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Host modulation therapy (HMT), as a treatment concept for periodontitis, aims to modulate the host immune responses during the pathogenesis of periodontitis. Various drugs have been evaluated as HMT, including subdose doxycycline (SDD), nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, and cytokine receptors, to modify or modulate inflammatory mediators and associated signaling pathways in the immune-inflammatory response, as well as connective tissue breakdown and bone resorption. SDD, a member of the tetracycline drug family, has been reported to improve periodontal treatment outcomes by inhibiting periodontal breakdown through inhibiting MMPs. NSAIDs may suppress periodontal inflammation by reducing cyclooxygenase-2(COX-2) activity. Combined application of SSD and NSAIDs may achieve a better clinical outcome. Recent studies of HMT treatment have focused on the prevention of excessive inflammation by regulating mediators using endogenous lipid mediators. Local administration of bisphosphonates and histone deacetylase inhibitors can inhibit osteoclast activity and regulate bone tissue remodeling. Currently, SSD is approved by the FDA for periodontal treatment. Other drugs, such as COX-2 selective inhibitor, nonsteroidal anti-inflammatory drugs, bisphosphonates, triclosan and iNOS inhibitors, have good application prospects in the prevention and treatment of periodontal disease, and the mechanism and side effects of these drugs remain to be further investigated.