Periodontitis represents a chronic inflammatory disease characterized by progressive destruction of periodontal supporting tissues, affecting millions worldwide. Stage III periodontitis, classified by severe clinical attachment loss and radiographic bone loss, presents significant therapeutic challenges requiring comprehensive management strategies. Host-modulation therapy using sub-antimicrobial dose doxycycline (SDD) has emerged as a promising adjunctive treatment modality that targets the host inflammatory response rather than microbial pathogens. This review comprehensively examines the influence of SDD on clinical parameters and salivary biomarkers in Stage III periodontitis management. Evidence demonstrates that SDD at 20 mg twice daily effectively inhibits matrix metalloproteinases (MMPs), particularly MMP-8 and MMP-9, which are pivotal enzymes in periodontal tissue destruction. Clinical studies reveal significant improvements in probing depth reduction, clinical attachment level gain, and bleeding on probing when SDD is used adjunctively with scaling and root planing. Salivary biomarker analysis shows substantial reductions in pro-inflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), alongside decreased MMP-8 and myeloperoxidase (MPO) levels. The mechanism of action involves direct MMP inhibition through calcium and zinc chelation, suppression of oxidative activation, and down-regulation of inflammatory mediator production. Importantly, SDD does not exhibit antimicrobial effects at this dosage, thereby avoiding antibiotic resistance development. This review synthesizes current evidence supporting SDD as an effective host-modulating agent that enhances periodontal treatment outcomes in Stage III periodontitis by modulating the destructive host inflammatory response and promoting favorable healing conditions
Keywords: Sub-antimicrobial dose doxycycline, Stage III periodontitis, Host modulation therapy, matrix metalloproteinases, salivary biomarkers, periodontal inflammation, scaling and root planing
How to cite this article:Alshehri AFD, Alshammari MJS, Alhazmi RM, Alrahmah SA, Alnori AH, Alanze RNK, Alqahtani NSM, Influence of Host-Modulation Therapy Using Sub-Antimicrobial Dose Doxycycline on Clinical and Salivary Biomarkers in Stage III Periodontitis. 2026;16(1s): 840-852; DOI: 10.25258/ijddt.16. 840-852