Sex-related differences in the skeletal phenotype of aged vitamin D receptor global knockout mice

•Adult male Vdr−/− mice exhibit bone loss despite being fed the rescue diet.•Female Vdr−/− mice exhibit vertebral bone loss and yet increased femoral bone volume.•Rescue diet fed to Vdr−/− mice does not normalise bone volume.•In addition to the intestine, VDR may be required to directly regulate bone homeostasis.

The role of the vitamin D receptor (VDR) in maintaining skeletal health appears to be complex and dependent on the physiological context. Global Vdr deletion in a mouse model (Vdr−/−) results in hypocalcemia, secondary hyperparathyroidism and bone features typical of vitamin D-dependent rickets type II. When weanling Vdr−/− mice are fed a diet containing high levels of calcium, phosphorus and lactose, termed the rescue diet, normalisation of serum calcium, phosphate and parathyroid hormone levels results in prevention of rickets at 10 weeks of age. However, 17 week old male Vdr −/− mice, fed the rescue diet, have been reported as osteopenic due to a decrease in bone formation when compared to wild type mice. We now report confirmation of this finding with further data on the effect of the rescue diet on appendicular and axial skeletal structures in male and female Vdr−/− mice at 26 weeks of age compared to Vdr+/− controls. All Vdr−/− mice were normocalcemic with no evidence of any mineralization defect. However, male Vdr−/− mice exhibited significantly reduced mineral in femoral and vertebral bones when compared to control littermate Vdr+ /− mice, consistent with the previously reported data. In contrast, 26-week-old female Vdr−/− mice demonstrated significantly increased femoral trabecular bone volume although there was decreased vertebral trabecular bone volume, similar to males, and femoral cortical bone volume was unchanged. Thus, the Vdr−/− mouse model displays sex- and site-specific differences in skeletal structures with long-term feeding of a rescue diet. Although the global Vdr−/− ablation does not permit the determination of skeletal mechanisms producing these differences, these data confirm skeletal changes even when fed the rescue diet.