While observational studies have shown that higher 25-hydroxyvitamin D (25[OH]D) blood concentrations are associated with lower risk for any fracture and hip fracture specifically, randomized controlled trials demonstrate no fracture risk reduction with vitamin D supplements alone, according to a systematic review and meta-analysis published in JAMA Network Open.
Vitamin D and calcium supplements are recommended for preventing fractures, but studies have reported conflicting results on the effectiveness of vitamin D with or without calcium for reducing fracture risk. The goal of the current systematic review and meta-analysis was to explore changes in fracture risk associated with 25(OH)D concentrations based on observational data and to use data from randomized controlled trials to investigate the effectiveness of vitamin D alone or in combination with calcium for reducing the risk for fracture.
The systematic review included observational studies of 25(OH)D and fracture risk that were required to have reported ≥200 cases of fracture. Furthermore, all randomized controlled trials of vitamin D alone or calcium plus vitamin D were published before January 1, 2019, and included ≥500 participants and ≥10 incident fractures.
Of 618 observational studies, 11 eligible studies (39,141 patients; 6278 fractures, 2367 hip fractures) were included in the systematic review. An increase of 10.0 ng/mL in blood 25(OH)D concentration was associated with 7% lower risk for any fracture (relative risk [RR], 0.93; 95% CI, 0.89-0.96) and 20% lower risk for hip fracture (RR, 0.80; 95% CI, 0.75-0.86).
Of 1262 randomized controlled trials, the systematic review and meta-analysis included 11 studies of vitamin D alone (34,243 patients; 2843 fractures, 740 hip fractures) and 6 studies of calcium and vitamin D (49,282 participants; 5449 fractures, 730 hip fractures).
Supplementation with vitamin D alone (daily or intermittent dose of 400-30,000 IU) was associated with a median difference in blood 25(OH)D concentration of 8.4 ng/mL but was not linked to risk for any fracture (RR, 1.06; 95% CI, 0.98-1.14) or hip fracture (RR, 1.14; 95% CI, 0.98-1.32).
Supplementation with combination vitamin D (400-800 IU/d) and calcium (1000-1200 mg/d) for approximately 6 years was associated with a 6% reduced risk for any fracture (RR, 0.94; 95% CI, 0.89-0.99) and a 16% reduced risk for hip fracture (RR, 0.84; 95% CI, 0.72-0.97). These reductions in risk in the randomized controlled trials of calcium plus vitamin D were somewhat greater in studies that included older participants living in institutions and those in which greater differences in blood 25(OH)D concentrations were achieved between the allocated treatment groups.
The researchers also noted that a there are 7 ongoing large randomized controlled trials that are expected to report the effects of supplementation with higher doses of vitamin D on risk for fracture.
The researchers acknowledged several limitations to the present meta-analysis, including heterogeneity between the results of the observational studies and assays used to measure 25(OH)D concentration. In addition, potential publication bias and inability to assess sex-specific treatment effects limited the findings.
“[T]he available evidence from completed [randomized controlled trials] provided no support for the effects of vitamin D alone on prevention of fracture, but most of these [randomized controlled trials] were constrained by methodological problems,” noted the researchers.
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.