Moisture‐Tolerant Polyurethane‐Based Bone Cement Containing Enoxacin for the Sex‐Specific Repair of Osteoporotic Defects

ABSTRACT To address the challenges associated with bone cement curing in the presence of bleeding, a moisture‐tolerant polyurethane‐based cement was developed, demonstrating gender‐specific therapeutic efficacy when repairing osteoporotic bone defects. The synthesized cements (PHE‐1, PHE‐2, and PHE‐3) incorporated osteoinductive nano‐hydroxyapatite (20 wt%) and varying concentrations of enoxacin (EN, 1–3 wt%) as an osteoclast inhibitor. These formulations exhibited moderate curing temperatures (36.8°C–40.7°C), maintained mechanical stability in the presence of blood, and achieved 99% monomer conversion within 240 min via moisture‐triggered –NCO reactions. In vitro evaluations showed that PHE‐2 effectively inhibited osteoclastogenesis in RAW 264.7 cells while simultaneously promoting osteogenic differentiation in bone marrow‐derived mesenchymal stem cells. In vivo studies revealed more efficacious bone healing in ovariectomized rats compared to orchiectomized rats after 8 weeks of implantation. This difference was attributed to estrogen deficiency accelerating the degradation of the bone organic matrix, whereas androgen deficiency impaired biomineralization processes. Further mechanistic analysis indicated that gender‐specific differences in bone turnover result from the enhanced matrix degradation induced by estrogen deficiency. Notably, PHE‐2 effectively mitigated matrix‐related pathologies associated with ovariectomies. This study highlights the importance of gender‐specific approaches in managing osteoporotic bone defects and underscores the therapeutic potential of EN‐loaded polyurethane cement for treating osteoporotic defects.