Endocrine Abstracts

Introduction: Vitamin D deficiency is a prevalent condition worldwide. Low serum 25(OH)D levels are associated with several diseases, being age and obesity strongly related to hypovitaminosis D. In addition, several genetic variants have also been associated with lower and/or higher 25(OH)D levels.

Objective: We aimed to assess the potential influence of age, BMI, waist circumference and genetic variants on the efficacy of 12-month treatment with calcifediol compared to cholecalciferol in postmenopausal women with vitamin D deficiency. Genetic influence on 25(OH)D modulation was assessed studying 14 polymorphisms linked to VDR and vitamin D metabolism.

Methodology: This was a long-term, phase III-IV, double blind, randomized, controlled, multicenter clinical trial including postmenopausal women with basal 25(OH)D levels <20 ng/ml treated monthly with calcifediol (0.266 mg, n=101) or cholecalciferol (0.625 mg, n=98). Subgroup analyses were performed using ANOVA analysis if there was no baseline effect of the response variable; otherwise, ANCOVA analysis was used. In both cases, Weighted Least Squares (WLS) was considered if the assumptions of the model were not met. Polymorphisms were analyzed using a multivariate mixed model approach.

Results: Change in 25(OH)D levels from baseline to month 12 was significantly affected by BMI in patients treated with cholecalciferol (ANOVA P=0.0177; ANCOVA P=0.0068), whereas no significant differences were observed when treated with calcifediol (P=0.4582). Accordingly, abdominal circumference ≥80 cm produced lower 25(OH)D increments in cholecalciferol group (ANOVA P=0.0259; ANCOVA P=0.0274; WLS P=0.0871), but not in calcifediol group (P=0.6899). When results were analyzed among three different age subgroups (<65;65-74;>74 years), no differences in efficacy were observed for any of the treatments tested. Modulation of 25(OH)D levels according to genotype (PP population) shows certain association for GC and VDR in cholecalciferol group and for CYP2R1 in calcifediol group. CYP2R1, that encodes 25-hydroxilase, shows that the less frequent allele of this polymorphism is linked to higher 25(OH)D levels in the calcifediol group. In the cholecalciferol group, the polymorphism rs7041 (GC) and rs2228570 (VDR) under recessive models shows a lower response due to its effect on the transporter protein and a lower affinity of the active metabolite on the receptor. These results suggest pharmacogenetic differences between calcifediol and cholecalciferol.

Conclusion: Increments on 25(OH)D levels after calcifediol treatment are independent of patient´s age and BMI, whereas cholecalciferol treatment shows a lower rise in 25(OH)D levels in obese patients. Pharmacogenetic differences between calcifediol and cholecalciferol were observed, although their clinical relevance remains unclear.