Predisposition to vitamin D deficiency osteomalacia and rickets in females is linked to their 25(OH)D and calcium intake rather than vitamin D receptor gene polymorphism

Abstract

Background: Osteomalacia (OSM) and rickets are widely prevalent in developing countries especially in females. The factors associated with such predisposition are not known. Objectives: To identify nutritional, endocrine and genetic factors related to calcium and vitamin D metabolism that are associated with OSM/rickets in females. Subjects and methods: We studied 98 patients with OSM or rickets and their relatives including male and female sibs and parents (n = 221) for the presence of biochemical OSM {low serum 25-hydroxyvitamin D [25(OH)D], raised intact PTH (iPTH) and raised alkaline phosphatase} and associated nutritional and genetic factors. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used for genotyping vitamin D receptor (VDR) (BsmI and FokI) and PTH gene (BstBI and DraII) single nucleotide polymorphisms (SNPs) in 74 families. The differences in the factors associated with calcium and vitamin D among the different groups were analysed by analysis of variance (ANOVA). Logistic regression analysis and the transmission disequilibrium test (TDT) were carried out to assess association between nutritional and genetic factors, and the disease, respectively. Results: Most of the patients were female (91.8%). The mean serum 25(OH)D level of the female patients was comparable to that of the female sibs (14.4 ± 5.7 vs. 18.3 ± 9.7 nmol/l). The frequency of biochemical OSM was fivefold higher in female than in male sibs (24.4%vs. 4.9%). Female sibs also had significantly lower 25(OH)D, dietary calcium intake and sunshine exposure than male sibs. The frequency of biochemical OSM was comparable between mothers and fathers. The odds of biochemical OSM in the family members was reduced by 11% per 15-min daily sunshine exposure [odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.81-0.98, P = 0.02] and decreased by 20% per 100 mg dietary calcium intake (OR = 0.80, 95% CI = 0.67-0.96, P = 0.02). VDR/PTH gene SNPs showed no association with OSM/rickets on TDT analysis. Conclusion: Among the immediate family members of patients with OSM/rickets, female sibs have features of biochemical OSM in up to 24.4%. Female sibs, unlike male sibs, share with patients features of markedly low serum 25(OH)D levels, poor dietary calcium intake and poor exposure to sunshine. Genetic factors such as VDR and PTH gene SNPs were not associated with OSM/rickets.