MACROPHAGE POLARIZATION AT A SITE WITH PERI-IMPLANTITIS IN RATS UNDERGOING ZOLEDRONATE THERAPY: STUDY AIMING TO INVESTIGATE CHANGES THAT PREDISPOSE TO MEDICATION-RELATED OSTEONECROSIS OF THE JAW ASSOCIATED WITH DENTAL IMPLANTS

• Grant number: 24/23178-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2025
• End date: February 28, 2026
• Field of knowledge: Health Sciences - Dentistry - Oral and Maxillofacial Surgery
• Principal Investigator: Edilson Ervolino
• Grantee: Rodrigo Isaías Lopes Pereira
• Host Institution: Faculdade de Odontologia (FOA). Universidade Estadual Paulista (UNESP). Campus de Araçatuba. Araçatuba , SP, Brazil

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is an adverse effect triggered by the use of antiresorptive drugs. In recent years, the number of cases of MRONJ associated with dental implants (MRONJ-DI) that are already osseointegrated and functioning in the oral cavity, during or after the use of antiresorptive drugs, has increased substantially. Studies correlate antiresorptive drugs and peri-implantitis (PI) with the onset of MRONJ-DI. Macrophages are cells involved in the etiopathogenesis of both peri-implantitis and MRONJ. Some studies indicate that treatment with antiresorptive drugs may act on this cell type. Since macrophages can currently be specific targets in the treatment of some diseases, understanding how this cell behaves in a site with peri-implantitis under the influence of an antiresorptive drug could help elucidate the etiopathogenesis of MRONJ-DI and, in the future, even assist in its treatment, which still constitutes a great challenge for dentistry. The objective of this research project will be to analyze the polarization of macrophages (M1 and M2) in a site with experimental peri-implantitis in senescent female rats subjected to treatment with the antiresorptive drug zoledronate, aiming to investigate changes in such cells that may predispose to MRONJ-DI. Twenty senescent female rats will be used. At week 0, the upper right incisor will be extracted and a titanium implant will be installed in the tooth extraction site. In the 8th week, after osseointegration of these implants, their platform will be exposed and a transmucosal component will be attached to it. In the 9th week, the rats will be randomly distributed into two experimental groups: VEH-EPI, in which rats will be treated with 0.45 ml of vehicle; and ZOL-EPI, in which rats will be treated with 0.45 ml of vehicle plus 100 µg/kg of zoledronate. The administration of vehicle or zoledronate will occur intraperitoneally every four days until the end of the experimental period (9th week - 19th week). In the 14th week, a cotton ligature will be placed around the transmucosal component/implant so that the accumulation of biofilm triggers the PI. At week 19, the rats will be euthanized, a clinical evaluation of the EPI site and its surroundings will be performed, and the maxillary samples containing the implant will be dissected. These samples will undergo conventional histological processing and will be stained with hematoxylin-eosin for histopathological analysis of the EPI site; or they will be submitted to the indirect immunofluorescence method for detection of F4/80, a general marker of macrophages; F4/80+CD80, a double labeling specifically for M1 macrophages; and F4/80+CD206, a double labeling specifically for M2 macrophages. Qualitative clinical and histological and quantitative immunohistochemical analysis will be performed on the samples. The data obtained will be subjected to statistical analysis with a significance level of 5%.