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 or sham-operated (SHAM). Eight rats served as baseline controls. Groups of OVX rats (n = 7-8 each) received vehicle alone or graded oral doses of 1,24,25(OH)(3)D-3 (0.05, 0.1, 0.2, and 0.3 mu g/kg BW/day), starting five days after surgery. Urine and blood samples were collected one, two, three, and four months after surgery. Serum samples were analyzed for total calcium and alkaline phosphatase. Calcium, hydroxyproline, and collagen crosslinks (HPLC) were determined in urine. After fluorochrome double labeling, the rats were sacrificed four months postsurgery and the first lumbar vertebrae and the proximal tibiae were processed undecalcified for bone histomorphometry. Ovariectomy induced a 28% and a 69% reduction in vertebral and tibial cancellous bone area, respectively. Osteopenia in OVX rats was associated with increased histomorphometric and biochemical indices of bone turnover. The administration of 1,24,25(OH)(3)D-3 to OVX rats dose-dependently increased vertebral and tibial cancellous bone mass, serum calcium, and urinary calcium 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. Even at high doses, 1,24,25(OH)(3)D-3 did not impair bone mineralization. We conclude that oral administration of 1,24,25(OH)(3)D-3 can effectively prevent estrogen depletion-induced cancellous bone osteopenia in 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 calcitriol.