Bisphosphonate zoledronic acid blocks secretory autophagy and inhibits bone resorptive functions in osteoclasts

Bisphosphonates (BPs) are the most widely used anti-resorptive agents and first-line drugs for managing bone-related diseases, such as osteoporosis, Paget disease of bone, and bone metastatic cancer. BPs are known to inhibit osteoclasts’ functions, and recent studies have highlighted the importance of macroautophagy/autophagy in osteoclasts. However, the involvement of autophagy in BP-mediated inhibition of osteoclast functions remains unclear. In this study, we showed that BPs inhibit the bone resorptive functions of osteoclasts by blocking autophagy. At the non-apoptotic doses, zoledronic acid (ZOL) inhibited autophagy by blocking autophagic flux and delaying the degradation of autophagy-related proteins. ZOL also prevented the cleavage and secretion of secretory proteins such as CTSK, ACP5/TRAP, and MMP9 essential for bone resorption. Mechanistically, ZOL inhibits the prenylation of the RAB7 small GTPase, a key protein that is required for autolysosome formation. In vivo studies showed that osteoclast-specific rab7 conditional knockout mice exhibited osteopetrotic phenotypes. These findings provide insights into how BPs disrupt osteoclast function by blocking autophagy and suggest that targeting autophagy in osteoclasts could be a potential therapeutic approach for bone-related diseases.