Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin

Glucocorticoid-induced osteoporosis may be due, in part, to increased apopt osis of osteocytes and osteoblasts, and bisphosphonates (BPs) are effective in the management of this condition. We have tested the hypothesis that BP s suppress apoptosis in these cell types. Etidronate, alendronate, pamidron ate, olpadronate, or amino-olpadronate (IG9402, a bisphosphonate that lacks antiresorptive activity) at 10(-9) to 10(-6) M prevented apoptosis of muri ne osteocytic MLO-Y4 cells, whether it was induced by etoposide, TNF-alpha, or the synthetic glucocorticoid dexamethasone. BPs also inhibited apoptosi s of primary murine osteoblastic cells isolated from calvaria. Similar anti apoptotic effects on MLO-Y4 and osteoblastic cells were seen with nanomolar concentrations of the peptide hormone calcitonin. The antiapoptotic effect of BPs and calcitonin was associated with a rapid increase in the phosphor ylated fraction of extracellular signal regulated kinases (ERKs) and was bl ocked by specific inhibitors of ERK activation. Consistent with these in vi tro results, alendronate abolished the increased prevalence of apoptosis in vertebral cancellous bone osteocytes and osteoblasts that follows predniso lone administration to mice. These results suggest that the therapeutic eff icacy of BPs or calcitonin in diseases such as glucocorticoid-induced osteo porosis may be due, in part, to their ability to prevent osteocyte and oste oblast apoptosis.