Background and purpose: Chronic inflammation may affect bone metabolism, leading to consequent bone loss and increased fracture risk. Lipopolysaccharide (LPS), a major component of Gram-negative bacteria from an infection or leaky gut, may cause chronic inflammatory bone loss. This study aims to enrich the mechanism by which LPS promotes the pathogenesis of bone loss. Experimental approach: C57BL/6 mice were treated with 1.5 mg•kg-1 of LPS or vehicle by intraperitoneal injection 3 times a week. The pharmacological effect of disulfiram, resatorvid, erlotinib were assessed in mice models of chronic inflammatory bone loss induced by LPS. Primary bone marrow-derived macrophages (BMDMs) were used to evaluate the roles of toll-like receptor (TLR) 4 and epidermal growth factor receptor (EGFR) signaling in pyroptosis. Key results: We demonstrated that TLR4 and EGFR signaling differentially regulated pyroptosis in BMDMs, mediating LPS-induced low proliferation of osteoprogenitors and inflammatory bone destruction. Pharmacological treatment of LPS-treated mice with pyroptosis inhibitor by disulfiram, TLR4 signaling inhibitor by resatorvid, or EGFR signaling inhibitor by erlotinib protected mice against loss of osteoblasts and osteoprogenitors, and rescued inflammatory bone destruction as well. Mechanistically, we found that LPS suppressed the proliferation of osteoprogenitors by activating pyroptosis in BMDMs. Further, EGFR signaling mediated the mRNA expression of IL-1β and IL-18 while TLR4 signaling mediated LPS-induced pyroptosis and release of IL-1β and IL-18. Conclusion and implications: These findings have identified TLR4 and EGFR signaling in BMDMs as a co-regulator of pyroptosis and inflammatory bone destruction, highlighting the importance of targeting pyroptosis against LPS-induced bone loss.