Elsevier

The Lancet

Volume 383, Issue 9912, 11–17 January 2014, Pages 146-155
The Lancet

Articles
Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis

https://doi.org/10.1016/S0140-6736(13)61647-5Get rights and content

Summary

Background

Findings from recent meta-analyses of vitamin D supplementation without co-administration of calcium have not shown fracture prevention, possibly because of insufficient power or inappropriate doses, or because the intervention was not targeted to deficient populations. Despite these data, almost half of older adults (older than 50 years) continue to use these supplements. Bone mineral density can be used to detect biologically significant effects in much smaller cohorts. We investigated whether vitamin D supplementation affects bone mineral density.

Methods

We searched Web of Science, Embase, and the Cochrane Database, from inception to July 8, 2012, for trials assessing the effects of vitamin D (D3 or D2, but not vitamin D metabolites) on bone mineral density. We included all randomised trials comparing interventions that differed only in vitamin D content, and which included adults (average age >20 years) without other metabolic bone diseases. We pooled data with a random effects meta-analysis with weighted mean differences and 95% CIs reported. To assess heterogeneity in results of individual studies, we used Cochran's Q statistic and the I2 statistic. The primary endpoint was the percentage change in bone mineral density from baseline.

Findings

Of 3930 citations identified by the search strategy, 23 studies (mean duration 23·5 months, comprising 4082 participants, 92% women, average age 59 years) met the inclusion criteria. 19 studies had mainly white populations. Mean baseline serum 25-hydroxyvitamin D concentration was less than 50 nmol/L in eight studies (n=1791). In ten studies (n=2294), individuals were given vitamin D doses less than 800 IU per day. Bone mineral density was measured at one to five sites (lumbar spine, femoral neck, total hip, trochanter, total body, or forearm) in each study, so 70 tests of statistical significance were done across the studies. There were six findings of significant benefit, two of significant detriment, and the rest were non-significant. Only one study showed benefit at more than one site. Results of our meta-analysis showed a small benefit at the femoral neck (weighted mean difference 0·8%, 95% CI 0·2–1·4) with heterogeneity among trials (I2=67%, p<0·00027). No effect at any other site was reported, including the total hip. We recorded a bias toward positive results at the femoral neck and total hip.

Interpretation

Continuing widespread use of vitamin D for osteoporosis prevention in community-dwelling adults without specific risk factors for vitamin D deficiency seems to be inappropriate.

Funding

Health Research Council of New Zealand.

Introduction

Vitamin D, like calcium, has long been regarded as a fundamental part of the prevention and treatment of osteoporosis. Low vitamin D concentrations result in secondary hyperparathyroidism and accelerated bone loss, although the development of secondary hyperparathyroidism varies, even in patients with severe vitamin D deficiency.1, 2 Findings from observational studies show inconsistent associations between bone mineral density and vitamin D status,3, 4 and debate continues regarding optimum concentrations of 25-hydroxyvitamin D for the best possible skeletal health.5, 6 However, results from meta-analyses of trials of vitamin D alone (ie, not with calcium) failed to show an association between supplementation and fracture prevention.7, 8 This finding could be attributable to aspects of the study design (eg, study power, the population recruited, or the vitamin D dose used). Alternatively, vitamin D might not have a protective effect on bone, as has been postulated.7 Therefore, surrogate endpoints such as bone mineral density, which can be used to detect biologically significant effects in small cohorts, should be examined closer.

Furthermore, some studies might have used inadequate doses of vitamin D or a baseline vitamin D status of the populations studied that was not low enough for the intervention to produce a significant effect. Thus, the study of the effect of vitamin D supplementation on bone density in terms of the dose given and baseline vitamin D status are important questions that can be addressed in the many studies assessing bone mineral density. Concerns about the cardiovascular safety of calcium plus vitamin D supplements9 warrant the investigation of vitamin D as a monotherapy.

