Impact of late administration of oral biphosphonate on perimplantar repair process in osteopenic rats. Can the implant's functionalization act favorably on this response?

Abstract

Osteoporosis is a disease that mainly affects postmenopausal women. Currently, there are many therapies available for its treatment, including oral bisphosphonates, which are drugs with an anti-bone remodeling effect, which may lead to some adverse effects in the long term. Other therapeutic or adjuvant options have been considered in order to improve anti-osteoporosis therapies, among them, we highlight osteoforming drugs, such as teriparatide, or supplements such as vitamin K2. Therefore, the aim of this project is to evaluate bone quality during peri-implant repair in osteoporotic rats, in a situation where drug treatment with alendronate sodium occurs after the installation of implants functionalized with teriparatide or vitamin K2. This project will be divided into two stages. In the first stage, the titanium implants will be functionalized with teriparatide or vitamin K2 using the layer-by-layer technique, physical tests and in vitro tests (cell cultures) in order to evaluate the properties of the functionalized surface to improve the osteogenic responses. The second step will consist of in vivo experiments to evaluate the effect of this functionalized surface during peri-implant repair. Ninety-six rats will be used, divided into two large groups, according to osteoporosis induction surgery and systemic medication: 1 - OVX SAL: rats submitted to bilateral ovariectomy and treated with saline solution and 2 - OVX ALE: rats submitted to bilateral ovariectomy and treated with sodium alendronate. Within each experimental group there will be three subgroups, according to the type of local treatment of the implants: 1 - CONV (n = 8 per subgroup): conventional implants that will not have any type of local treatment; 2 - TERI (n = 8 per subgroup): implants that will be functionalized with teriparatide (PTH, 1-34) and 3 - VK (n = 8 per subgroup): implants that will be functionalized with vitamin K2. After 2 weeks of ovariectomy surgery, all animals will have implants installed in the right and left tibial metaphysis (n = 192 implants), either conventional (CONV), functionalized with teriparatide (TERI) or vitamin K2 (VK). After 2 weeks, the animals will receive drug treatment by gavage, being saline solution (0.7 mg/kg weekly) for the animals in the (SAL) group and sodium alendronate (0.7 mg/kg weekly) for the animals in the (ALE) group. Euthanasia will occur in two periods, at the 8th and 12th weeks considering the beginning of the experiment. The collected tibiae will be used for biomechanical analysis (counter-torque), PCR - real time (expression of OPG, RANKL, OPN, ALP, OCN, VEGF, Wnt genes), computerized microtomography following the parameters: BV/TV, Tb.Th, Tb. N, Tp.Sp, Po(tot) and BIC, laser confocal microscopy: (analysis of peri-implant bone dynamics, active mineralization surface and daily bone apposition rate) and histometric analysis. Quantitative data will be submitted to homoscedasticity test for the selection of the appropriate statistical test (parametric vs. non-parametric), with a significance level of 5%.