6652 Precision Diagnostic Approaches for Assessing Clinical Vitamin D Status

Abstract Disclosure: Z. Shahidzadeh Yazdi: None. E.A. Streeten: None. 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.. Background . The body has evolved effective homeostatic mechanisms to maintain free 1,25-dihydroxyvitamin D [1,25(OH)2D] within narrow physiological ranges. Using a mathematical model to quantitate 24-hydroxylase activity, we concluded that mild-moderate vitamin D [VitD] deficiency suppresses 24-hydroxylase activity (the first line of defense), thereby suppressing clearance of 1,25(OH)2D. Severe VitD deficiency triggers secondary hyperparathyroidism (the second line of defense) to sustain physiological levels of 1,25(OH)2D. Objective. To compare performance of various indices of VitD status in predicting whether homeostatic mechanisms have been triggered. Methods. We studied 11 otherwise healthy VitD deficient (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL) participants before and after VitD3 supplementation (50,000 IU once or twice a week depending on BMI for 4-6 weeks). We measured 25(OH)D, 1,25(OH)2D, 24,25-dihydroxyvitamin D [24,25(OH)2D], PTH, and FGF23 before and after VitD3 supplementation. We calculated three VitD metabolite ratios and also a PTH index (i.e., PTH level before divided by PTH level after VitD3 supplementation) to normalize PTH levels relative to each individual’s setpoint. We then compared the correlation between the PTH index and various indices of VitD status. Results. VitD3 supplements induced a 2.7-fold increase (p=0.0006) in mean 25(OH)D and a 4.3-fold increase (p=0.0002) in 24,25(OH)2D, but did not change 1,25(OH)2D, PTH, or FGF23. While relative 24-hydroxylase activity (h) was highly correlated with the 1,25(OH)2D/24,25(OH)2D ratio (ρ2=0.94; p=3E-13), it was less well correlated with the 24,25(OH)2D/25(OH) ratio (ρ2=0.67; p=3E-06) and baseline total 25(OH)D (ρ2=0.72; p=7E-07). Furthermore, we investigated the correlation between the PTH index and baseline 25(OH)D and three VitD metabolite ratios. The correlation coefficient was higher when we plotted the PTH index as a function of baseline 25(OH)D before VitD3 supplementation (R2=0.23; p=2E-06) compared to the correlation of baseline PTH with baseline 25(OH)D (R2=0.08; p=5E-05). While the correlation coefficient for the correlation of PTH index with 1,25(OH)2D/24,25(OH)2D was 0.60 (R2=0.36; p=0.0002), it was 0.44 for 25(OH)D/1,25(OH)2D ratio (R2=0.20; p=0.0001) and 0.35 for the 24,25(OH)2D/25(OH)D ratio (R2=0.12; p=2E-06). Conclusions. Measuring total 25(OH)D level did not provide optimal assessment of clinical VitD status – probably because it does not account for the threefold inter-individual variation in VitD binding protein level. Of all the indices, the 1,25(OH)2D/24,25(OH)2D ratio best predicted triggering of two homeostatic mechanisms: suppression of 24-hydroxylase and induction of secondary hyperparathyroidism due to VitD deficiency. Presentation: 6/2/2024