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This study investigated the effect of exogenous OPG on ultra\u2010high\u2010molecular\u2010weight polyethylene (UHMWPE) particle\u2013induced osteolysis. The murine calvarial osteolysis model was utilized in 28 C57BL\/6J mice randomized to four groups. Group I underwent sham surgery only, group II received UHMWPE particles, and group III and IV particles and subcutaneous OPG starting from day 0 (group III) or day 5 (group IV) until sacrifice. After 2 weeks, calvaria were prepared for histology and histomorphometry. Bone resorption was measured within the midline suture using Giemsa staining and osteoclast numbers were determined using TRAP staining. UHMWPE particle implantation resulted in grossly pronounced osteoclastogenesis and bone resorption. Both immediate and delayed treatment with OPG counteracted these particle\u2010induced effects significantly, suppressing osteoclast formation and bone resorption (<jats:italic>p<\/jats:italic> &lt; 0.001 and <jats:italic>p<\/jats:italic> &lt; 0.001, respectively). In conclusion, exogenous OPG markedly suppressed UHMWPE particle\u2013induced osteolysis in a murine calvarial model. This important finding underscores the crucial significance of the OPG\u2010RANKL\u2010RANK signaling in wear particle\u2013induced osteolysis. Exogenous OPG may prove an effective treatment modality for wear debris\u2010mediated periprosthetic osteolysis after total joint arthroplasty. \u00a9 2005 Wiley Periodicals, Inc. 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