PROPHYLACTIC EFFECTS OF 1,24,25-TRIHYDROXYVITAMIN-D-3 ON OVARIECTOMY-INDUCED CANCELLOUS BONE LOSS IN THE RAT

Vitamin D metabolites can prevent estrogen depletion-induced bone loss in ovariectomized (OVX) rats. In this study, we investigated the bone -sparing effects of oral 1 alpha,24R,25-trihydroxyvitamin D-3 (1,24,25 (OH)(3)D-3) in a wide dose range in aged OVX rats. Fifty-three female Fischer-344 rats (6 months old, 170 g BW) were either ovariectomized o r sham-operated (SHAM). Eight rats served as baseline controls. Groups of OVX rats (n = 7-8 each) received vehicle alone or graded oral dose s of 1,24,25(OH)(3)D-3 (0.05, 0.1, 0.2, and 0.3 mu g/kg BW/day), start ing five days after surgery. Urine and blood samples were collected on e, two, three, and four months after surgery. Serum samples were analy zed for total calcium and alkaline phosphatase. Calcium, hydroxyprolin e, and collagen crosslinks (HPLC) were determined in urine. After fluo rochrome double labeling, the rats were sacrificed four months postsur gery and the first lumbar vertebrae and the proximal tibiae were proce ssed undecalcified for bone histomorphometry. Ovariectomy induced a 28 % and a 69% reduction in vertebral and tibial cancellous bone area, re spectively. Osteopenia in OVX rats was associated with increased histo morphometric and biochemical indices of bone turnover. The administrat ion of 1,24,25(OH)(3)D-3 to OVX rats dose-dependently increased verteb ral and tibial cancellous bone mass, serum calcium, and urinary calciu m excretion, and reduced histomorphometric and biochemical indices of bone resorption. 1,24,25(OH)(3)D-3 at doses of 0.2 and 0.3 mu g/kg/day produced strong anabolic effects, especially on vertebral cancellous bone in OVX rats, and increased mineral apposition rate and wall width of completed remodeling units relative to vehicle-treated OVX rats. E ven at high doses, 1,24,25(OH)(3)D-3 did not impair bone mineralizatio n. We conclude that oral administration of 1,24,25(OH)(3)D-3 can effec tively prevent estrogen depletion-induced cancellous bone osteopenia i n the aged OVX rat model. The therapeutic window for 1,24,25(OH)(3)D-3 in OVX rats, however, is also narrow, comparable to that for calcitri ol.