Vitamin D Needs Calcium to Help Lower
Fracture Risk

Diana Swift

December 23, 2019

Once regarded as a potent silver bullet for preventing fractures, vitamin D appears to need calcium to exert a preventive effect. Neither intermittent nor daily consumption of standard doses of vitamin D alone was associated with a reduced fracture risk, a systematic review and meta-analysis of studies in elderly individuals reports. Daily supplementation with both vitamin D and calcium, however, appeared more promising, correlating to a 16% reduced risk of hip fracture.

Meta-analyzing 11 randomized controlled trials (RCTs) with 34,243 participants, Pang Yao, PhD, a research fellow and nutritional epidemiologist in the Nuffield Department of Population Health at the University of Oxford, United Kingdom, and colleagues found no significant association with risk of any fracture or of hip fracture with vitamin D supplements alone. In contrast, adding daily calcium was associated in six RCTs involving 49,282 participants with a marginally significant 16% reduction in hip fracture risk.

The results, based on RCTs and observational studies from 1992 to 2014, were published online December 20 in JAMA Network Open.

In the 11 RCTs of vitamin D alone, participants sustained 2843 fractures and 740 hip fractures. Among these individuals, vitamin D alone did not lower the reduced risk of any fracture: (rate ratio [RR], 1.06) or hip fracture (RR, 1.14). These studies used daily or intermittent doses of 400 to 30,000 international units (IU), which resulted in a median difference in blood levels of 25[OH]D concentration of 8.4 ng/mL.

A meta-analysis of the six RCTs combining calcium with vitamin D, however, found a 6% reduced RR of any fracture (0.94) as well as the 16% lowered risk for hip fracture (RR, 0.84). These studies identified 5449 fractures overall and 740 hip fractures. Daily vitamin D doses ranged from 400 to 800 IU, leading to a median difference in 25[OH]D concentration of 9.2 ng/mL; calcium doses varied from 1000 to 1200 mg per day.

Furthermore, in a meta-analysis of 11 observational studies with 39,141 participants incurring 6278 fractures and 2367 hip fractures, each increase of 10 ng/mL (25 nmol/L) in 25[OH]D concentration was associated with an adjusted RR for any fracture of 0.93 and an adjusted RR for hip fracture of 0.80.

The risk reductions achieved in the RCTs of calcium plus vitamin D were somewhat greater in trials involving older participants living in institutions and in trials that achieved greater differences in blood 25[OH]D concentrations between the allocated treatment groups  note. “However, given these uncertainties, further large RCTs of combined treatment with vitamin D and calcium are needed before advocating vitamin D and calcium supplements or fortified foods with vitamin D and calcium for prevention of hip fracture,” the authors write.

Combined supplementation with 800 IU of vitamin D and 1200 mg of calcium per day has been recommended for older people living in nursing homes/institutional living facilities or having low vitamin D status, the authors point out. But previous RCTs of such regimens have yielded disparate results, fostering uncertainty about optimal supplementation regimens, although the observational studies in the current analysis showed an association between low blood levels of vitamin D and higher fracture risk.

"In people older than 80 years and those living in institutions, the effects of combined therapy were greater, with the risk of hip fracture lowered by almost one third," senior author Robert Clarke, MD, FRCP, a professor of epidemiology and public health medicine at University of Oxford, told Medscape Medical News. "While the trials of vitamin D alone did not show a reduction in the risk of fracture, these trials included some large studies of very high annual doses of vitamin D, which increased the risk of fracture, and few of the trials tested doses of vitamin D high enough to raise the blood levels sufficiently to reduce the fracture risk."

In Clarke's view, generally supplementing older people at high risk of hip fracture with daily vitamin D plus calcium would likely lower the risk of hip fracture by the one third observed in the meta-analysis. "In addition to being safe and effective, such treatment is also likely to be cost-effective," he said.

Earlier this year, researchers in Boston, Massachusetts reported that high-dose vitamin D supplements yielded no structural bone benefits in healthy men and women.

Notably, seven large ongoing RCTs involving 62,857 participants will report the effects on fracture risk of higher daily doses of vitamin D. At a weighted mean daily dose (or equivalent) of 2094 IU, these studies will likely result in an increase of approximately 20 ng/mL in blood 25[OH]D concentration in participants with full adherence to allocated treatment and of 12-16 ng/mL in an intention-to-treat analysis.

Based on the findings from the observational studies in the meta-analysis, the ongoing RCTs are expected to yield a 9% reduction in the risk of any fracture and 19% reduction in the risk of hip fracture. "However, assuming an annual event rate of 2% for any fracture and of 0.5% for hip fracture, none of the individual RCTs alone is likely to have sufficient power to detect a significant reduction in risk of any fracture or hip fracture," the authors write. Large RCTs of combination supplementation in high-risk groups are needed to clarify its relevance for preventing hip and other fragility fractures.

Study author Jane Armitage reports receiving grants from the UK Medical Research Council during the conduct of the study. The remaining authors have disclosed no other relevant financial relationships.

JAMA Netw Open. Published online December 20, 2019. Full text

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