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 Dec 2;2(12):e1917789. doi: 10.1001/jamanetworkopen.2019.17789. (Systematic review)

Importance: Vitamin D and calcium supplements are recommended for the prevention of fracture, but previous randomized clinical trials (RCTs) have reported conflicting results, with uncertainty about optimal doses and regimens for supplementation and their overall effectiveness.

Objective: To assess the risks of fracture associated with differences in concentrations of 25-hydroxyvitamin D (25[OH]D) in observational studies and the risks of fracture associated with supplementation with vitamin D alone or in combination with calcium in RCTs.

Data Sources: PubMed, EMBASE, Cochrane Library, and other RCT databases were searched from database inception until December 31, 2018. Searches were performed between July 2018 and December 2018.

Study Selection: Observational studies involving at least 200 fracture cases and RCTs enrolling at least 500 participants and reporting at least 10 incident fractures were included. Randomized clinical trials compared vitamin D or vitamin D and calcium with control.

Data Extraction and Synthesis: Two researchers independently extracted data according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and assessed possible bias. Rate ratios (RRs) were estimated using fixed-effects meta-analysis. Data extraction and synthesis took place between July 2018 and June 2019.

Main Outcomes and Measures: Any fracture and hip fracture.

Results: In a meta-analysis of 11 observational studies (39?141 participants, 6278 fractures, 2367 hip fractures), each increase of 10.0 ng/mL (ie, 25 nmol/L) in 25 (OH)D concentration was associated with an adjusted RR for any fracture of 0.93 (95% CI, 0.89-0.96) and an adjusted RR for hip fracture of 0.80 (95% CI, 0.75-0.86). A meta-analysis of 11 RCTs (34?243 participants, 2843 fractures, 740 hip fractures) of vitamin D supplementation alone (daily or intermittent dose of 400-30?000 IU, yielding a median difference in 25[OH]D concentration of 8.4 ng/mL) did not find a reduced risk of any fracture (RR, 1.06; 95% CI, 0.98-1.14) or hip fracture (RR, 1.14; 95% CI, 0.98-1.32), but these trials were constrained by infrequent intermittent dosing, low daily doses of vitamin D, or an inadequate number of participants. In contrast, a meta-analysis of 6 RCTs (49?282 participants, 5449 fractures, 730 hip fractures) of combined supplementation with vitamin D (daily doses of 400-800 IU, yielding a median difference in 25[OH]D concentration of 9.2 ng/mL) and calcium (daily doses of 1000-1200 mg) found a 6% reduced risk of any fracture (RR, 0.94; 95% CI, 0.89-0.99) and a 16% reduced risk of hip fracture (RR, 0.84; 95% CI, 0.72-0.97).

Conclusions and Relevance: In this systematic review and meta-analysis, neither intermittent nor daily dosing with standard doses of vitamin D alone was associated with reduced risk of fracture, but daily supplementation with both vitamin D and calcium was a more promising strategy.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Public Health 6 / 7
Internal Medicine 5 / 7
Comments from MORE raters

Internal Medicine rater

The data seem to change all the time. It's tough to know what the best strategy is.

Internal Medicine rater

Vitamin D has definitely been the vitamin of the decade, similar to the hype around vitamin C, then vitamin E and the homocystine craze (B6, B12 folate). Everyone appeared to be deficient and observational studies looked great. Then came the randomized controlled trials. This is worth knowing because it looks like Vitamin D does not make a tremendous difference here either. Recommendations to take calcium and Vitamin D still appear to be accurate, but large doses of just Vitamin D are not likely to be worthwhile.

Internal Medicine rater

This horse has been beaten to death so many times that I am surprised it needs another beating. It has been well known for years that the data on Ca and Vit D on their own or in combination confer at best a modest benefit. EVERY study of pharmaceutical osteoporosis medications (bisphosphonates, etc.) has all the patients on Ca and Vit D, and thus if one is going to treat LBD or osteoporosis, then patients need to go on Ca and Vit D. I don't know any PCP who recommends Vit D alone, so their null result on this is clinically meaningless.

Public Health rater

As with many systematic reviews, this one highlights that we need more data to be confident about the effect of Vit D and calcium on fracture risk. The estimates point to a relatively small effect. Future trials may clarify this further.
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