Publications of the Week: Vitamin D and fractures

2022-08-17

Vitamin D supplementation and fractures in midlife and older adults

LeBoff MS, Chou SH, Ratliff KA, et al. Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults. N Engl J Med. 2022 Jul 28;387(4):299-309. doi: 10.1056/NEJMoa2202106. PMID: 35939577.

Background: Vitamin D supplementation is widely used in middle-aged to elderly people to maintain overall bone health alongside putative anticancer and immunity-enhancing benefits, but it is uncertain if vitamin D supplements prevent fractures.

Methods: This study, an ancillary component of VITAL (Vitamin D and Omega-3 Trial), assessed whether vitamin D supplementation would lower patients’ risk of fractures. VITAL is a 2 × 2 factorial, randomized, placebo-controlled trial investigating if supplemental vitamin D3 (2000 IU/d), n-3 fatty acids (1 g/d), or both prevent cancer and cardiovascular disease in men aged ≥50 years and women aged ≥55 years. Participants were not identified on the basis of whether they had vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were documented using yearly questionnaires given to participants and were adjudicated by an independent, centralized medical-record review. The primary end points were total fractures, nonvertebral fractures, and hip fractures. Proportional hazards models were applied to estimate the treatment effect using intention-to-treat analyses.

Results: There were 25,871 participants (50.6% women), with a median follow-up of 5.3 years. A total of 769 fractures occurred in 12,927 participants in the vitamin D group and 782 fractures in 12,944 participants in the placebo group, a difference that was not statistically significant (hazard ratio [HR], 0.98; 95% CI, 0.89-1.08). There was also no significant difference for the outcomes of nonvertebral fractures (HR, 0.97; 95% CI, 0.87-1.07) and hip fractures (HR, 1.01; 95% CI, 0.70-1.47). No modification of the treatment effect was observed according to baseline characteristics, including age, sex, race or ethnic group, body-mass index (BMI), or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in terms of adverse events as assessed in the parent trial. Subgroup analyses showed a similar lack of effect on fracture risk based on sex, age, race or ethnic group, and BMI.

Conclusions: The authors concluded that vitamin D3 supplementation did not result in a significantly lower risk of fractures compared with placebo among generally healthy midlife and older adults whose participation in the study was not due to vitamin D deficiency, low bone mass, or osteoporosis.

McMaster editors’ commentary: In this and related studies (doi: 10.1210/clinem/dgaa311; doi: 10.1016/j.cct.2011.09.009), there were no patient subgroups, whether with vitamin D insufficiency (25-hydroxyvitamin D level <30 ng/mL) or deficiency (<20 ng/mL), that benefited from vitamin D supplementation, which thereby questions the current approach of widespread screening and vitamin D supplementation. There may be a role for vitamin D to reduce fracture risk in selected patients, such as those who have limited exposure to sunlight or those who have genetic variations in vitamin D absorption and metabolism or receptor function. Notwithstanding these points, this is a paradigm-shifting study, especially as regards the limited value of wide screening for vitamin D deficiency.

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