Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse

Abstract

The hypophosphatemic male mouse, an animal model for human vitamin D-resistant rickets, is characterized by low serum phosphorus concentration due to increased urinary phosphate excretion, rickets, osteomalacia, and dwarfism. Because phosphate administration can heal rickets but not osteomalacia in the human disease, we have compared the effect of phosphate supplementation on the epiphyseal and endosteal bone mineralization in the mutant animal. Phosphate was given in drinking water for 137 d and the biochemical and bone responses were assessed by analytical and histomorphometric methods. Treatment with phosphate normalized the endochondrial calcification (vertebral growthplate thickness: 83±5 SD vs. controls [+/Y] 73±8 μm, NS), but did not correct the endosteal bone mineralization (mineralization front: 13.6±2.7 vs. +/Y 67.1±6.9% osteoid surface, P < 0.001, endosteal mean osteoid seam thickness: 46.4±6.1 vs. +/Y 3.3±0.3 μm, P < 0.001). In addition, both osteoblastic and osteoclastic recruitment and activity were stimulated, as a result of a probable increase in parathyroid hormone secretion following the phosphate induced fall in serum calcium. Our results show that in the hypophosphatemic mouse, phosphate supplementation can heal the epiphyseal, but not the endosteal defective bone mineralization. Then, the biochemical and skeletal response to phosphate therapy appear to be similar to what we have observed in the human disease, further stressing the interest of the animal model.