BACKGROUND: Medication-related osteonecrosis of the Jaw (MRONJ) is a rare but severe side effect in patients treated with medications such as Bisphosphonates (BPs). Its pathophysiological mechanism needs to be more precise. Establishing preventive measures and treatment standards is necessary. This study aimed to develop a composite hydrogel scaffold constituted by methacrylated gelatin (GelMA), methacrylated heparin (HepMA) and PRF, and investigate its potential application value in the prevention of MRONJ.
METHODS: GelMA, HepMA, and PRF were prepared using specific ratios for hydrogel scaffolds. Through mechanical properties and biocompatibility analysis, the release rate of growth factors and the ability to promote bone differentiation in vitro were evaluated. To explore the healing-enhancing effects of hydrogels in vivo, the composite hydrogel scaffold was implanted to the MRONJ rat model. Micro-computed tomography (Micro-CT) and histological examination were conducted to evaluate the bone morphology and tissue regeneration.
RESULTS: The Hep/GelMA-PRF hydrogel improved the degradation rate and swelling rate. It was also used to control the release rate of growth factors effectively. In vitro, the Hep/GelMA-PRF hydrogel was biocompatible and capable of reversing the inhibitory effect of zoledronic acid (ZOL) on the osteogenic differentiation of MC3T3-E1s. In vivo, the micro-CT analysis and histological evaluation demonstrated that the Hep/GelMA-PRF group exhibited the best tissue reconstruction. Moreover, compared to the ZOL group, the expression of osteogenesis proteins, including osteocalcin (OCN), type collagen I (Col I), and bone morphogenetic protein-2 (BMP-2) in the Hep/GelMA-PRF group were all significantly upregulated (P < 0.05).
CONCLUSIONS: The Hep/GelMA-PRF hydrogel scaffold could effectively control the release rate of growth factors, induce osteogenic differentiation, reduce inflammation, and keep a stable microenvironment for tissue repair. It has potential application value in the prevention of MRONJ.

UNASSIGNED: Medication-related osteonecrosis of the Jaw (MRONJ) is an adverse drug reaction that affects the mandible and maxilla of patients exposed to BMA and AA therapies, causing the progressive destruction and death of bone. To date, oral health preventive measures remain the most effective strategy to reduce MRONJ incidence, and, in this sense, the major goal is to diagnose, treat, and eradicate any oral diseases that could compromise oral health. The present systematic review aims to investigate the awareness of MRONJ among patients assuming BMAs.
UNASSIGNED: A systematic literature search was performed, selecting studies that concern the awareness of patients of the risk of MRONJ.
UNASSIGNED: Six studies were included in this review. In total, 483 patients were evaluated. Of the 483 included patients, 391 were not aware of the possibility of MRONJ onset (391/483, 81%) and 92 were aware of it (92/483, 19%).
UNASSIGNED: The problem of patient\'s lack of awareness with respect to MRONJ risk presents different layers of complexity (\"what?\", \"who?\", \"where?\", \"when?\" and \"why?\"). Among its causal factors, there are an inadequate level of communication with patients and the lack of collaboration between healthcare professionals, which is related to an individualistic view of liability and deontological duties. MRONJ is a drug adverse reaction that can greatly affect the quality of life of patients if not promptly diagnosed and treated. Therefore, patients must be fully aware of the risks of adverse and the importance of preventive measures, which imply effective and exhaustive communication by each member of the multidisciplinary team. Effective teamwork and collaborative care should be promoted to positively impact patients\' awareness.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) represents a serious health condition, impacting the lives of many patients worldwide. The condition challenges clinical care due to its complex etiology and limited therapeutic options. A thorough understanding of the pathophysiological and patient-related factors that promote disease development is essential. Recently, the oral microbiome has been implicated as a potential driver and modulating factor of BRONJ by several studies. Modern genomic sequencing methods have provided a wealth of data on the microbial composition of BRONJ lesions; however, the role of individual species in the process of disease development remains elusive. A comprehensive PubMed search was conducted to identify relevant studies on the microbiome of BRONJ patients using the terms \"microbiome\", \"osteonecrosis of the jaws\", and \"bisphosphonates\". Studies focusing on symptoms, epidemiology, pathophysiology, risk factors, and treatment options were included. The principal risk factors for BRONJ are tooth extraction, surgical procedures, and the administration of high doses of bisphosphonates. Importantly, the oral microbiome plays a significant role in the progression of the disease. Several studies have identified alterations of microbial composition in BRONJ lesions. However, there is no consensus regarding bacterial species that are associated with BRONJ across studies. The bacterial genera typically found include Actinomyces, Fusobacterium, and Streptococcus. It is postulated that these microbes contribute to the pathogenesis of BRONJ by promoting inflammation and disrupting normal bone remodeling processes. Current therapeutic approaches are disease-stage-specific and the necessity for more effective treatment strategies remains. This review examines the potential causes of and therapeutic approaches to BRONJ, highlighting the link between microbial colonization and BRONJ development. Future research should seek to more thoroughly investigate the interactions between bisphosphonates, the oral microbiome, and the immune system in order to develop targeted therapies.

