24R,25-DIHYDROXYVITAMIN D-3 PROMOTES BONE-FORMATION WITHOUT CAUSING EXCESSIVE RESORPTION IN HYPOPHOSPHATEMIC MICE

To clarify the differences in the action of 1,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] and 24,25-(OH)(2)D-3 in hypophosphatemic (Hyp) mice, a model for familial X-linked hypophosphatemic rickets in humans, we carried out histomorphometric examinations of the effects of these age nts in the lumbar vertebra of these mice. The Hyp mice received 1-1000 mu g/kg . day 24,25-(OH)(2)D-3, 0.01-0.1 mu g/kg . day 1,25-(OH)(2)D- 3, or vehicle alone given daily for 28 days by ip injection. Histomorp hometrically, 1,25-(OH)(2)D-3 and 24,25-(OH)(2)D-3 showed similar effe cts on bone formation. The parameters of bone formation, mineralized b one volume/bone volume, mineral apposition rate, and bone formation ra te/bone surface, were improved to a similar extent in a dose-dependent manner by 1,25-(OH)(2)D-3 and 24,25-(OH)(2)D-3, but there were remark able differences in the indexes of the bone resorption between these t wo metabolites. In 24,25-(OH)(2)D-3-treated Hyp mice, osteoclast numbe r/bone perimeter and osteoclast surface/bone surface, the parameters o f bone resorption, increased to control levels and did not change acco rding to the dose of 24,25-(OH)(2)D-3. However, in 1,25-(OH)(2)D-3-tre ated Hyp mice, these values increased remarkably, exceeding the contro l level. That is, 24,25-(OH)(2)D-3 normalized bone resorption in the r achitic mice, whereas 1,25-(OH)(2)D-3 caused excessive stimulation of bone resorption. This qualitative difference between the two compounds contributes to the superior effects exerted by 24,25-(OH)(2)D-3 in im proving the bone lesion in Hyp mice. At doses from 1-1000 mu g/kg . da y, 24,25-(OH)(2)D-3 had dose-dependent effects in increasing bone form ation without promoting excessive bone resorption, as shown by histomo rphometric analysis.