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23 Speciale Perio Tribune Italian Edition - Ottobre 2016 < < pagina 22 Several clinical studies have demon- strated it.3,4,47 These studies showed that levels of melatonin in serum, saliva, gingival crevicular fluid or all three are inversely associated with the severi- ty of the disease, which indicates that melatonin may have a protective role against periodontal disease. Moreover, the effects of melatonin on the reduction of osteoclastogenesis, the capture of reactive oxygen species and their metabolites in the inflamed area, the increase in bone mineralization through the increase in proliferation, differentiation and activity of osteo- blasts, and collagen and BSP regulation, as already explained, together with its anti-fibrotic and anti-inflammatory ef- fectsongingivaltissuebyareductionof the matrix metalloproteinase-1/tissue inhibitor of metalloproteinases-1 ratio, suggest the possibility of using mela- tonin as a host-modulating agent in the treatment and control of periodontal disease, improving the bone tissue con- ditions and the soft-tissue stability.48 The in vivo administration of local or systemicmelatonincould,therefore,be indicatedinthesepatients,althoughno studieshaveyetbeenperformedinthis sense with validated methods. Melatonin and dental implants Dental implants are commonly used in current treatment of tooth loss. However, to avoid potential early com- plications and implant failures,49,50 bone healing must occur in the proper way. Bone remodeling around dental implants is highly influenced by the implant surface characteristics and evolves as a balance between the ac- tivity of osteoblasts and osteoclasts.51,52 Therefore, the use of melatonin as a topical agent to induce biomimetic properties of the implant surface has emerged as a promising technique.53 Melatonin directly influences the os- teoblast’s response to the implant sur- face and osseointegration. The addition of melatonin improves results for cell adhesion, proliferation and differen- tiation on different titanium surface modifications at early time points, al- though longer culturing times seem to reducethosedifferences.54 Theseeffects have been confirmed in vivo in several studies.55,56 The effects around dental implants are similar to those that take place in bone repair. Bone repair con- sists, biologically, of three different stages: inflammatory, proliferative and remodeling. Melatonin may play a role in these phases owing to its regulatory effects on inflammation, antioxidant properties, regulation of bone cells, and stimulation of collagen synthesis and deposition. Moreover, melatonin has been shown to increase the number of blood vessels, which is a prerequi- site for the supply of mineral elements and the migration of angiogenic and osteogenic cells. As a consequence, his- tological evaluation of the periimplant bone shows more trabecular bone, but less cortical bone and higher bone-to- implant contact in melatonin-treated sockets compared with controls.55 Therefore, the use of melatonin for os- seointegration might be of interest as a biomimetic agent. Moreover, it has been suggested to induce bone growth when applied in combination with bone grafts.56 However, its potential use in regenerating post-periimplantitis defects has not been studied yet. Conclusion Melatonin positive regulation of bone formation and homeostasis, in combi- nation with the inhibitory effects on bone resorption, highlights the poten- tialuseofmelatoninasamarkerofper- iodontal and periimplant bone-related diseases. Moreover, in vitro and animal studies are starting to show promis- ing results on its use as a regenerative agent,althoughnoclinicalstudieshave yet been performed. This new strategy may create possibilities for novel ther- apies in the treatment of periodontal disease or enhancing the outcomes of implant dentistry. Competing interests The authors declare that they have no conflictofinterestsrelatedtothisstudy. Acknowledgments The authors would like to thank Mr. Chris Jung for the original images pre- sented in this review. 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