Five analogs of 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] [1], 26,27-dimethyl-1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2(Me)2D3] [2], 26,27-dimethyl-1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2(Et)2D3] [3], 26,27-dipropyl-1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2(Pr)2D3] [4], 26,27-dimethyl-24,24-difluoro-1 alpha,25-dihydroxyvitamin D3 [24F2-1,25(OH)2(Me)2D3], and [5] 24a-homo-24,24-difluoro-1 alpha,25- dihydroxyvitamin D3 [24aF2-homo-1,25(OH)2D3] were investigated to clarify the possibility that prevents osteopenia induced in rats by ovariectomy and sciatic neurotomy. The objective of our studies was to determine whether these analogs may be effective for treatment of subjects with osteoporosis. 1,25(OH)2(Me)2D3, 24F2-1,25(OH)2(Me)2D3, and 24aF2-homo-1,25(OH)2D3 prevented decreases in bone mineral density (BMD) of the femur, as measured by dual energy X-ray absorptiometry (DXA). The potency of 1,25(OH)2(Me)2D3 in this test was higher than that of 1,25(OH)2D3. The potencies of 24F2-1,25(OH)2(Me)2D3 and 24aF2-homo-1,25(OH)2D3 were similar to that of 1,25(OH)2D3. On the other hand, though 1,25(OH)2(Et)2D3 and 1,25(OH)2(Pr)2D3 had a preventive effect on the decrease in BMD, the potency of two analogs was lower than that of 1,25(OH)2D3. Decreases in cortical and trabecular bone areas of the femur were prevented by three analogs of 1,25(OH)2D3, 1,25(OH)2(Me)2D3, 24F2-1,25(OH)2(Me)2D3, and 24aF2-homo-1,25(OH)2D3. Serum calcium (Ca) concentration was elevated at the last administration of three analogs of 1,25(OH)2D3, 1,25(OH)2(Me)2D3, 24F2-1,25(OH)2-(Me)2D3 and 24aF2-homo-1,25(OH)2D3.(ABSTRACT TRUNCATED AT 250 WORDS)