CRD summary

This well-conducted systematic review concluded that 700 to 800 IU/day oral vitamin D supplementation appears to reduce the risk of hip and nonvertebral fractures in older persons, whereas 400 IU/day is insufficient for fracture prevention. However, the trials' concurrent administration of calcium means that the independent effect of vitamin D cannot be determined.

Authors' objectives

To assess the effectiveness of oral vitamin D supplementation in preventing hip and nonvertebral fractures in older people.

Searching

MEDLINE (1960 to January 2005), EMBASE (1991 to January 2005) and the Cochrane Controlled Trials Register (1960 to January 2005) were searched for English and non-English articles; the search terms were reported. Reference lists and abstracts presented at the American Society for Bone and Mineral Research (1995 to 2004) were handsearched. The authors also contacted experts for additional publications. Only published trials were eligible for inclusion in the review.

Study selection

Assessment of study quality

The authors assessed the following aspects of study quality: randomisation, random allocation concealment, masking of treatment allocation, blinding and withdrawals. The authors did not state how the papers were assessed for quality, or how many reviewers performed the quality assessment.

Data extraction

Two independent reviewers extracted the data; consensus was achieved for all data. Data on the relative risk (RR) of a first hip or nonvertebral fracture, as well as associated 95% confidence intervals (CIs), were extracted in an intention-to-treat format.

Methods of synthesis

Results of the review

Seven RCTs (n=9,820) were included in the review.

The authors stated that there was no evidence of publication bias when using the Begg and Egger test. The funnel plot suggested a possible absence of negative studies involving small sample sizes; however, the trim-and-fill analysis did not confirm this suggestion.

Hip fractures.

When studies with high and low dosages of oral vitamin D supplementation were pooled together, there was no statistically significant reduction in the RR of hip fracture (5 trials; RR 0.88, 95% CI: 0.69, 1.13) but significant heterogeneity between studies (P=0.09). When 2 trials reporting one hip fracture each were included in a sensitivity analysis, there was still no statistically significant reduction in the RR of hip fracture (7 trials; RR 0.87, 95% CI: 0.70, 1.09).

There was a statistically significant reduction in the RR of hip fracture (3 trials; RR 0.74, 95% CI: 0.61, 0.88) for patients receiving 700 to 800 IU/day oral vitamin D supplementation, with no significant heterogeneity between studies (P=0.74). The pooled risk difference was 2% (95% CI: 1, 4, P<0.001), therefore the NNT was 45 (95% CI: 28, 114) for a treatment duration of 24 to 60 months. When 2 trials that only reported one hip fracture each were included in a sensitivity analysis, there was still a statistically significant reduction in the RR of hip fracture (RR 0.73, 95% CI: 0.61, 0.88).

There was no reduction in the RR of hip fracture (2 trials; RR 1.15, 95% CI: 0.88, 1.50) for patients receiving 400 IU/day oral vitamin D supplementation, with no significant heterogeneity between studies (P=0.68). A greater reduction in hip fractures (meta-regression P=0.02) and any nonvertebral fracture (meta-regression P=0.03) was observed with higher achieved 25-hydroxyvitamin D levels in the treatment group. The results were unchanged in a sensitivity analysis that included 3 additional studies that did not meet the inclusion criteria for the review.

Nonvertebral fractures.

When studies with high and low dosages of oral vitamin D supplementation were pooled together, there was a statistically significant reduction in the RR of any nonvertebral fracture (7 trials; RR 0.83, 95% CI: 0.70, 0.98) but significant heterogeneity between studies (P=0.07). There was a statistically significant reduction in the RR of any nonvertebral fracture (5 trials; RR 0.77, 95% CI: 0.68, 0.87) for patients receiving 700 to 800 IU/day oral vitamin D supplementation, with no significant heterogeneity between studies (P=0.41). The pooled risk difference was 4% (95% CI: 2, 5, P=0.02), therefore the NNT was 27 (95% CI: 19, 49) for a treatment duration of 12 to 60 months. There was no reduction in the RR of any nonvertebral fracture (2 trials; RR 1.03, 95% CI: 0.86, 1.24) for patients receiving 400 IU/day oral vitamin D supplementation, with no significant heterogeneity between studies (P=0.36).

In a subgroup analysis by gender, there was a statistically significant reduction in the RR of hip fracture (3 trials; RR 0.73, 95% CI: 0.61, 0.89) and any nonvertebral fracture (4 trials; RR 0.80, 95% CI: 0.70, 0.91) for women taking oral vitamin D supplementation. However, there was no statistically significant reduction in the RR of hip fracture (1 trial; RR 0.76, 95% CI: 0.35, 1.67) or any nonvertebral fracture (1 trial; RR 0.70, 95% CI: 0.40, 1.20) for men taking oral vitamin D supplementation.

Authors' conclusions

Oral vitamin D supplementation between 700 and 800 IU/day appears to reduce the risk of hip and nonvertebral fractures in ambulatory or institutionalised elderly people. However, a dose of 400 IU/day is insufficient for fracture prevention.

CRD commentary

The review question was clear in terms of the study design, participants, intervention and outcomes of interest. Three relevant electronic databases were searched without language restrictions, thus reducing the potential for language bias. Unpublished data were sought, but these were only included in a sensitivity analysis. The authors reported that there was no evidence of publication bias when using the Begg and Egger test or trim-and-fill analysis. The data extraction was carried out in duplicate, thus reducing the potential for errors and reviewer bias. However, the study selection and quality assessment procedures were not reported, and so cannot be assessed. The quality of the included studies was assessed using appropriate criteria.

Adequate details of the included studies were presented. The authors assessed and investigated sources of heterogeneity, and the methods used to combine the studies were appropriate. This was a well-conducted systematic review and, although the authors' conclusion that dietary supplements reduce fractures is likely to be reliable, it should be noted that all but one of the higher dose vitamin D trials also administered calcium; therefore, the independent effect of vitamin D could not be determined.

Implications of the review for practice and research

Practice: The authors stated that their results are compelling for general vitamin D supplementation in the range of 700 to 800 IU/day in elderly people, and for increasing the suggested dose in the current vitamin D intake recommendations (currently 400 to 600 IU/day) for middle-aged and older adults.

Research: The authors stated that future research should focus on testing higher doses of vitamin D and assessing whether, and in what dose, calcium is adding value to the efficacy of vitamin D.

Funding

Medical Foundation; James Knox Memorial Foundation.

Bibliographic details

Bischoff-Ferrari H A, Willett W C, Wong J B, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005; 293(18): 2257-2264. [PubMed: 15886381]

Original Paper URL

http://jama.ama-assn.org/

Other publications of related interest

This additional published commentary may also be of interest. Bogaisky M, Leipzig RM. Review: 700 to 800 IU/d of vitamin D reduces hip and nonvertebral fractures in older persons. ACP J Club 2005;143:72-4.

Indexing Status

Subject indexing assigned by NLM

MeSH

Aged; Cholecalciferol /therapeutic use; Dietary Supplements; Ergocalciferols /therapeutic use; Fractures, Bone /prevention & control; Humans; Randomized Controlled Trials as Topic; Vitamin D /administration & dosage /therapeutic use

AccessionNumber

12005008239

Database entry date

30/04/2006

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.