Yao P, Bennett D, Mafham M, et al.
JAMA Netw Open. 2019;2:e1917789. https://pubmed.ncbi.nlm.nih.gov/31860103
Does supplementation with vitamin D, alone or with calcium, reduce risk for fractures?
Multiple databases searched to Dec 2018 for English-language randomized controlled trials (RCTs) that compared vitamin D or vitamin D plus calcium supplements with placebo or no treatment, had ≥ 500 participants, and reported ≥ 10 incident fractures.
16 RCTs, including 1 factorial RCT, met inclusion criteria: 11 (n = 34 243, weighted mean age 77 y, 60% women, weighted mean follow-up 3.1 y) evaluated vitamin D supplements alone, and 6 (n = 49 282, weighted mean age 66 y, 99% women, weighted mean follow-up 5.9 y) evaluated vitamin D plus calcium supplements. In RCTs of vitamin D alone, dosing varied from daily (400 to 800 IU in 3 RCTs) to annually (300 000 to 500 000 IU in 2 RCTs), with a median equivalent dose of 833 IU/d. All RCTs of vitamin D plus calcium used daily dosing: vitamin D, 800 IU/d, and calcium, 1000 to 1200 mg/d, in 5 RCTs; the largest RCT (n = 36 282) used vitamin D, 400 IU/d, and calcium, 1000 mg/d. 11 RCTs had low risk of bias for allocation concealment, 11 for blinding participants and personnel, 13 for blinding outcome assessment, and 6 for incomplete outcome data.
Medical Research Council.
Supplementation with vitamin D plus calcium reduces risk for fracture compared with placebo or no treatment. Vitamin D supplementation alone does not reduce risk for fracture.
Results: Supplementation with vitamin D, alone or with calcium, vs placebo or no treatment (control) for fracture prevention
|Supplements||Outcomes||Number of RCTs (n)||Weighted event rates*||RRI (95% CI)* at a mean 3.1 y||NNH|
|Vitamin D alone||Any fracture||11 (34 243)||8.5% vs 8.0%||6% (−2 to 14)||NS|
|Hip fracture||8 (27 938)||2.7% vs 2.4%||14% (−2 to 32)||NS|
|RRR (CI)* at a mean 5.9 y||NNT (CI)*|
|Vitamin D plus calcium||Any fracture||6 (49 282)||10.5% vs 11.2%||6% (1 to 11)||149 (82 to 893)|
|Hip fracture||6 (49 282)||1.3% vs 1.6%||16% (3 to 28)||391 (224 to 2084)|
RCT = randomized controlled trial; other abbreviations defined in Glossary.
*Weighted event rates, RRI, RRR, NNT, and CI calculated from control event rates and rate ratios in article using a fixed-effect model.
Vitamin D is a prohormone that is critical to calcium and phosphorus metabolism as well as overall skeletal health. Observational studies have shown an inverse linear relation between vitamin D levels and risk for fractures, which have high rates of morbidity and mortality (1).
In their meta-analysis, Yao and colleagues reviewed large RCTs of vitamin D and calcium supplementation (each with ≥ 500 participants and ≥ 10 fractures) to determine effects on fracture risk. They reached similar conclusions to previous meta-analyses (2): Vitamin D supplementation alone does not alter risk, and vitamin D with calcium may have a small reduction (6%) in overall fracture risk. In comparison, bisphosphonates have a 47% reduction in fracture risk in meta-analyses (3).
The power of meta-analyses lies in examining trends across trials, but combining trials assumes that included trials have similar populations (similar osteoporosis risks, vitamin levels, overall health) and similar interventions (drug formulations, doses, and administration intervals). Large analyses may include subpopulations that benefit but will not be identified when pooled with lower-risk participants. Yao and colleagues did not try to quantify risk for potential harms of vitamin D and calcium supplementation, which may include nephrolithiasis and cardiovascular disease (2).
7 ongoing trials are studying higher and more consistent vitamin D dosing and may identify subpopulations that may benefit and better quantify risks. Until then, we agree with the current US Preventive Services Task Force recommendations that there is still insufficient evidence for vitamin D with calcium supplementation for primary prevention of fracture in the low-risk community-dwelling population (4).
1 Feng Y, Cheng G, Wang H, Chen B. The associations between serum 25-hydroxyvitamin D level and the risk of total fracture and hip fracture. Osteoporos Int. 2017;28:1641-52. [PMID: 28220196]
2 Avenell A, Mak JC, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev. 2014;(4):CD000227. [PMID: 24729336]
3 Saito T, Sterbenz JM, Malay S, et al. Effectiveness of anti-osteoporotic drugs to prevent secondary fragility fractures: systematic review and meta-analysis. Osteoporos Int. 2017;28:3289-300. [PMID: 28770272]
4 US Preventive Services Task Force, Grossman DC, Curry SJ, et al. Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults. JAMA. 2018;319:1592-9. [PMID: 29677309]