The dynamic relationships between the active and catabolic vitamin D metabolites, their ratios, and associations with PTH

Vitamin D status, assessed by serum concentration of 25(OH)D, is the prime candidate marker for many disease-association studies, but the interplay between the subsequent 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and 24,25-dihydroxyvitamin D (24,25(OH)(2)D) metabolites is unclear. In this study, we conducted an analysis from a large cohort of healthy, physically fit, young army recruits (n = 940). We found a significant, inverse relationship between serum 25(OH)D and 1,25(OH)(2)D:24,25(OH)(2)D vitamin D metabolite ratio (VMR) (r(2)Exp = 0.582, p < 0.0001), and demonstrated a significant association with increasing PTH concentration (p < 0.001). Circannual rhythms were evident for all vitamin D metabolites and VMRs except for 1,25(OH)(2)D when fitted to Cosinor curves. We estimated 1,25(OH)(2)D:24,25(OH)(2)D VMR of ≥35 to be the threshold value for vitamin D insufficiency, and ≥51 to be predictive of vitamin D deficiency. Our three-dimensional model provides mechanistic insight into the vitamin D-PTH endocrine system, and further substantiates the role of 24,25(OH)(2)D in human physiology. The model sets a new paradigm for vitamin D treatment strategy, and may help the establishment of vitamin D-adjusted PTH reference intervals. The study was approved by the UK Ministry of Defence research ethics committee (MODREC 165/Gen/10 and 692/MoDREC/15). ClinicalTrials.gov Identifier NCT02416895.