A potent analog of 1α,25-dihydroxyvitamin D3 selectively induces bone formation

1,25-Dihydroxyvitamin D-3 [1,25(OH)(2)D-3] is a principal regulator of calcium and phosphorus homeostasis through actions on intestine, kidney, and bone. 1,25(OH)(2)D-3 is not considered to play a significant role in bone formation, except for its role in supporting mineralization. We report here on the properties of 2-methylene-19-nor-(20S)-1alpha,25(OH)(2)D-3 (2MD), a highly potent analog of 1,25(OH)(2)D-3 that induces bone formation both in vitro and in vivo. Selectivity for bone was first demonstrated through the observation that 2MD is at least 30-fold more effective than 1,25(OH)(2)D-3 in stimulating osteoblast-mediated bone calcium mobilization while being only slightly more potent in supporting intestinal calcium transport. 2MD is also highly potent in promoting osteoblast-mediated osteoclast formation in vitro, a process essential to both bone resorption and formation. Most significantly, 2MD at concentrations as low as 10(-12) M causes primary cultures of osteoblasts to produce bone in vitro. This effect is not found with 1,25(OH)(2)D-3 even at 10(-8) M, suggesting that 2MD might be osteogenic in vivo. Indeed, 2MD (7 pmol/day) causes a substantial increase (9%) in total body bone mass in ovariectomized rats over a 23-week period. 1,25(OH)(2)D-3 (500 pmol three times a week on prevented the bone loss associated with ovariectomy and did not increase bone mass. These results indicate that 2MD is a potent bone-selective analog of 1,25(OH)(2)D-3 potentially effective in treating bone loss diseases.