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

Jonathan C Y Tang, Sarah Jackson, Neil P Walsh, Julie Greeves, William D Fraser, Bioanalytical Facility team, Nicole Ball, John Dutton, Holly Nicholls, Isabelle Piec, Christopher J Washbourne, Jonathan C Y Tang, Sarah Jackson, Neil P Walsh, Julie Greeves, William D Fraser, Bioanalytical Facility team, Nicole Ball, John Dutton, Holly Nicholls, Isabelle Piec, Christopher J Washbourne

Abstract

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)2D) and 24,25-dihydroxyvitamin D (24,25(OH)2D) 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)2D:24,25(OH)2D vitamin D metabolite ratio (VMR) (r2Exp = 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)2D when fitted to Cosinor curves. We estimated 1,25(OH)2D:24,25(OH)2D 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)2D 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.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Non-parametric correlations of (a) 24,25(OH)2D (b) 1,25(OH)2D (c) 25(OH)D:24,25(OH)2D VMR and (d) 1,25(OH)2D:24,25(OH)2D VMR, against their respective 25(OH)D concentration. Solid lines in (a,b) represent linear regression line. LOWESS fitted curve in (c,d) (99% point fit). The mean 24,25(OH)2D and 1,25(OH)2D concentrations, 25(OH)D:24,25(OH)2D VMR and 1,25(OH)2D:24,25(OH)2D VMR represent 8.7%, 222.4%, 20.8% and 60.9% of their respective 25(OH)D concentration. Assay lower limit of quantification (LLoQ): 25(OH)D and 24,25(OH)2D = 0.1 nmol/L, 1,25(OH)2D = 12 pmol/L.
Figure 2
Figure 2
Distribution of 25(OH)D:24,25(OH)2D VMR by 25(OH)D intervals. Each interval contains an equal number of subjects to illustrate the significantly elevated ratio in those with serum 25(OH)D ≤ 50 nmol/L. Box and whiskers represent the median, interquartile range and 95% population intervals.
Figure 3
Figure 3
Distribution of 1,25(OH)2D:24,25(OH)2D VMR by 25(OH)D intervals. It demonstrates the exponential increase in 1,25(OH)2D:24,25(OH)2D VMR with the decrease in serum 25(OH)D. Box and whiskers represent the median, interquartile range and 95% population intervals. Each interval contains an equal number of subjects.
Figure 4
Figure 4
Diagnostic performance of 1,25(OH)2D:24,25(OH)2D VMR in the assessment of vitamin D status during winter months (Jan–April) (n = 402). Receiver Operating Characteristic (ROC) curve depicts diagnostic sensitivity and specificity levels. (O) represents decision threshold for (a) vitamin D replete (i.e. 25(OH)D ≥ 50 nmol/L), 1,25(OH)2D:24,25(OH)2D VMR threshold value of 35 (sensitivity = 80%, specificity = 78%), (b) vitamin D insufficiency (i.e. 25(OH)D ≥ 30 nmol/L), 1,25(OH)2D:24,25(OH)2D VMR threshold value of 51 (sensitivity = 82%, specificity = 74%). The diagonal lines represent the line of no discrimination.
Figure 5
Figure 5
Cosinor-fit circannual rhythm for (a) 25(OH)D, (b) 24,25(OH)2D, (c) 1,25(OH)2D, (d) 25(OH)D:24,25(OH)2D, (e) 1,25(OH)2D:24,25(OH)2D, (f) PTH. Error bars represent 95% CI.

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