Periprosthetic osteolysis and aseptic loosening are the leading causes of total joint arthroplasty failure. Wear debris triggers chronic sterile inflammation, driving excessive osteoclast activation and insufficient osteoblastic bone formation. Drug-target Mendelian randomization showed that genetically predicted higher systemic expression of glucagon-like peptide-1 receptor (GLP-1R) is causally associated with a reduced risk of clinical revision arthroplasty. Histological analysis confirmed GLP-1R expression within osteolytic bone tissues. Whether local activation of GLP-1R could counter particle-induced osteolysis, however, remained untested. To address this, we evaluated the therapeutic potential of the GLP-1R agonist, Exendin-4, across animal models and in vitro assays. In a murine model of ultra-high-molecular-weight polyethylene (UHMWPE)-induced calvarial osteolysis, local Exendin-4 administration significantly mitigated bone resorption, suppressed osteoclastogenesis, and stimulated periprosthetic bone formation. Mechanistically, Exendin-4 shifted macrophages from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, reducing osteolytic cytokines such as IL-6 and TNF-α; In vitro, it also acted directly on osteoclast precursors to suppress RANKL-driven osteoclastogenesis and rescued the osteogenic differentiation of bone marrow mesenchymal stem cells. These findings demonstrate that targeting GLP-1R signaling effectively restores the uncoupled bone homeostatic axis, offering a promising translational strategy for treating periprosthetic osteolysis. STATEMENT OF SIGNIFICANCE: Periprosthetic osteolysis (PPO) caused by wear debris is a major cause of joint replacement failure. While traditional treatments focus only on slowing down bone loss, strategies that can both stop bone destruction and promote bone healing are critically needed. In this study, we combined human genetic evidence with animal models to show that targeting the local GLP-1 receptor via Exendin-4 effectively treats PPO. Locally delivering Exendin-4 successfully switches pro-inflammatory M1 macrophages to an anti-inflammatory M2 phenotype and directly rescues the multi-stage bone formation process of stem cells under wear-particle stress, without causing systemic toxicity. This study provides a practical, biosafe strategy for reusing clinical metabolic drugs to balance bone remodeling and extend implant survival.
