Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin

TLDR

Glucocorticoid‑induced osteoporosis is partly driven by increased osteocyte and osteoblast apoptosis, and bisphosphonates are effective treatments. The study tested whether bisphosphonates suppress apoptosis in osteocytes and osteoblasts. Bisphosphonates and calcitonin at nanomolar concentrations prevented apoptosis of murine osteocytic and osteoblastic cells in vitro via ERK activation, and alendronate reduced glucocorticoid‑induced osteocyte and osteoblast apoptosis in mouse vertebral bone, supporting their antiapoptotic contribution to therapeutic efficacy.

Abstract

Glucocorticoid-induced osteoporosis may be due, in part, to increased apoptosis of osteocytes and osteoblasts, and bisphosphonates (BPs) are effective in the management of this condition. We have tested the hypothesis that BPs suppress apoptosis in these cell types. Etidronate, alendronate, pamidronate, olpadronate, or amino-olpadronate (IG9402, a bisphosphonate that lacks antiresorptive activity) at 10–9 to 10–6 M prevented apoptosis of murine osteocytic MLO-Y4 cells, whether it was induced by etoposide, TNF-α, or the synthetic glucocorticoid dexamethasone. BPs also inhibited apoptosis of primary murine osteoblastic cells isolated from calvaria. Similar antiapoptotic 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 phosphorylated fraction of extracellular signal regulated kinases (ERKs) and was blocked by specific inhibitors of ERK activation. Consistent with these in vitro results, alendronate abolished the increased prevalence of apoptosis in vertebral cancellous bone osteocytes and osteoblasts that follows prednisolone administration to mice. These results suggest that the therapeutic efficacy of BPs or calcitonin in diseases such as glucocorticoid-induced osteoporosis may be due, in part, to their ability to prevent osteocyte and osteoblast apoptosis.