Abstract
Treatment with cumulative dosages of zoledronic acid (ZA) in elderly patients is a risk factor for the development of medication-related osteonecrosis of the jaws (MRONJ), mainly related to surgical triggers such as tooth extraction. However, animal models for the investigation and understanding of MRONJ pathophysiology in senescent and postmenopausal stages remains to be developed and characterized. The aim of this study was to analyze MRONJ development in senescent female mice treated with cumulative dosages of ZA. For this purpose, twenty 129/Sv female mice, 64 weeks old, were treated with 0.9% saline solution as control group (n = 10), and with ZA at 250μg/Kg (n = 10), once a week, starting 4 weeks before the upper right incisor extraction and until the end of the experimental time points (7 days and 21 days). At 7 and 21 days post-surgery, specimens were harvested for microCT, histological, birefringence and immunohistochemical analysis. Clinically, an incomplete epithelialization was observed in ZA group at 7 days and a delayed bone matrix mineralization and collagen maturation at 7 and 21 days compared to the controls. Controls revealed sockets filled with mature bone at 21 days as observed by microCT and birefringence, while ZA group presented delayed bone deposition at 7 and 21 days, as well increased leukocyte infiltration and blood clot at 7 days, and increased bone sequestrum and empty osteocyte lacunae at 21 days (p<0.05). Also, ZA group presented decreased quantity of TGFb+ and Runx-2+ cells at 7 days, and decreased quantity of TRAP+ osteoclasts compared to the control at 21 days (p<0.05). Altogether, these data demonstrate the usefulness of this model to understanding the pathophysiology of MRONJ.
Highlights
The chronic use of antiresorptive drugs, such as nitrogen-containing bisphosphonates, is a risk factor in medication-related osteonecrosis of the jaw (MRONJ), and has been clearly associated with the disease onset [1,2,3]
The Control group was treated with IP injection of 0.01ml of sterile 0.9% saline solution; while the zoledronic acid (ZA) group was treated with an IP injection of Zoledronic Acid (Merck KGaA, SML0223, Darmstadt, Germany) at 250 μg/kg diluted in 0.9% sterile solution once a week
Given the advantages for using a mouse as an animal model for immunological studies, our primary interest in this study was to investigate the bone healing in senescent and postmenopausal 129 Sv female mice treated with ZA, in order to provide a tool for understanding the MRONJ pathophysiology
Summary
The chronic use of antiresorptive drugs, such as nitrogen-containing bisphosphonates (nBP’s), is a risk factor in medication-related osteonecrosis of the jaw (MRONJ), and has been clearly associated with the disease onset [1,2,3]. Zoledronic acid (ZA) is 100 to 1000-fold more potent than other nBP’s [8], and it is the first choice for the treatment of patient with bony metastasis [9]. It is a highly effective drug for severe postmenopausal osteoporosis in elderly women [10], thereby reducing the risk of vertebral and hip fractures by up to 70% and 41%, respectively [11]
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