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Randomized Controlled Trial
. 2023 May;11(5):324-332.
doi: 10.1016/S2213-8587(23)00063-3. Epub 2023 Mar 31.

The effect of monthly vitamin D supplementation on fractures: a tertiary outcome from the population-based, double-blind, randomised, placebo-controlled D-Health trial

Mary Waterhouse  1 , Peter R Ebeling  2 , Donald S A McLeod  3 , Dallas English  4 , Briony Duarte Romero  1 , Catherine Baxter  1 , Bruce K Armstrong  5 , Gunter Hartel  1 , Michael Kimlin  6 , Rachel L O'Connell  7 , Jolieke C van der Pols  8 , Alison J Venn  9 , Penelope M Webb  10 , David C Whiteman  1 , Rachel E Neale  11
Affiliations
Randomized Controlled Trial

The effect of monthly vitamin D supplementation on fractures: a tertiary outcome from the population-based, double-blind, randomised, placebo-controlled D-Health trial

Mary Waterhouse et al. Lancet Diabetes Endocrinol. 2023 May.

Abstract

Background: Low serum 25-hydroxy vitamin D concentration is associated with increased fracture risk. It is uncertain whether vitamin D supplementation reduces fractures, or whether intermittent doses are harmful. We aimed to investigate if supplementing adults living in Australia with monthly doses of 60 000 international units (IU) vitamin D3 for 5 years or less altered the rate of fractures.

Methods: We did a population-based, double-blind, randomised, placebo-controlled trial of oral vitamin D3 supplementation (60 000 IU per month) for up to 5 years in adults aged 60-84 years living in Australia. We randomly assigned (1:1) 21 315 participants to either vitamin D or placebo. We ascertained fractures through linkage with administrative datasets. The main outcome was total fractures. Additional outcomes were non-vertebral, major osteoporotic (hip, wrist, proximal humerus, and spine), and hip fractures. We excluded participants (989 [4·6%]) without linked data, and estimated hazard ratios (HRs) and 95% CIs using flexible parametric survival models. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763, and the trial intervention ended in February, 2020.

Findings: Between Feb 14, 2014, and June 17, 2015, we recruited 21 315 participants. For the current analysis, we included 20 326 participants (vitamin D 10 154 [50·0%]; placebo 10 172 [50·0%]). 9295 (45·7%) of 20 326 participants were women and the mean age was 69·3 years (SD 5·5). Over a median follow-up of 5·1 years (IQR 5·1-5·1), 568 (5·6%) participants in the vitamin D group and 603 (5·9%) in the placebo group had one or more fractures. There was no effect on fracture risk overall (HR 0·94 [95% CI 0·84-1·06]), and the interaction between randomisation group and time was not significant (p=0·14). However, the HR for total fractures appeared to decrease with increasing follow-up time. The overall HRs for non-vertebral, major osteoporotic, and hip fractures were 0·96 (95% CI 0·85-1·08), 1·00 (0·85-1·18), and 1·11 (0·86-1·45), respectively.

Interpretation: These findings do not support concerns that bolus doses of vitamin D administered monthly increase fracture risk. Long-term supplementation might reduce the incidence of total fractures, but additional research is needed to clarify this effect.

Funding: Australian National Health and Medical Research Council.

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Conflict of interest statement

Declaration of interests PMW has funding from AstraZeneca for an unrelated study of ovarian cancer and funding from the National Health and Medical Research Council (NHMRC). PRE reports grants and speaker fees from Amgen, grants from Sanofi, grants from Alexion, and a grant from the NHMRC. PRE is past-president and a councilor (unpaid) of the American Society for Bone and Mineral Research, a board member (unpaid) of the International Osteoporosis Foundation, and chair of the board of directors (unpaid) of Health Bones Australia. REN has funding from Viatris for an unrelated study of pancreatic cancer, has received speaker fees and travels cost from Viatris to speak at the Australasian Gastrointestinal Trials Group annual meeting, and has grant payments from the NHMRC paid to QIMR Berghofer Medical Research Institute. REN is leader of one of the working groups of the Environmental Effects Assessment Panel (unpaid) of the UN Environment Program. DE reports funding from the NHMRC, paid to QIMR Berghofer Medical Research Institute. DCW reports funding from the NHMRC, paid to QIMR Berghofer Medical Research Institute, and speaker fees from Pierre Fabre Australia for the 2020 COSA Conference. DCW is also an unpaid director for a not-for-profit research institute (Sax Institute). MK is a board director of the Skin Cancer College Australasia, and a board director of Melanoma and Skin Cancer Trials Limited. All other authors declare no competing interests.

Comment in

  • Vitamin D and fractures.
    Reid IR. Reid IR. Lancet Diabetes Endocrinol. 2023 May;11(5):301-302. doi: 10.1016/S2213-8587(23)00087-6. Epub 2023 Mar 31. Lancet Diabetes Endocrinol. 2023. PMID: 37011648 No abstract available.

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