The decrease in intestinal calcium absorption and lower blood levels of 1,25-dihydroxyvitamin D [1,25-(OH)2D3] have been implicated in the pathogenesis of postmenopausal osteoporosis. This study evaluates the effects on bone of 1,25-(OH)2D3 therapy using the ovariohysterectomized dog model. The cessation of ovarian function was ascertained by an increase in serum LH levels 4 weeks after ovariohysterectomy, and significant bone loss was revealed four months after ovariohysterectomy. The bone loss was associated with an increase in the number of bone-forming cells and a decrease in the activity of these cells. The administration of 1,25-(OH)2D3 increased the activity of the bone cells and resulted in a reversal of all abnormalities in structural parameters of bone, including cancellous bone mass, trabecular wall thickness, trabecular plate separation, trabecular plate density, and trabecular plate thickness (which increased above normal). However, 1,25-(OH)2D3 therapy was also associated with a significant decrease in the number of bone-forming cells, resulting in lower bone formation at the tissue level. The results of this study indicate that 1,25-(OH)2D3 therapy can reverse the bone loss and osteoblastic insufficiency responsible for the maintenance of negative bone balance after the cessation of ovarian function. However, this therapy has a suppressive effect on bone cell number and bone turnover. This undesired side-effect of 1,25-(OH)2D3 therapy renders a chronic therapeutic regimen inefficient for the long term management of patients with osteoporosis. Intermittent 1,25-(OH)2D3 therapy or a sequential therapy using 1,25-(OH)2D3 along with substances known to increase the number of bone-forming cells is strongly suggested by these results.