Treatment with antiresorptive drugs: action on osseointegrated implants, effects on experimental peri-implantitis and interference with the response of peri-implantary tissues through different local therapies

Abstract

Medication-related osteonecrosis of the jaws (MRONJ) is a serious adverse effect triggered by using of antiresorptive drugs (AD). Last years, it has been increasing reports of cases of MRONJ related to the presence of osseointegrated implants (MRONJ-OI) and in function in the oral cavity, during or after using AD. Some studies correlate AD and peri-implantitis (PI) with the development of MRONJ-OI. An effective and safe treatment for PI during the therapy with AD may mean the maintenance of implant and to prevent MRONJ-OI. Antimicrobial photodynamic therapy (aPDT) has antimicrobial and biostimulatory actions, which makes it as a potential strategy for treatment of this condition, either as monotherapy, or as adjuvant therapy in conventional mechanical treatment (MT). The aims of this research project are: to clarify the effects of AD on osseointegrated implants in the oral cavity, with or without PI, and to verify if the presence of the implants under these conditions can trigger MRONJ-OI during the treatment with DA; to evaluate the safety and the effectiveness of using MT, aPDT or MT associated with aPDT in PI during the treatment with AD. Senescent female rats (13 months-old) will be used in this study. At the 0th week, the upper right maxillary first molar will be extracted and a titanium implant will be installed in the site of tooth extraction. At the 8th week, rats will be distributed into ten experimental groups: VEH, VEH-NLT, VEH-MT, VEH-aPDT, VEH-MT-aPDT, which will be treated with 0.45 ml of vehicle, and ZOL, ZOL-NLT, ZOL-MT, ZOL-aPDT, ZOL-MT-aPDT, which will be treated with 0.45 ml of vehicle plus 100 Ug/Kg of zoledronate. Administration of vehicle or zoledronate will occur by intraperitoneal route every four days until the end of the experimental period. At the 15th week a transmucosal component will be installed in the implants, and at the 16th week a cotton ligature will be installed around the implants in order that the accumulation of biofilm triggers PI, except in VEI and ZOL where PI will not be induced. At the 17th week, the ligature will be removed and the groups will be submitted to the following local procedures: VEH-NLT and ZOL-NLT, no local treatment; VEH-MT and ZOL-MT, one MT session; VEH-aPDT and ZOL-aPDT, three sessions of aPDT and; VEH-MT-aPDT and ZOL-MT-aPDT, one session of MT and three sessions of aPDT. MT will consist of peri-implant scaling with plastic curettes. The aPDT will consist on the application of photosensitizer (500 microliters of butyl toluidine blue - 0.5 mg/ml) in the peri-implant region (60 s) and the low-level laser irradiation (laser: InGaAlP; 660 nm; 35 mW; 74.2 J/cm2; 60 s) at 0, 2 and 4 days after removal of the ligature. At the 20st week, rats will be euthanized, the intraoral clinical analysis will be performed and the samples of maxilla containing implant will be dissected. Half of samples from each experimental group will be submitted to microtomographic scanning for analysis of the microarchitecture peri-implant bone, and later will be destined to ground-section histological processing for histometric analysis of the bone-implant contact. The other half of samples from each experimental group will be submitted to conventional histological processing and will be destined or to hematoxylin-eosin staining, for histopathological analysis of the peri-implant tissues and histometric analysis of the percentage of total bone tissue and the percentage of non-vital bone tissue in the peri-implant area; or will be submitted to indirect immunoperoxidase method for detection of cytokines with action on inflammation and tissue repair (TNFalpha, IL1beta, IL6, IL10 and TGFbeta1), regulators of angiogenesis and vasculature (HIF1alpha and VEGF), regulators of osteoblastogenesis and osteoblastic cells activity (BMP2, BMP7 and OCN), regulators of osteoclastogenesis and osteoclast activity (RANKL and OPG) and and osteoclast biomarker (TRAP). Results will be analysed properly. (AU)