EVALUATION OF ELP-004 AS A THERAPEUTIC STRATEGY TO PRESERVE BONE INTEGRITY IN A PRECLINICAL PROSTHETIC JOINT INFECTION MODEL

Prosthetic joint infection (PJI) is a severe complication associated with significant morbidity and mortality. Chronic infection and inflammation drive osteolysis, degrading bone quality, complicating reimplantation. The impact of PJI on the bone quality has been neglected in treatment strategies. ELP-004 is a novel osteoclast inhibitor that blocks Transient Receptor Potential Canonical (TRPC) channels and inhibits inflammatory cytokine-driven osteoclast differentiation, without affecting normal (RANKL-dependent) osteoclastogenesis, thereby preserving physiological bone remodeling. The aim of this study was to evaluate ELP-004 efficacy in preserving bone integrity in a preclinical PJI model. A preclinical PJI model was established using Methicillin-sensitive Staphylococcus aureus (ATCC 25923) in Sprague Dawley rats, in accordance with Institutional Animal Care and Use Committee approval. Animals were divided into seven experimental groups (n=8/group): control (Ctrl), drug only (ELP), surgery only (Surg), surgery + infection (Surg + Inf), surgery + drug (Surg + ELP), surgery + infection + vehicle (Surg + Inf + Veh), and surgery + infection + drug (Surg + Inf + ELP). The right femurs of each rat underwent K-wire implantation, and designated groups were inoculated with 10 5 CFU of MSSA. Treatment groups received ELP-004 via oral gavage at 180 mg/kg daily. Animals were euthanized on postoperative day 56, and whole femurs were harvested for micro-computed tomography analysis* to quantify bone microarchitecture. Infection was confirmed by quantitative culture of periprosthetic tissue and K-wire. One-way ANOVA with Tukey's multiple comparisons test was used, with significance set at p < 0.05. Eight weeks of ELP-004 treatment resulted in a significant increase in bone mineral density in female treatment groups (p< 0.0001). This effect was not seen in the male groups. Bone Volume/Total Volume % and trabecular number were significantly increased compared to infected controls (BV/TV; p <0.0002, Tb. N; p<0.0419, respectively). Linear regression analysis demonstrated infection-induced bone loss was more strongly associated with trabecular number reduction rather than trabecular thinning (p< 0.0001), suggesting that osteoclast-mediated resorption is the dominant mechanism of periprosthetic bone loss in this model. ELP-004 effectively mitigated infection-induced osteolysis, with significant preservation of bone microarchitecture observed in female subjects. The sex-specific response warrants dedicated investigation and may reflect differential pharmacokinetics or bone marrow drug distribution. These findings identify ELP-004 as a candidate adjunct therapeutic strategy for preserving periprosthetic bone integrity, particularly in female subjects undergoing treatment for PJI. * Bruker SkyScan 1172