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) 2 D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis. Objective To investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status. Design Crossover clinical trial studying participants before and after VitD3-supplementation. Setting Community. Participants 11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL). Interventions VitD3-supplements (50,000 IU once or twice a week depending on BMI, for 4-6 weeks) were administered to achieve 25(OH)D≥30 ng/mL. Results VitD3-supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH) 2 D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH) 2 D did not change. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D≥50 ng/mL and achieved a minimum (∼90% suppression) with 25(OH)D<10-20 ng/mL. The 1,25(OH) 2 D/24,25(OH) 2 D ratio better predicted modeled 24-hydroxylase activity ( h ) (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and the 24,25(OH) 2 D/25(OH)D ratio (ρ=0.37; p=0.3). Conclusions Suppression of 24-hydroxylase provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH) 2 D. The 1,25(OH) 2 D/24,25(OH) 2 D ratio provides a useful index of VitD status since it incorporates 24,25(OH) 2 D 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) 2 D and increasing the 1,25(OH) 2 D/24,25(OH) 2 D ratio. Thus, an increased 1,25(OH) 2 D/24,25(OH) 2 D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.