Role of vitamin D metabolites in the prevention of the osteopenia induced by ovariectomy in the axial and appendicular skeleton of the rat.

Forty Fischer-344 rats (10 weeks old, 130 g BW) were either bilaterally ovariectomized (OVX) or sham-operated (SHAM). The rats were allocated to the following groups: SHAM; OVX; OVX + 15 ng 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]/rat/d; OVX + 30 ng 1 alpha,24R,25-trihydroxyvitamin D3 [1,24,25(OH)3D3]/rat/d; OVX + 15 ng 1,25(OH)2D3/rat/d + 30 ng 1,24,25(OH)3D3/rat/d. The vitamin D metabolites were fed orally starting 4 weeks after surgery. Urine and blood samples were taken at several time points during the experiment. Twenty-one weeks after surgery all rats were sacrificed, and the proximal tibiae and the first lumbar vertebrae were processed undecalcified for static bone histomorphometry. Ovariectomy induced a 40% reduction in vertebral cancellous bone area, and a 69% reduction in tibial cancellous bone area. This bone loss in OVX rats was associated with moderately increased biochemical and histomorphometric indices of bone formation and resorption as compared to values in sham-operated animals. Through inhibition of bone resorption, treatment of OVX rats with 1,25(OH)2D3, 1,24,25(OH)3D3, and the metabolite combination prevented the ovariectomy-induced osteopenia in the lumbar vertebra, and partially prevented cancellous bone osteopenia in the tibial metaphysis. However, OVX rats receiving 1,25(OH)2D3 alone or in combination with 1,24,25(OH)3D3 exhibited hypercalcemia, hyperphosphatemia, hypercalciuria, and impaired bone mineralization. Treatment of OVX rats with 1,24,25(OH)3D3 alone, on the other hand, only slightly increased serum calcium levels and did not impair bone mineralization. Furthermore, the inclusion of 1,24,25(OH)3D3 with 1,25(OH)2D3 partially antagonized the untoward effects of 1,25(OH)2D3 on bone mineralization. These data suggest that the actions of 1,24,25(OH)3D3 on bone metabolism might differ from that of 1,25(OH)2D3, and that 1,25(OH)2D3 and, particularly, 1,24,25(OH)3D3 may be potentially effective agents for the prophylaxis of postmenopausal osteoporosis.