Observational studies have linked vitamin D to a number of musculoskeletal, neoplastic, metabolic, and cardiovascular disorders, but these findings have not been confirmed to a sufficient degree by large-scale and long-term randomized controlled trials, according to the findings of a recent review.

Clifford J. Rosen, MD, from the Tufts University School of Medicine in Boston, Massachusetts, and colleagues published their findings online May 17 and in the June print issue of Endocrine Reviews.

The authors noted that the therapeutic role of vitamin D remains a popular research topic. "[I]n a 2-month span during the summer of 2011, there were more than 500 publications centered on vitamin D, most of which were related to its relationship to nonskeletal tissues," the authors write. "However, the results from those studies, as well as others, are confounded and difficult to interpret."

Preclinical Efficacy of Vitamin D Supplementation

The authors note that several beneficial effects of vitamin D have been reported in the literature. For example, they note, humans and mice lacking the vitamin D receptor develop alopecia, and that mice lacking the receptor, but not those lacking CYP27B1 (the enzyme that 1α-hydroxylates vitamin D metabolites), exhibit increased susceptibility to chemically or ultraviolet-induced tumors.

The authors also note that several observational studies have revealed an association between vitamin D deficiency and obesity. For example, low vitamin D levels were associated with increased adiposity in a study of black and white youths.

The authors also cite several studies suggesting an inverse relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and colorectal cancer incidence. For example, a 2008 meta-analysis performed by the International Agency for Research on Cancer that revealed a significant inverse association between serum 25(OH)D and cancer risk, although significant between-study heterogeneity was observed.

The authors also report that several observational studies revealed an increased risk for cardiovascular disease among patients with low vitamin D levels. In the Framingham Offspring Study, participants with 25(OH)D levels of less than 15 ng/mL had a greater risk for incident cardiovascular events than the other participants (hazard ratio, 1.62; 95% confidence interval, 1.11 - 2.36; P = .01).

Lack of Clinical Data

Despite the body of research on the nonskeletal effects of vitamin D, there is a paucity of clinical data supporting its efficacy. The authors report that no large-scale, randomized, placebo-controlled clinical trials have demonstrated the superior efficacy of vitamin D metabolites over other treatments for proliferative skin disorders or skin cancer.

Similarly, the authors state that no currently available clinical evidence demonstrates the efficacy of vitamin D supplementation in reducing the risk for type 2 diabetes or metabolic syndrome. Although the authors suggest that vitamin D supplementation reduces the risks for falls, the threshold 25(OH)D level needed for this effect remains uncertain.

Despite the strong experimental evidence of the efficacy of vitamin D in reducing colorectal cancer risk, the limited clinical trial data did not support this finding. Moreover, to date, no benefit of vitamin D has been clinically demonstrated for other types of cancer such as breast and prostate cancers.

The authors additionally indicate that there is insufficient clinical evidence supporting the use of vitamin D to reduce the risk for cardiovascular disease.

Future Directions

The authors reaffirm the need for additional clinical trials to clarify the effects of vitamin D on nonskeletal disorders and note that clinical trials have been initiated in this regard.

For example, the 20,000-person Vitamin D and Omega-3 Trial (VITAL) is evaluating the effects of vitamin D supplementation on neoplastic and cardiovascular outcomes. The authors also note that a large, placebo-controlled, randomized trial of vitamin D supplementation in the prevention of the onset of type 2 diabetes in patients with prediabetes is being planned.

However, the authors indicate that these trials may not completely clarify the roles of vitamin D in nonskeletal disorders. "[L]arge-scale clinical trials of a single nutrient may not fully answer the many questions inherent in vitamin D actions," the authors write. "Thus, the role of vitamin D supplementation in the prevention and treatment of chronic nonskeletal diseases remains to be determined."

This work was supported by funding from the National Institutes of Health, the Veterans Administration, and the Canadian Institutes of Health Research. The authors have disclosed no relevant financial relationships.

Endocr Rev. 2012;33:456-492. Abstract

Joe Barber Jr, PhD • Medscape Medical News © 2012 WebMD, LLC