Osteoporosis following ovariectomy has been suggested to modulate bone response to polyethylene wear debris. In this work, we evaluate the influence of estrogen deficiency on experimental particle-induced osteolysis. Polyethylene (PE) particles were implanted onto the calvaria of wild-type (WT), sham-ovariectomized (OVX), OVX mice and OVX mice supplemented with estrogen (OVX+E2) (12 mice per group). Sham-implanted mice served as internal controls. After 14 days, seven skulls per group were analyzed with a high-resolution micro-computed tomography (CT) and by histomorphometry, and for tartrate-specific alkaline phosphatase. Five calvariae per group were cultured for the assay of IL-1, IL-6, TNF- and RANKL secretion using quantitative ELISA. The expression of RANKL and OPG mRNA were evaluated using real-time PCR. As assessed by CT and by histomorphometry, PE particles induced an extensive bone resorption and an intense inflammatory reaction in WT, sham-OVX and OVX+E2 mice. In OVX mice group, these features appeared considerably attenuated. In WT, sham-OVX and OVX+E2 mice, PE particles induced an increase in serum IL-6, in TNF-and RANKL local concentrations, and resulted in a two-fold increase in RANKL/OPG mRNA ratio. Conversely, these parameters remained unchanged in OVX mice after PE implantation. The combination of two well-known bone resorptive mechanisms ultimately attenuated osteolytic response, suggesting a protective effect of estrogen deficiency on particle-induced osteolysis. This paradoxical phenomenon was associated with a downregulation of pro-resorptive cytokines. It is hypothesized that excessive inflammatory response was controlled, illustrated by the absence of increase of serum IL-6 in OVX mice after PE implantation.