 150 µmol/L
(1.7 mg/dL); or current use of vitamin D, ≥ 400 IU, calcitriol, or
antifracture therapy.
Intervention: Cholecalciferol, 500 000 IU (n = 1131), or match-
ing placebo (n = 1127) given as 10 tablets to be taken on a single
day in the autumn or winter each year for 3 to 5 years.
Outcomes: Self-reported falls and fractures (radiologically con-
firmed). 6855 person-years were needed to detect a 22% relative
difference in fractures with 80% power (α = 0.05).
Patient follow-up: 90% completed follow-up (99.9% included in
intention-to-treat analysis).
Main results
Fall rate was 83.4/100 person-years in the vitamin D group and
72.7/100 person-years in the placebo group; fracture rate was
4.9/100 person-years and 3.9/100 person-years, respectively.
Women in the vitamin D group had a greater risk for falls and
fractures than those in the placebo group. (Table)
Conclusion
In older women, a single, annual, high dose of oral vitamin D
increased risk for falls and fractures compared with placebo.
*See Glossary.
†Information provided by author.
Sources of funding: National Health and Medical Research Council
and Australian Government Department of Health and Ageing.
Annual high-dose oral vitamin D vs placebo in older women at
risk for fractures‡
Outcomes Vitamin D Placebo At a median follow-up of 2.96 y
RRI (95% CI)
First fall 74% 68% 15% (2 to 30)
First fracture 14% 11% 26% (0 to 59)
‡Abbreviations defined in Glossary. RRI, NNH, and CI calculated from control event rates
and incidence rate ratios in article.
21 September 2010 | ACP Journal Club | Volume 153 • Number 3
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 02/04/2015
Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral
vitamin D and falls and fractures in older women: a randomized
controlled trial. JAMA. 2010;303:1815-22.
For correspondence: Dr. K. Sanders, Barwon Health, Geelong,
Victoria, Australia. E-mail kerrie@barwonhealth.org.au. ■
Commentary
“D”éjà vu? Enthusiasm for the health benefits of vitamin A, B, C,
and E supplements was followed by randomized controlled trials
(RCTs) that found them to be ineffective or harmful (1). Current
enthusiasm for vitamin D also exceeds the evidence from RCTs
for prevention of fractures, cancer, or heart disease.
Recent rigorous meta-analyses found that ≤ 1000 IU/d of supple-
mental vitamin D does not reduce risk for fractures (2, 3). Sanders
and colleagues tested a higher dose—500 000 IU of vitamin D3
once a year, equivalent to 1400 IU/d—and found that it increased
risk for fractures and falls. Some propose that ≥ 90 nmol/L is
the ideal level of 25(OH)vitamin D (4). Sanders and colleagues
exceeded that mean level during the first 3 months after dosing,
and this increased the risk for fractures and falls. The Inter-
national Osteoporosis Foundation recommends maintaining
levels > 75 nmol/L (5). Sanders and colleagues achieved such
levels on average during the other 9 months of the year but with
no reduction in fractures or falls. The results also seem to contra-
dict a meta-analysis finding that 700 to 1000 IU/d may reduce
falls in persons ≥ 65 years of age (6).
Another RCT found that 300 000 IU once a year in persons ≥ 75
years of age increased risk for hip fractures and nonvertebral frac-
tures in women (7). Perhaps yearly dosing with transiently high
levels is harmful and daily or weekly dosing is safer. However,
trials must show that a given dose, regimen, or level is not just
safe but beneficial.
Supplementation with 1.2 g of calcium and 800 IU of vitamin D
reduces the risk for hip fractures in institutionalized elderly per-
sons and should be a routine part of care (8). For others, the
common practice of prescribing > 800 IU of vitamin D daily to
achieve 25(OH)vitamin D levels ≥ 75 nmol/L lacks evidence for
efficacy or safety and should be discouraged until large RCTs
prove that the benefits outweigh the risks.
Steven R. Cummings, MD
CPMC Research Institute and
University of California, San Francisco
San Francisco, California, USA
References
1. Byers T. Am J Epidemiol. 2010;172:1-3.
2. Avenell A, Gillespie WJ, Gillespie LD, O’Connell D. Cochrane
Database Syst Rev. 2009;(2):CD000227.
3. DIPART (vitamin D Individual Patient Analysis of Randomized Trials)
Group. BMJ. 2010;340:b5463.
4. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-
Hughes B. Am J Clin Nutr. 2006;84:18-28.
5. Dawson-Hughes B, Mithal A, Bonjour JP, et al. Osteoporos Int. 2010;
21:1151-4.
NNH (CI) 6. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. BMJ.
10 (5 to 74) 2009;339:b3692.
35 (16 to ∞) 7. Smith H, Anderson F, Raphael H, et al. Rheumatology (Oxford).
2007;46:1852-7.
8. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Lancet.
2007;370:657-66.
© 2010 American College of Physicians JC3-3