Critical Role for 24-Hydroxylation in Homeostatic Regulation of Vitamin D Metabolism

Abstract Context The body has evolved homeostatic mechanisms to maintain free levels of Ca+2 and 1,25-dihydroxyvitamin D (1,25(OH)2D) within narrow physiological ranges. Clinical guidelines emphasize important contributions of parathyroid hormone (PTH) in maintaining this homeostasis. Objective This work aimed to investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status. Methods This crossover clinical trial studied community participants before and after VitD3 supplementation. Participants included 11 otherwise healthy individuals with VitD deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL). VitD3 supplements (50 000 IU once or twice a week depending on body mass index, for 4-6 weeks) were administered to achieve 25(OH)D of 30 ng/mL or greater. Results VitD3 supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D (24,25(OH)2D) by 4.3-fold. In contrast, mean levels of PTH, fibroblast growth factor-23, and 1,25(OH)2D did not change. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D 50 ng/mL or greater and achieved a minimum (∼90% suppression) with 25(OH)D less than 10 to 20 ng/mL. The 1,25(OH)2D/24,25(OH)2D ratio better predicted modeled 24-hydroxylase activity (h) (ρ = −0.85; P = .001) compared to total plasma 25(OH)D (ρ = 0.51; P = .01) and the 24,25(OH)2D/25(OH)D ratio (ρ = 0.37; P = .3). Conclusion Suppression of 24-hydroxylase provides a first line of defense against symptomatic VitD deficiency by decreasing metabolic clearance of 1,25(OH)2D. The 1,25(OH)2D/24,25(OH)2D ratio provides a useful index of VitD status since it incorporates 24,25(OH)2D levels, and therefore provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity—thereby decreasing the level of 24,25(OH)2D and increasing the 1,25(OH)2D/24,25(OH)2D ratio. Thus, an increased 1,25(OH)2D/24,25(OH)2D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD deficiency.