Clinical review: The role of the parent compound vitamin D with respect to metabolism and function: Why clinical dose intervals can affect clinical outcomes

Abstract

Context: There is no doubt that vitamin D must be activated to the hormonal form 1,25-dihydroxyvitamin D to achieve full biological activity or that many tissues participate in this activation process-be it endocrine or autocrine. We believe that not only is 25-hydroxyvitamin D important to tissue delivery for this activation process, but also that intact vitamin D has a pivotal role in this process.

Objective: In this review, evidence on the vitamin D endocrine/autocrine system is presented and discussed in relation to vitamin D-binding protein affinity, circulating half-lives, and enzymatic transformations of vitamin D metabolites, and how these affect biological action in any given tissue.

Conclusions: Circulating vitamin D, the parent compound, likely plays an important physiological role with respect to the vitamin D endocrine/autocrine system, as a substrate in many tissues, not originally thought to be important. Based on emerging data from the laboratory, clinical trials, and data on circulating 25-hydroxyvitamin D amassed during many decades, it is likely that for the optimal functioning of these systems, significant vitamin D should be available on a daily basis to ensure stable circulating concentrations, implying that variation in vitamin D dosing schedules could have profound effects on the outcomes of clinical trials because of the short circulating half-life of intact vitamin D.

Figure 1.

Diagram of the metabolic processes providing vitamin D and its metabolites to various tissues of the body. Tissue distribution of vitamin D and 25(OH)D based on simple diffusion (red arrows) or endocytosis (green arrows). Endocytosis requires the tissue-specific megalin-cubilin system, whereas simple diffusion is primarily controlled by the dissociation constant of the vitamin D compound for the VDBP. Bolder red lines indicate greater diffusion rates due to a higher dissociation constant. t_1/2, half life.