26 Dec Vitamin D, With and Without Calcium, for the Prevention of Fracture
MedicalResearch.com Interview with:
Robert Clarke MD, FRCP, FFPH, FFPHI, MSc, DCH
Professor of Epidemiology and Public Health Medicine
Clinical Trial Service Unit (CTSU)
Nuffield Department of Population Health
University of Oxford
MedicalResearch.com: What is the background for this study?
Response: Approximately 1 in 2 women and 1 in 5 men aged 50 years or older will suffer from an osteoporotic fracture in their remaining lifetime. Hip fracture is the most serious type of osteoporotic fracture with an approximately 30% risk of death in the year following a hip fracture. Vitamin D is essential for optimal musculoskeletal health by promotion of calcium absorption, and mineralisation of osteoid tissue formation in bone and maintenance of muscle function. Low vitamin D status causes secondary hyperparathyroidism, bone loss and muscle weakness. Observational studies have reported that lower blood concentrations of vitamin D are associated with higher risks of falls and fractures.
Combined supplementation with 800 IU/day vitamin D and 1200 mg/day calcium has been recommended for prevention of fractures in older adults living in institutions and in those with low vitamin D status. However, previous trials and meta-analyses of vitamin D alone, or in combination with calcium for prevention of fracture in either community-dwelling or general population settings reported conflicting results, with some reporting protective effects against fractures, but others demonstrated no beneficial effects. However, most of the previous trials had only limited power to detect differences in risk of fracture predicted by the observational studies, largely because of a combination of small sample size, relatively low equivalent daily doses of vitamin D, intermittent dosing regimens (>1 month), and short duration of follow-up. In addition, interpretation of the results of previous meta-analyses of such trials is complicated by use of variable inclusion criteria, inappropriate statistical methods, inclusion of multiple small trials with very few fracture events, in addition to failure to report achieved differences in blood 25(OH)D concentrations.
We summarised the available evidence to guide clinical practice and future research, by conducting parallel meta-analyses of:
- (i) observational studies of risks of fracture associated with prolonged differences in blood concentrations of 25(OH)D;
- (ii) randomised trials of vitamin D alone versus placebo or no treatment for prevention of fracture; and
- (iii) randomised trials of calcium and vitamin D versus placebo or no treatment for prevention of fracture.In addition, we reviewed the design of the ongoing randomised trials assessing the effects of higher doses of vitamin D alone or in combination with calcium for prevention of fracture.
MedicalResearch.com: What are the main findings?
Response: The research team from the University of Oxford combined findings from 11 observational studies of vitamin D blood levels and the associated risk of fracture with more than 39,000 participants, 6 trials of combined vitamin D and calcium treatment with more than 49,000 participants, and 11 trials of vitamin D supplements alone with 34,000 participants.
The results demonstrated that supplementation with vitamin D alone had no significant effect on risk for any fracture or hip fracture. Moreover, subgroup analyses did not demonstrate any significant differences by age, residential status, geographic region, open-label design, daily supplementation and duration for any fracture or hip fracture.
In contrast, combined treatment with both calcium and vitamin D reduced the risk of hip fracture by one–sixth. Sub-group analyses indicated that the benefits of combined treatment were greater in individuals at high risk of fracture, including people with low blood levels of vitamin D or residents in nursing homes where combined treatment reduced the risk of hip fracture by one-third.
MedicalResearch.com: What should readers take away from the study?
Response: Observational studies demonstrated that low blood levels of vitamin D were associated with higher risks of hip fracture. Hence, it was widely believed that randomized trials of vitamin D should reduce the risk of hip fracture. The results demonstrated that treatment with vitamin D alone had no significant effects on risk for any fracture or hip fracture. However, interpretation of the results of these trials was constrained by their small sample size, short duration of treatment, high risk of bias (chiefly due to incomplete ascertainment of outcomes), intermittent dosing regimens of vitamin D and failure to achieve adequate differences in vitamin D concentrations. Furthermore, given that two trials which assessed effects of very high annual doses of vitamin D on fracture both appeared to increase the risk of fractures (and falls) among those allocated vitamin D, these results reinforce the conclusion that intermittent dosing regimens with high doses of vitamin D cause toxicity.
While there was some evidence that higher doses of vitamin D that yielded greater treatment differences were associated with greater benefits, the available evidence on daily doses of vitamin D of 2000 IU daily or greater is limited. The results of ongoing testing the effects of 2000 IU daily are awaited. In contrast, combined treatment with both calcium and vitamin D reduced the risk of hip fracture by one–sixth.
MedicalResearch.com: What are the clinical implications of this research, if any?
Response: Observational studies had demonstrated that low blood levels of vitamin D were associated with higher risks of hip fracture. Hence, it was widely believed that randomized trials of vitamin D should reduce the risk of hip fracture. Vitamin D supplements have been advocated to improve bone health and prevent fracture, but the available evidence from this review of the trials provided no support for the hypothesis that vitamin D when administered alone lowers the risk of fracture. However, the available evidence on adequate daily doses of vitamin D (~2000 IU daily) is limited and results of ongoing trials testing the effects of 2000 IU vitamin D daily are awaited.
In contrast, vitamin D when administered with calcium reduced the risk of hip fracture by one sixth. The beneficial effects of combined supplements of calcium and vitamin D were greater in high risk older people with low blood levels of vitamin D or who were living in institutions.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Further randomised trials are needed to assess the efficacy and safety of higher daily doses of vitamin D administered together with calcium in high-risk individuals for prevention of fracture.
Yao P, Bennett D, Mafham M, et al. Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis. JAMA Netw Open. 2019;2(12):e1917789. doi:https://doi.org/10.1001/jamanetworkopen.2019.17789
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