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