Healing of Bone Lesions with 1,25-Dihydroxyvitamin D3in the Young X-Linked Hypophosphatemic Male Mouse*

Abstract

The χ-linked hypophosphatemic (Hyp) mouse presents with biochemical and skeletal abnormalities similar to those of human vitamin D-resistant rickets and hence is considered as a model of the human disease. In an attempt to correct osteomalacia, young (21-day-old) mutant male mice were infused continuously for 4 weeks with 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃; 0.05–0.25 μg/kg·day]. Mineral and skeletal changes were assessed by serum, urinary, and bone ash concentrations of calcium, phosphorus, and magnesium and by histomorphometric analysis of bone formation measured on histological sections of tetracycline dual labeled undecalcified caudal vertebrae. Treatment with 1,25-(OH)₂D₃ produced a dose-dependent elevation of serum phosphorus that could be assigned to increased intestinal phosphate absorption. Concomitantly, epiphyseal, endosteal, and periosteal bone mineralization were improved in correlation with both the dosage of 1,25-(OH)₂D₃ and the serum phosphorus level. Normalization of serum calcium and phosphorus but not of urinary phosphate excretion were achieved together with complete healing of bone mineralization when the highest doses of 1,25-(OH)₂D₃ (0.175 –0.25 μg/kg·day) were given. The data show that rickets and osteomalacia, which characterize the young Hyp mouse, can be healed by 1,25-(OH)₂D₃ in doses high enough to normalize serum mineral concentrations. Unlike the renal phosphate leak, the phenotypic expression of the Hyp gene pertaining to bone mineralization is then corrected by 1,25-(OH)₂D₃ supplementation.