General conclusions from studies of vitamin D supplementation are mixed; conclusions related to skeletal and non-skeletal conditions are discussed below.
Most of these studies were conceived after it became clear that the vitamin D receptor (VDR) and the vitamin D enzyme system exist in most cells in the body, and that activation of this signaling pathway causes the ubiquitous transcription of several vitamin D-dependent genes. Based on this, investigators asked if vitamin D could prevent skeletal and non-skeletal conditions and conducted randomized clinical trials comparing patients who received vitamin D supplements to those who received placebo.
Skeletal conditions
Population-based studies have shown that higher levels of serum 25(OH)D are associated with higher bone mineral density,28-31 while low serum concentrations of 25(OH)D are associated with hip fracture risk, particularly among individuals with serum 25(OH)D <12 compared to those with ≥30 ng/mL.32-35 In contrast, prospective, randomized, placebo-controlled trials have shown either that vitamin D does not prevent fractures27,36-39 or, if given at high doses, increases fracture rate.40
Results of vitamin D combined with calcium are more variable and are either associated with decreased fracture rate41 or have no effect on fracture rate.36,42 However, most such studies have found an association of calcium and vitamin D supplementation with increased bone mineral density.43-45
The majority of these trials evaluated a generally healthy population of older adults not selected for vitamin D deficiency or a diagnosis of osteoporosis; such an approach may not have captured the effect of supplementation in vitamin D deficient patients. Thus, future investigations should include more senior people at higher risk for vitamin D deficiency (eg, living in nursing homes, housebound, or with a heavy burden of chronic disease).
Non-skeletal conditions
Despite an epidemiological association between vitamin D deficiency and various non-skeletal conditions, studies have not conclusively established that vitamin D supplementation has an effect in preventing falls,27 cardiovascular diseases,27,46,47 diabetes,27,48 respiratory infections,49 tuberculosis,50 COVID-19,51 or cancer.27,47,52
However, it may reduce cancer mortality53 and help prevent autoimmune diseases.54 Despite supplementation not being associated with beneficial effects on some endpoints, patients with overt vitamin D deficiency (serum 25[OH]D <20 ng/mL [50 nmol/L]) should receive vitamin D supplementation to treat the deficiency.