Reference: JAMA Netw Open. 2019 Dec 2;2(12) (level 2 [mid-level] evidence)
Broken hips and osteoporotic fractures of all types are common, and hip fractures can even portend death. There is a confusing array of recommendations for supplementation with calcium, vitamin D, or both. Research in this area is complicated by variations in baseline diet, exercise, health, and dosing/adherence, as well as the long follow-up needed to assess the effects of supplements on fracture rates. A systematic review and meta-analysis of studies looking at baseline vitamin D levels and supplementation with vitamin D alone or combined with calcium was recently published by a group from Oxford.
This group selected randomized controlled trials comparing either vitamin D or vitamin D plus calcium with placebo and observational studies that measured 25(OH)D levels with 200 fracture events. They thoughtfully analyzed studies for bias and restricted analysis to trials with more than 500 subjects and 10 incident fractures to minimize sampling bias. In the trials comparing vitamin D vs. placebo, ingestion ranged from 400 IU/day to a one-time annual dose of 500,000 IU, with a mean dose of 833 IU/day. The vitamin D studies enrolled a fairly even mixture of men and women and up to 47% of patients in some studies had a prior fracture. The trials comparing combined supplements to placebo had a more homogenous dosing: 400-800 IUs of vitamin D with 1000-1200 mg/day of calcium. In the combined supplement group, 5 of the 6 studies only enrolled women, and 1 enrolled 85% women and 15% men. The authors reported between 13%-100% of enrollees had either a prior fall or fracture.
The meta-analysis of observational studies included 11 studies with a total of 16,220 participants included in the analysis for hip fracture. A higher serum vitamin D level was associated with a lower rate of hip fractures (rate ratio 0.8, 95% CI 0.75-0.86). A second analysis of 14,045 patients from randomized trials failed to show a significant difference, with a rate ratio for hip fracture of 1.14 (95% CI 0.98-1.32) for vitamin D over placebo. Finally, the third arm of this analysis looked at randomized controlled trials involving 24,866 patients who took either combined vitamin D/calcium or placebo, and demonstrated a significant reduction in hip fractures for the supplement group (rate ratio 0.84, 95% CI 0.72-0.97).
This paper, taken as a whole, demonstrates the statistical concept that observational data are more likely to imply potential benefits which may not be borne out in randomized trials that limit bias. Major areas of bias in the interventional studies reported here include risk to generalizability due to incomplete outcome data, heterogeneity of dosing schedules and participant sex ratios, and lack of direct comparison between vitamin D/calcium and vitamin D alone. The meta-analysis of observational studies suggests that higher serum vitamin D levels may be associated with fewer hip fractures, but the trial data failed to show benefit of vitamin D supplementation alone. The one outcome that seems well supported by both observational and trial data is that combined vitamin D/calcium supplementation was associated with a reduction in hip fractures.
For more information, see the topic Calcium and Vitamin D for Treatment and Prevention of Osteoporosis in DynaMed.
DYNAMED EBM FOCUS EDITORIAL TEAM
This EBM Focus was written by Dan Randall, MD, Deputy Editor for Internal Medicine at DynaMed. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School and Katharine DeGeorge, MD, MS, Associate Professor of Family Medicine at the University of Virginia and Clinical Editor at DynaMed.