We aimed to address these questions by systematically reviewing all randomised, controlled trials of cholecalciferol or ergocalciferol that have included bone mineral density data, irrespective of whether this was the primary endpoint of the study, in populations without other disorders likely to affect bone and calcium metabolism. Despite the negative findings from fracture studies, almost half of adults in the USA use vitamin D supplements.10 Therefore, to ensure appropriate targeting of this common intervention, investigators need to establish in which groups the vitamin improves bone health.

Section snippets

Search strategy and selection criteria

We did a systematic review and meta-analysis in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and meta-Analyses) guidelines, and used a predetermined protocol. To qualify for inclusion, studies had to be randomised controlled trials comparing interventions that differed only in vitamin D content, which were done in adults (average age >20 years). The intervention could be a preparation of vitamin D3 or D2, but not a vitamin D metabolite. If other interventions

Results

Our search strategy identified 3930 unique publications, the titles and abstracts of which were screened for inclusion. The full text of 54 articles was retrieved, of which 23 met the inclusion criteria (appendix). Reasons for exclusion of the remaining articles were: intervention not vitamin D (12), patients too young (two), study not randomised (two), duplicate publication (five), no data for bone mineral density presented (six), and patients had other major pathologies (four).

Table 1 shows

Discussion

This systematic review provides very little evidence of an overall benefit of vitamin D supplementation on bone density. Although small increases in bone density at some skeletal sites in some studies were reported, when these increases are offset against the individual findings of deleterious effects, the number of positive results is little better than what would have been expected by chance. Findings of the meta-analysis are similar; we reported a small but significant increase in bone

References (60)

  • A Arabi et al.

    PTH level but not 25 (OH) vitamin D level predicts bone loss rates in the elderly

    Osteoporos Int

    (2012)
  • MC Chapuy et al.

    Prevalence of vitamin D insufficiency in an adult normal population

    Osteoporos Int

    (1997)
  • RK Marwaha et al.

    Bone health in healthy Indian population aged 50 years and above

    Osteoporos Int

    (2011)
  • HA Bischoff-Ferrari et al.

    Dietary calcium and serum 25-hydroxyvitamin D status in relation to BMD among US adults

    J Bone Miner Res

    (2009)
  • Dietary reference intakes for calcium and vitamin D

    (2010)
  • B Dawson-Hughes et al.

    Estimates of optimal vitamin D status

    Osteoporos Int

    (2005)
  • A Avenell et al.

    Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis

    Cochrane Database Syst Rev

    (2009)
  • B Abrahamsen et al.

    Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe

    BMJ

    (2010)
  • MJ Bolland et al.

    Calcium/vitamin D supplements and cardiovascular events: a re-analysis of the Women's Health Initiative limited-access dataset, and meta-analysis of calcium with or without vitamin D

    BMJ

    (2011)
  • A Cranney et al.

    Effectiveness and safety of vitamin D in relation to bone health

    Evid Rep Technol Assess (Full Rep)

    (2007)
  • M Chung et al.

    Vitamin D and calcium: a systematic review of health outcomes

    Evid Rep Technol Assess (Full Rep)

    (2009)
  • MF Holick et al.

    Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline

    J Clin Endocrinol Metab

    (2011)
  • M Chung et al.

    Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the US Preventive Services Task Force

    Ann Intern Med

    (2011)
  • E Papadimitropoulos et al.

    Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women

    Endocrine Rev

    (2002)
  • JPT Higgins et al.

    Assessing risk of bias in inlcuded studies

  • C Christiansen et al.

    Prevention of early postmenopausal bone loss: controlled 2-year study in 315 normal females

    Eur J Clin Invest

    (1980)
  • B Dawson-Hughes et al.

    Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women

    Ann Intern Med

    (1991)
  • ME Ooms et al.

    Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial

    J Clin Endocrinol Metab

    (1995)
  • MT Tuppurainen et al.

    Does vitamin D strengthen the increase in femoral neck bmd in osteoporotic women treated with estrogen

    Osteoporos Int

    (1998)
  • M Komulainen et al.

    Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D, in early postmenopausal women: a population-based 5-year randomized trial

    J Clin Endocrinol Metab

    (1999)
  • Cited by (466)

    View all citing articles on Scopus
    View full text