The study investigates the antiapoptotic effects of bisphosphonates (BPs) and calcitonin on osteocytes and osteoblasts, which are crucial for bone health. BPs, including etidronate, alendronate, pamidronate, olpadronate, and amino-olpadronate (IG9402), were found to prevent apoptosis in murine osteocytic MLO-Y4 cells and primary murine osteoblastic cells, regardless of the proapoptotic stimulus used. These effects were observed at concentrations much lower than those required for promoting osteoclast apoptosis. The antiapoptotic action of BPs was associated with the rapid activation of extracellular signal-regulated kinases (ERKs), which was blocked by specific ERK inhibitors. Similar results were obtained with salmon calcitonin, which also induced ERK phosphorylation. In vivo, alendronate administration prevented glucocorticoid-induced bone loss and increased osteocyte apoptosis in vertebral cancellous bone. These findings suggest that the therapeutic efficacy of BPs and calcitonin in conditions like glucocorticoid-induced osteoporosis may be partly due to their ability to prevent osteocyte and osteoblast apoptosis, thereby enhancing bone strength and reducing fracture risk.The study investigates the antiapoptotic effects of bisphosphonates (BPs) and calcitonin on osteocytes and osteoblasts, which are crucial for bone health. BPs, including etidronate, alendronate, pamidronate, olpadronate, and amino-olpadronate (IG9402), were found to prevent apoptosis in murine osteocytic MLO-Y4 cells and primary murine osteoblastic cells, regardless of the proapoptotic stimulus used. These effects were observed at concentrations much lower than those required for promoting osteoclast apoptosis. The antiapoptotic action of BPs was associated with the rapid activation of extracellular signal-regulated kinases (ERKs), which was blocked by specific ERK inhibitors. Similar results were obtained with salmon calcitonin, which also induced ERK phosphorylation. In vivo, alendronate administration prevented glucocorticoid-induced bone loss and increased osteocyte apoptosis in vertebral cancellous bone. These findings suggest that the therapeutic efficacy of BPs and calcitonin in conditions like glucocorticoid-induced osteoporosis may be partly due to their ability to prevent osteocyte and osteoblast apoptosis, thereby enhancing bone strength and reducing fracture risk.