Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: research for evidence and a scientific statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO)

Abstract

Introduction: Optimal vitamin D status promotes skeletal health and is recommended with specific treatment in individuals at high risk for fragility fractures. A growing body of literature has provided indirect and some direct evidence for possible extraskeletal vitamin D-related effects.

Purpose and methods: Members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis have reviewed the main evidence for possible proven benefits of vitamin D supplementation in adults at risk of or with overt chronic extra-skeletal diseases, providing recommendations and guidelines for future studies in this field.

Results and conclusions: Robust mechanistic evidence is available from in vitro studies and in vivo animal studies, usually employing cholecalciferol, calcidiol or calcitriol in pharmacologic rather than physiologic doses. Although many cross-sectional and prospective association studies in humans have shown that low 25-hydroxyvitamin D levels (i.e., <50 nmol/L) are consistently associated with chronic diseases, further strengthened by a dose-response relationship, several meta-analyses of clinical trials have shown contradictory results. Overall, large randomized controlled trials with sufficient doses of vitamin D are missing, and available small to moderate-size trials often included people with baseline levels of serum 25-hydroxyvitamin D levels >50 nmol/L, did not simultaneously assess multiple outcomes, and did not report overall safety (e.g., falls). Thus, no recommendations can be made to date for the use of vitamin D supplementation in general, parental compounds, or non-hypercalcemic vitamin D analogs in the prevention and treatment of extra-skeletal chronic diseases. Moreover, attainment of serum 25-hydroxyvitamin D levels well above the threshold desired for bone health cannot be recommended based on current evidence, since safety has yet to be confirmed. Finally, the promising findings from mechanistic studies, large cohort studies, and small clinical trials obtained for autoimmune diseases (including type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus), cardiovascular disorders, and overall reduction in mortality require further confirmation.

Keywords: Autoimmune diseases; Cancer; Cardiovascular diseases; Cholecalciferol; Diabetes; Mortality.

Fig. 1

Vitamin D metabolism. Endogenous or exogenous cholecalciferol and calcidiol are the inactive precursors of the biological active hormone calcitriol. Calcitriol, classically produced in the kidneys under the positive and negative regulation of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), respectively, can also be synthesized in extra-renal tissues, where its production is mainly driven by the substrate, 25 hydroxyvitamin D (25(OH)D). The nearly ubiquitously expressed vitamin D receptor (VDR) mediates calcitriol actions in skeletal and extra-skeletal tissues

Fig. 2

Calcitriol-mediated extraskeletal effects, as demonstrated in vitro and in vivo in animal models, likely mediating the possible extraskeletal effects in chronic diseases in humans (Asterisk shown according to Evidence Based Medicine’s levels 1b–2b; ND not demonstrated, i.e. level of evidence 2c and below). The extraskeletal effects have to be further confirmed given contradictory results in meta-analyses and randomized controlled trials (RCT)