Osteonecrosis of the jaws caused by bisphosphonate treatment and oxidative stress in mice

Abstract

Aging is a significant risk factor for the development of bisphosphonate-related osteonecrosis of the jaws (BRONJ). Accumulating evidence suggests that bone aging is associated with oxidative stress (OS), and OS is associated with osteonecrosis. To elucidate the mechanisms of the onset of BRONJ, the present study focused on OS and the effects of treatment with the pro-oxidant DL-buthionine-(S,R)-sulfoximine (BSO), an oxidative stressor, on healing of a surgically induced penetrating injury of the palate. Six-week-old C57BL/6J mice were randomly divided into four groups (n=5 each) and treated with or without zoledronic acid (ZOL) and with or without BSO (experimental groups: ZOL, BSO, and ZOL+BSO; control group: saline solution). A penetrating injury of the midline palate was surgically created using a root elevator. ZOL (250 µg/kg/day) was injected intraperitoneally every day from 7 days prior to the surgical treatment to 4 days following the surgical treatment. BSO (500 µg/kg/day) was administered 7 days prior to the surgical treatment as a single intraperitoneal injection. The maxillae were harvested at 5 days following the surgical treatment for histological and histochemical studies. The presence of empty osteocyte lacunae in the palatal bone was increased by ZOL and BSO treatment. The highest number of empty osteocyte lacunae was observed in the ZOL+BSO group. The number of tartrate-resistant acid phosphatase-positive cells was decreased by ZOL treatment and increased by BSO treatment. The number of canaliculi per osteocyte lacuna was significantly decreased by BSO treatment. The mineral apposition rate was significantly lower in the treatment groups than the control group. Bisphosphonates and OS suppressed bone turnover. The present study has demonstrated that BSO treatment affects osteocytes, and OS in osteocytes exacerbates impairment of the osteocytic canalicular networks. As a result, bisphosphonates and OS may induce osteonecrosis following invasive dentoalveolar surgery. OS has been identified as an additional risk factor for the development of BRONJ.

Cross-modality imaging of bisphosphonate-treated murine jawbones

“…Increased calcium and phosphorus concentrations are in line with the expectations for BIS treatment since BISs, per se, increase bone mineral density ubiquitously as they accelerate osteoclast apoptosis and inhibit bone resorption. 6,54 Zinc deficiency was shown to be associated with bone growth retardation, and an increase in zinc concentrations might be beneficial for the development, growth, and health of the bone. 55,56 (b) Our results did not indicate that the applied PBMT or ESWT influenced bone alterations considerably concerning the mechanical and elemental composition since the measured parameters of these groups did not change significantly compared to the BIS-treated positive controls that did not receive physical therapies (Fig.…”

Conditioned Medium from Bone Marrow Mesenchymal Stem Cells Restored Oxidative Stress-Related Impaired Osteogenic Differentiation

“…Other studies also found profound effects of MSC-CM in recovering osteogenic capacity in oxidative stress-related bone diseases [15,44,45]. Oxidative stress also can have a role in the development of other bone diseases, such as osteonecrosis [46]. Therefore, Ogata et al, tested the effect of MSC-CM in osteonecrosis both in vitro and in vivo using an osteonecrosis model in rat jaw [15].…”

Role of cytochrome P450 2C8 genetic polymorphism and epoxygenase uncoupling in periodontal remodelling affecting orthodontic treatment

“…Taniguchi et al had shown that bisphosphonates can trigger ROS production in human periodontal ligament cells thereby inhibiting the migration and proliferation of oral fibroblasts 4 . Tamaoka et al described increased ROS levels in long‐term treatment with bisphosphonates as risk factor for the development of ONJ due to its ability to induce apoptosis in osteoblasts and differentiation in osteoclasts 14 …”