Sex-Based Differences in the Vitamin D Metabolite Ratio and Its Associated Factors Among Healthy Japanese Adults: A Cross-Sectional Study.

Background/Objectives: Vitamin D is a pleiotropic substance that plays a pivotal role in the human body. Several studies have suggested sex-based differences in vitamin D metabolism. Recently, the vitamin D metabolite ratio (VMR), defined as the ratio of serum 24,25-dihydroxyvitamin D [24,25(OH)2D] to 25-hydroxyvitamin D [25(OH)D], has been identified as a novel marker that may more accurately reflect vitamin D status than serum 25(OH)D alone. This study aimed to assess whether significant variability exists in the VMR across different demographic groups. Methods: Residual serum samples and laboratory data were collected from healthy adults who underwent health checkups at a health center in Japan. Serum concentrations of 25(OH)D3 and 24,25(OH)2D3 were simultaneously measured using a fully automated liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. Factors affecting the levels of 25(OH)D3, 24,25(OH)2D3, and VMR were analyzed using multiple regression analysis and the stabilized inverse probability weighting method. Results: Tentative reference intervals for 24,25(OH)2D3 were found to be 0.3-3.0 ng/mL for males and 0.2-2.3 ng/mL for females. Those for VMR were found to be 3.0-11.8% for males and 2.5-10.4% for females, demonstrating statistically significant but moderate differences between the sexes. These differences remained significant even after adjusting for baseline covariates including 25(OH)D3. However, the standard deviation ratios were less than 0.5. An estimated glomerular filtration rate and an age of ≥50 years were positively associated with 24,25(OH)2D3 and VMR, whereas diabetic status was negatively associated with these markers. Conclusions: This study revealed moderate sex-based differences in markers of vitamin D metabolism. Although further research is needed to determine whether these differences are consistent across other populations, future epidemiology and clinical interventions should take into consideration of the sex-based differences in vitamin D metabolism.