Two novel approaches to increasing bone mass. Bone mass reflects the relative rates of bone formation, mediated by osteoblasts, and of bone resorption, mediated by osteoclasts. Parathyroid hormone (PTH) has complex effects on bone mass, since it stimulates both of these processes, but treatment with estrogen, bisphoshponates, or other agents specifically blocks its effects on bone resorption. PTH promotes bone formation by several mechanisms, enhancing the proliferation of cells of the osteoblastic lineage, and promoting osteoblastic function. Some of these anabolic effects of PTH are mediated by IGF I. PTH secretion from the parathyroid gland is suppressed by signaling through the calcium receptor (CaR), which senses extracellular calcium levels. The new drug NPS 2143 acts by reducing the sensitivity of the calcium receptor to extracellular calcium, thereby enhancing PTH secretion and promoting osteoblast function. The drug SB 242784 acts by a complementary strategy, specifically inhibiting the vacuolar ATPase and thereby blocking osteoclast-mediated acidification of the bone matrix, which is required for bone resorption.