THU397 Homeostatic Regulation Of 1,25-dihydroxyvitamin D: Critical Role Of 24-hydroxylation (CYP24A1)

Disclosure: Z. Shahidzadeh Yazdi: None. E.A. Streeten: Grant Recipient; Self; Regeneron Pharmaceuticals. H.B. Whitlatch: Grant Recipient; Self; Regeneron Pharmaceuticals. M.E. Montasser: Grant Recipient; Self; Regeneron Pharmaceuticals. A.L. Beitelshees: None. S.I. Taylor: Consulting Fee; Self; Ionis Pharmaceuticals Inc. The VITAL study raised substantial questions whether current Endocrine Society guidelines provide optimal criteria to identify patients whose bone health would benefit from vitamin D (VitD) supplements. We investigated the impact of VitD supplements on levels of VitD metabolites and other biomarkers in the context of studying interactions between VitD and canagliflozin. 11 healthy Amish participants with 25-hydroxyvitamin-D (25(OH)D) levels ≤20 ng/mL were recruited in the context of our ongoing pharmacogenomic study of canagliflozin. RESULTS: VitD supplements increased mean levels of 25(OH)D from 16.5±1.6 ng/mL to 44.3±5.5 ng/mL (p=0.0006) and 24,25(OH)(2)D from 1.0±0.1 ng/mL to 4.3±0.6 ng/mL (p=0.0002). Mean levels of 1,25(OH)(2)D and PTH were unchanged: 43.8±3.6 vs. 44.9±4.1 pg/mL for 1,25(OH)(2)D and 47.5±4.8 vs. 48.4±5.1 pg/mL for PTH. We applied mathematical modeling, which suggested that regulation of 24-hydroxylation was the principal mechanism responsible for maintaining 1,25(OH)(2)D levels within a narrow range in our mildly VitD deficient research participants [25(OH)D levels: 10-20 ng/mL]. When 25(OH)D levels were low (<20 ng/mL), 24-hydroxylation was maximally suppressed. Low levels of 24-hydroxylase activity tend to sustain levels of 1,25(OH)(2)D by decreasing its rate of metabolic clearance. VitD supplementation induced 24-hydroxylase activity by ∼5-fold – reaching a plateau when 25(OH)D levels >60 ng/mL. As suggested in the literature (JCY Tang et al, Sci Rep, 9:6974, 2019), we calculated ratios of 1,25(OH)(2)D/24,25(OH)(2)D as an index for the homeostatic response to VitD status. When we plotted the 1,25(OH)(2)D/24,25(OH)(2)D ratio as a function of 25(OH)D/1,25(OH)(2)D, we observed an extremely high degree of correlation (Spearman correlation coefficient of -0.94; p=10(-10)). DISCUSSION: Clinical assessment of thyroid status provides a highly relevant historical precedent. 50 years ago, thyroid status was assessed by measurement of total serum thyroxine (T4) levels. Diagnostic accuracy was greatly improved when total T4 was replaced by laboratory measurement of either free T4 or TSH (an index of the homeostatic response to thyroid status). Current clinical guidelines recommend assessment of VitD status by measuring total levels of 25(OH)D, which unfortunately are confounded by inter-individual variation in levels of VitD binding proteins (VDBP). We anticipate that diagnostic accuracy would be greatly enhanced if clinicians replaced measurement of total 25(OH)D by laboratory measurements that are not affected by variation in levels of VDBP. By analogy to the approach to clinical assessment of thyroid status, we recommend consideration of VDBP-independent indices of VitD status including 25(OH)D/1,25(OH)(2)D as an index of VitD stores and 1,25(OH)(2)D/24,25(OH)(2)D as an index for the body’s homeostatic response to VitD status. Presentation: Thursday, June 15, 2023