Toward Sex-Specific Host Modulation Therapy for Periodontitis

Periodontitis, a leading cause of tooth loss worldwide, arises from a dysregulated host immune response, and males consistently show higher prevalence and more severe disease than females. This disparity historically has been attributed to behavioral/environmental factors, but growing evidence indicates that biological sex, acting through hormonal signaling and sex chromosome-linked genetic mechanisms, independently shapes periodontal immune responses and subsequent bone resorption. In this review, we examine preclinical and clinical evidence on the impact of biological sex on host modulation therapies to prevent periodontitis. The IL-1β/inflammasome pathway and osteoclast differentiation via receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) signaling both show clear sex-dependent regulation in experimental periodontitis, illustrating the biological complexity that single-target therapies must address in this heterogeneous condition. In a mouse model, inflammasome-mediated IL-1β signaling drives alveolar bone loss selectively in males, while females progress to comparable bone loss through IL-1β-independent mechanisms. IL-17 plays a dual role, driving inflammatory bone resorption while also supporting antimicrobial defense, and evidence points to this balance being sex dependent, with more severe effects observed in females when IL-17 signaling is disrupted. IL-6 is an established driver of periodontal bone loss, and although sex-specific data within periodontitis remain limited, sex-dependent anti-IL-6 receptor treatment responses have been observed in other inflammatory diseases that warrant further investigation. Complement-mediated immunity shows biological sex differences in humans and animal models, though whether these discrepancies directly influence periodontal disease progression needs to be determined. Resolvins and cyclooxygenase inhibitors also show sex-dependent effects outside the periodontal field. Collectively, this evidence positions biological sex as a tractable, currently underappreciated variable to improve host modulation strategies. Incorporating sex as a biological variable into preclinical and clinical periodontal research and ensuring sex-disaggregated data reporting offer a clear opportunity to develop precise, sex-informed nonsurgical therapeutics that better serve both male and female patients.