Abstract
Objective This study aims to evaluate bone repair and the development of the medication related osteonecrosis of the jaw (MRONJ) associated with the use of zoledronic acid in Wistar rats.Methodology 48 male Wistar rats were divided into four groups: ZA, treated with intraperitoneal zoledronic acid, 0.6 mg/kg every 28 days, totaling five doses; control (C), treated with 0.9% sodium chloride; ZA-surgical (SZA) and C-surgical (SC), submitted to extraction of the right upper molars 45 days after the first application. Alveolar bone repair was evaluated by macroscopic and histological analysis. Protein expression evaluations were performed by qPCR.Results Macroscopic evaluation showed that 91.66% (11) of the animals in the SZA group and 41.66% (5) from the SC group presented solution of epithelium continuity (P<0.05). All animals in the SZA group and none in the SC group had bone sequestration. The area of osteonecrosis was higher in the SZA group than in the SC group (P<0.05). In molecular evaluation, the SZA group presented changes in the expression of markers for osteoclasts, with increased RANK and RANKL, and a decrease in OPG.Conclusion The results highlighted strong and evident interference of zoledronic acid in bone repair of the socket, causing osteonecrosis and delayed bone remodeling.
Highlights
The first report describing bone exposure associated with the use of bisphosphonates was published in 2003.2 In 2014, the disease nomenclature changed to Medication-Related Osteonecrosis of the Jaw (MRONJ), as it was found that other anti-resorptive drugs and angiogenesis inhibitors may cause bone exposure similar to that found in MRONJ, bisphosphonates are still the major cause, mainly by the use of zoledronic acid
RANK is a transmembrane receptor expressed on the surface of osteoclasts and osteoclasts precursor cells, and it is activated by the ligand RANKL, a protein typically produced by osteoblasts and T cells
MRONJ is a serious complication that can affect patients undergoing therapy with BF. 3 This study used as a reference a model reporting the development of clinical and histological lesions in 100% and 80% of the animals, respectively
Summary
Bisphosphonates (BF) are synthetic drugs analogous to inorganic pyrophosphate, which are most commonly used in the treatment of bone disorders such as osteoporosis, bone metastases, Paget’s disease, and Multiple Myeloma. The first report describing bone exposure associated with the use of bisphosphonates was published in 2003.2 In 2014, the disease nomenclature changed to Medication-Related Osteonecrosis of the Jaw (MRONJ), as it was found that other anti-resorptive drugs and angiogenesis inhibitors may cause bone exposure similar to that found in MRONJ, bisphosphonates are still the major cause, mainly by the use of zoledronic acid.3MRONJ pathophysiology is still unknown, risk factors for developing this condition can be classified into three categories: risk factors related to drug intake, local, and systemic risk factors. Among local risk factors, dentoalveolar surgeries, anatomical differences between maxilla and mandible; and preexisting oral pathology may be cited.One of the possible pathways affected by BF is the RANK/RANKL/OPG system. RANK is a transmembrane receptor expressed on the surface of osteoclasts and osteoclasts precursor cells, and it is activated by the ligand RANKL, a protein typically produced by osteoblasts and T cells. The first report describing bone exposure associated with the use of bisphosphonates was published in 2003.2 In 2014, the disease nomenclature changed to Medication-Related Osteonecrosis of the Jaw (MRONJ), as it was found that other anti-resorptive drugs and angiogenesis inhibitors may cause bone exposure similar to that found in MRONJ, bisphosphonates are still the major cause, mainly by the use of zoledronic acid.. RANK is a transmembrane receptor expressed on the surface of osteoclasts and osteoclasts precursor cells, and it is activated by the ligand RANKL, a protein typically produced by osteoblasts and T cells. In the presence of macrophage colony stimulating factor, RANKL stimulates the differentiation of osteoclast precursor cells into osteoclasts and stimulates its activation, stimulating bone resorption. As a regulatory element of this system, OPG is a soluble receptor acting as “decoy” of RANKL, preventing the interaction between RANK and RANKL and bone resorption.
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