Bisphosphonates (BPs) and calcitonin prevent apoptosis of osteocytes and osteoblasts, which may explain their therapeutic efficacy in glucocorticoid-induced osteoporosis. The study shows that BPs, including etidronate, alendronate, pamidronate, olpadronate, and IG9402, inhibit apoptosis in murine osteocytic MLO-Y4 cells and primary osteoblastic cells. Similar antiapoptotic effects are observed with calcitonin. These effects are associated with rapid activation of extracellular signal-regulated kinases (ERKs), which is blocked by ERK inhibitors. In vivo, alendronate prevents glucocorticoid-induced apoptosis in vertebral cancellous bone osteocytes and osteoblasts. The results suggest that BPs and calcitonin prevent osteocyte and osteoblast apoptosis, contributing to their effectiveness in managing glucocorticoid-induced osteoporosis. The antiapoptotic effects of BPs and calcitonin are mediated through ERK activation. The study also demonstrates that BPs inhibit osteoclast apoptosis, which is mediated through the mevalonate pathway. The findings indicate that BPs and calcitonin may enhance bone strength through mechanisms unrelated to bone mineral density (BMD). The study highlights the importance of osteocyte and osteoblast survival in maintaining bone quality and preventing fractures. The results suggest that BPs and calcitonin may reduce bone fragility by preserving the osteocyte network and preventing osteoblast apoptosis. The study also shows that BPs increase the survival of osteoblastic cells, which may contribute to their anabolic effects. The findings have implications for understanding the balance between bone resorption and formation, and for the development of therapies for bone diseases.Bisphosphonates (BPs) and calcitonin prevent apoptosis of osteocytes and osteoblasts, which may explain their therapeutic efficacy in glucocorticoid-induced osteoporosis. The study shows that BPs, including etidronate, alendronate, pamidronate, olpadronate, and IG9402, inhibit apoptosis in murine osteocytic MLO-Y4 cells and primary osteoblastic cells. Similar antiapoptotic effects are observed with calcitonin. These effects are associated with rapid activation of extracellular signal-regulated kinases (ERKs), which is blocked by ERK inhibitors. In vivo, alendronate prevents glucocorticoid-induced apoptosis in vertebral cancellous bone osteocytes and osteoblasts. The results suggest that BPs and calcitonin prevent osteocyte and osteoblast apoptosis, contributing to their effectiveness in managing glucocorticoid-induced osteoporosis. The antiapoptotic effects of BPs and calcitonin are mediated through ERK activation. The study also demonstrates that BPs inhibit osteoclast apoptosis, which is mediated through the mevalonate pathway. The findings indicate that BPs and calcitonin may enhance bone strength through mechanisms unrelated to bone mineral density (BMD). The study highlights the importance of osteocyte and osteoblast survival in maintaining bone quality and preventing fractures. The results suggest that BPs and calcitonin may reduce bone fragility by preserving the osteocyte network and preventing osteoblast apoptosis. The study also shows that BPs increase the survival of osteoblastic cells, which may contribute to their anabolic effects. The findings have implications for understanding the balance between bone resorption and formation, and for the development of therapies for bone diseases.