Bone response to phosphate and vitamin D metabolites in the hypophosphatemic male mouse.
The hypophosphatemic male mouse (Hyp/y), the proposed model for human vitamin D-resistant rickets (VDRR), is characterized by chronic hypophosphatemia, dwarfism, and rachitic and osteomalacic bone lesions. We have reported that treatment of Hyp/y mice with phosphate salts (Pi) heals rickets but does not correct the defective endosteal bone mineralization. In an attempt to cure osteomalacia, mutant male animals were treated with Pi combined with 25-hydroxyvitamin D3 (25OHD3, 1 microgram/kg/day), 24,25-dihydroxyvitamin D3 [24,25(OH)2D3, 0.5 microgram/kg/day], or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, 0.05--0.25 microgram/kg/day] infused constantly for 3 weeks. The biochemical and skeletal effects of treatment were assessed by analytical methods and bone histomorphometry. The results show that only 1,25(OH)2D3 produced a dose-dependent elevation of serum calcium and phosphorus, and greatly improved bone mineralization at doses high enough to increase serum calcium and phosphorus concentrations within or above the normal range. Better improvement of bone mineralization was obtained when Pi was combined to 1,25(OH)2D3. In conjunction with the correction of hypocalcemia, Pi + 1,25(OH)2D3 suppressed the stimulation of bone turnover induced by Pi supplementation. The results show that, as in VDRR children, 1,25(OH)2D3 produces beneficial effects on bone lesions in Hyp/y mice, mainly through enhancement of mineral availability. However, the persistence of osteomalacia despite correction of serum mineral concentrations suggests that there is a specific bone cell resistance to mineral and/or hormonal influences in Hyp/y mice.
D015650:24,25-Dihydroxyvitamin D 3; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects*; D002117:Calcitriol / Q000627:therapeutic use; D002118:Calcium / Q000097:blood; D004100:Dihydroxycholecalciferols / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006887:Hydroxycholecalciferols / Q000627:therapeutic use; D007015:Hypophosphatemia, Familial / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010018:Osteomalacia / Q000188:drug therapy; D010710:Phosphates / Q000097:blood / Q000627:therapeutic use*; D010758:Phosphorus / Q000097:blood; D051381:Rats; D014807:Vitamin D / Q000627:therapeutic use*
D004100:Dihydroxycholecalciferols; D006887:Hydroxycholecalciferols; D010710:Phosphates; D014807:Vitamin D; D010758:Phosphorus; D015650:24,25-Dihydroxyvitamin D 3; D002117:Calcitriol; D002118:Calcium