Preclinical studies on the prevention of medication-related osteonecrosis of the jaw and the underlying mechanism

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication associated with antiresorptive medications managing osteoporosis and cancer-related conditions. The frequency of MRONJ in osteoporosis patients receiving antiresorptive medications is estimated to be 0.001%-0.01%, and the frequency in oncology patients receiving higher doses is 1%-15%. The pathogenesis of MRONJ remains unclear and is likely multifactorial. Prevention strategies for MRONJ remain an active research area. Inhibition of bone turnover is one of the potential mechanisms underlying MRONJ development. The notion that a discontinuation of antiresorptive medications therapy before dental extraction, so called “drug holiday”, could resume the bone turnover and thereby prevent the onset of MRONJ in patients with osteoporosis is controversial. Here we proposed an experimental study using an osteoporotic animal model, aiming to evaluate the prevention of MRONJ in osteoporotic conditions, with the implementation of a drug holiday. An ovariectomy-induced osteoporotic rat model was established and then exposed to zoledronate for 8 weeks before dental extraction, with or without an 8 weeks’ drug holiday. A significantly increased number of osteoclasts was observed in the group with a drug holiday, while there were no significant differences in the occurrence of MRONJ-like lesion and osteoporotic changes in the femur between the groups. The current study provided the first evidence in an osteoporotic animal model demonstrating that the implementation of a drug holiday in prior to dental extraction could improve osteoclastic activity in alveolar bone but not prevent MRONJ development, while avoiding exacerbation of bone loss in the femur. Suppression of angiogenesis is another proposed pathogenesis for MRONJ. As magnesium (Mg)-based implants have proangiogenic effects, we hypothesized that biodegradable Mg implants could ameliorate the onset of MRONJ by enhancing angiogenesis. In this study, we aimed to investigate the effects of Mg on the pathological alterations of MRONJ-like lesions, and the role of vascular endothelial growth factor (VEGF)- and calcitonin gene-related peptide (CGRP)-mediated angiogenesis in the pathogenesis of MRONJ. Eight weeks postoperatively, the group implanted with Mg had a significantly decreased occurrence of MRONJ-like lesions and histological osteonecrosis, increased bone microstructural parameters, and elevated expressions of VEGFA and CGRP, compared with the control group. By concurrently inhibiting VEGF receptor-2 and CGRP receptor, the vessel volume and new bone formation in the group implanted with Mg were significantly reduced, whereas the occurrence of MRONJ-like lesions and histological osteonecrosis were significantly increased. This was the first study to investigate the effects of Mg on MRONJ and found that Mg ameliorated the onset of MRONJ-like lesions, possibly by upregulating VEGF- and CGRP-mediated angiogenesis. In conclusion, a drug holiday of bisphosphonate might have effects on osteoclasts, but the preventive effect on MRONJ should be further evaluated with a larger sample size. Mg has been proven to have a promising effect on preventing MRONJ, and Mg-based biodegradable implants have the potential to be developed as novel internal fixation devices with therapeutic value for patients at risk of MRONJ or with established MRONJ. Future clinical trials should be conducted to confirm the preventive and treatment outcomes of Mg-based implants.