Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows

Abstract

The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D.

Keywords: Vitamin D Standardization Program (VDSP); calcifediol; calcitriol; cholecalciferol; vitamin D; vitamin D assay.

Graphical Abstract

Figure 1.

Three-step mechanism of intestinal calcium absorption by vitamin D. An important function of vitamin D is stimulating intestinal calcium absorption by increasing the expression of calcium-permeable claudins, apical membrane calcium channels, and calcium-binding protein calbindins. The extrusion of calcium is across the basolateral membrane. This process is especially enhanced when dietary calcium intake is low.

Figure 2.

Overview of vitamin D metabolism. The figure shows metabolism of vitamin D in physiologic and deficient status, with specific reference to conditions in which vitamin D should be evaluated.

Figure 3.

Skeletal effects of vitamin D deficiency. A deficient vitamin D status can cause impairments in the skeletal system such as osteopenia, osteoporosis, osteomalacia, and rickets, resulting in high risk for fragility fractures. Clear boxes with dashed outlines refer to the risk factors for vitamin D deficiency; dark boxes refer to the negative skeletal effects of vitamin D deficiency.

Figure 4.

Putative extraskeletal effects of vitamin D deficiency and their implication in human health. A deficient vitamin D status is associated with several extraskeletal effects. These include increased risk of diabetes and autoimmune, infectious, cardiovascular, and respiratory diseases, as well as increase in cancer incidence and mortality. Such impairments result in lower quality of life and higher mortality, and can even increase acute COVID-19 severity and long COVID risk. Clear boxes with dashed outlines refer to the risk factors for vitamin D deficiency; dark boxes refer to the negative extra-skeletal effects of vitamin D deficiency.