Prevention of Nonvertebral Fractures With Oral Vitamin D and Dose Dependency

Centre on Aging and Mobility, University of Zurich, University Hospital, Switzerland.
Archives of internal medicine (Impact Factor: 17.33). 04/2009; 169(6):551-61. DOI: 10.1001/archinternmed.2008.600
Source: PubMed


Antifracture efficacy with supplemental vitamin D has been questioned by recent trials.
We performed a meta-analysis on the efficacy of oral supplemental vitamin D in preventing nonvertebral and hip fractures among older individuals (> or =65 years). We included 12 double-blind randomized controlled trials (RCTs) for nonvertebral fractures (n = 42 279) and 8 RCTs for hip fractures (n = 40 886) comparing oral vitamin D, with or without calcium, with calcium or placebo. To incorporate adherence to treatment, we multiplied the dose by the percentage of adherence to estimate the mean received dose (dose x adherence) for each trial.
The pooled relative risk (RR) was 0.86 (95% confidence interval [CI], 0.77-0.96) for prevention of nonvertebral fractures and 0.91 (95% CI, 0.78-1.05) for the prevention of hip fractures, but with significant heterogeneity for both end points. Including all trials, antifracture efficacy increased significantly with a higher dose and higher achieved blood 25-hydroxyvitamin D levels for both end points. Consistently, pooling trials with a higher received dose of more than 400 IU/d resolved heterogeneity. For the higher dose, the pooled RR was 0.80 (95% CI, 0.72-0.89; n = 33 265 subjects from 9 trials) for nonvertebral fractures and 0.82 (95% CI, 0.69-0.97; n = 31 872 subjects from 5 trials) for hip fractures. The higher dose reduced nonvertebral fractures in community-dwelling individuals (-29%) and institutionalized older individuals (-15%), and its effect was independent of additional calcium supplementation.
Nonvertebral fracture prevention with vitamin D is dose dependent, and a higher dose should reduce fractures by at least 20% for individuals aged 65 years or older.

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    • "Lower serum vitamin D levels have been shown to be associated with decreased bone mineral density of the total hip and hip trochanter, increased risk of hip fracture in older men and women, and reduced response to bisphosphonate treatment in postmenopausal women with osteoporosis [6] [7] [8] [9]. Conversely, though a recent meta-analysis suggests there is no clear association between vitamin D supplementation and bone mineral density in patients without vitamin D deficiency [10], vitamin D supplementation has been shown to reduce the risk of nonvertebral and hip fracture in a dose-dependent manner [11]. In accordance with these findings, it has been suggested that vitamin D may work through bone density-independent mechanisms to improve bone health [12]. "
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    • "Also, in various double-blind RCTs, vitamin D supplementation increased bone density and reduced bone loss [22, 23]. In a meta-analysis summarizing the evidence of 12 double-blind RCTs involving 42279 individuals aged 65 and older, oral vitamin D supplementation reduced the risk of hip fracture by 18% and the risk of any non-vertebral fracture by 20% [5]. However, similarly to fall prevention, the benefit on fracture prevention depends on the dose of vitamin D. Fracture prevention required a received dose (treatment dose*adherence) of more than 482 IU vitamin D per day. "
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    • "The strengths of this study are the inclusion of people with hip fracture who have similar characteristics to the Australian report of 16,518 patients with hip fracture [8] with a similar mean age (83.0 vs 83.9 years), hip fracture subtype (53% vs 51% with neck femur fractures), and mode of surgery (61.3% vs 60.1% internal fixation). The weaknesses of this study are in the under-recruitment of people with severe pre-existing disability compared to the usual population with hip fractures: (1) low number of participants from residential aged care facility; (2) participants with fewer total comorbidities; (3) a small number with preexisting cognitive impairment (16.0%), although one-sixth was actually documented in cognitive impairment in our cohort, suggesting either underreporting of the disease at recruitment, or first diagnosis of disease following a hip fracture. "
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