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Bone-modifying agents (BMAs) are integral to managing patients with advanced cancer. They improve quality of survival by reducing skeletal-related events, treating hypercalcaemia and chemotherapy-induced bone loss (Coleman in Clin Cancer Res 12: 6243s-6249s, 2006), (Coleman in Ann Oncol 31: 1650-1663, 2020). Two decades ago, medication-related osteonecrosis of the jaw (MRONJ) was first reported following BMA therapy (Marx in J Oral Maxillofac Surg 61: 1115-1117, 2003). The risk of MRONJ extends over a decade following BMA treatment with bisphosphonates, complicating dental care such as extractions. In addition, MRONJ has been reported following additional therapies such as antiangiogenic agents, cytotoxic agents, immunotherapy, and targeted agents. The use of BMAs in the curative and adjuvant cancer setting is increasing, consequently the implication of MRONJ is growing. Over the past 20 years, the literature has consolidated major risk factors for MRONJ, the pathophysiology and management strategies for MRONJ. Our review aims to document the development of MRONJ preventative and management strategies in cancer patients receiving a BMA. The authors advocate the incorporation of dental oncology strategies into contemporary cancer care, to optimise long-term quality of survival after cancer treatment.

OBJECTIVE: A MASCC/ISOO Clinical Practice Statement (CPS) is aimed at generating a concise tool for clinicians that concentrates practical information needed for the management of oral complications of cancer patients. This CPS raises awareness to the prevention of medication-related osteonecrosis of the jaw (MRONJ) in patients with breast cancer treated with adjuvant bone-modifying agents (BMA).
METHODS: This CPS was developed based on a critical evaluation of the literature followed by a structured discussion of a group of leading experts, members of the Oral Care Study Group of MASCC/ISOO. The information is presented in the form of succinct bullets and tables to generate a short manual about the best standard of care.
RESULTS: In patients treated with adjuvant BMA, dento-alveolar surgery poses a moderate risk for MRONJ that ranges between the high risk for MRONJ in patients with metastatic breast cancer and the low risk for MRONJ in patients with osteoporosis. Existing MRONJ guidelines serve as a starting point for adjuvant BMA use. Urgent procedures should be delivered without delay using the accepted precautions to prevent MRONJ. If elective surgery is considered, the individual risk for MRONJ following surgery should be assessed according to common risk factors.
CONCLUSIONS: Prevention of MRONJ in primary breast cancer patients treated with adjuvant BMA requires risk-benefit assessment; collaboration between the medical team, dental professional, and patient; and patient-specific tailored dental treatment planning. The patient should be informed about this risk. Additional research is needed to define optimal MRONJ care for this population.

Surgical intervention for medication-related jaw osteonecrosis (MRONJ) is currently the main treatment method, offering a higher healing rate than conservative approaches. However, the management of bony defects after sequestrectomy remains a challenging issue due to poor vascularization from the drug effect. The use of pedicled buccal fat pad (PBFP) for filling bone defects has become common and effective but is limited to the posterior maxillary region. To add to the advantages of the buccal fat pad, we explored a novel treatment approach using a free buccal fat pad (FBFP) to fill bone defects other than the posterior maxilla. While the FBFP has been employed in oral defect reconstruction, currently published cases have been utilized in recipient sites with good blood supply. There has yet to be any usage in poor vascularization defects like MRONJ. This article describes that the FBFP was used to fill the surgical defects of 8 patients who were diagnosed with MRONJ and who underwent sequestrectomy and saucerization. During follow-up visits, there was excellent wound healing and no significant tissue depression. Based on successful treatment experiences, FBFP is a reliable therapeutic option for the management of poor vascularization defects like MRONJ treated through surgical intervention.

BACKGROUND Bisphosphonates and anti-receptor activator of nuclear factor kappa B antibodies are used to treat bone diseases associated with increased osteoclast activity, including myeloma. However, they can cause osteonecrosis of the jaw, known as medication-related osteonecrosis of the jaw. This report presents a case of a patient with a history of myeloma who required posterior maxilla resection for bisphosphonate-related osteonecrosis of the jaw, in which preoperative embolization prevented unexpected bleeding related to vascular injury and allowed for a safe procedure with minimal bleeding. CASE REPORT An 84-year-old man presented to our department with a 3-year history of purulent drainage and bone exposure in the right maxilla. Based on the clinical findings at the initial visit, the clinical diagnosis was bisphosphonate-related osteonecrosis of the jaw, and the patient underwent a partial right maxillary osteotomy. This surgery was associated with a risk of unexpected bleeding from a branch of the maxillary artery during the posterior maxilla resection. A catheter-based embolization of the maxillary artery was performed the day before performing a partial maxillectomy to avoid unexpected bleeding risk. Thus, no abnormal bleeding occurred during partial maxillectomy, and no postoperative complications occurred for 3 years. CONCLUSIONS In the surgical treatment of medication-related osteonecrosis of the jaw, preoperative vascular embolization of the peripheral maxillary artery beyond the middle meningeal artery bifurcation is a valuable technique for safe maxillectomy involving the posterior maxilla.

UNASSIGNED: Zoledronate (ZA) stands as a highly effective antiresorptive agent known to trigger medication-related osteonecrosis of the jaw (MRONJ). Its clinical dosages primarily encompass those used for oncologic and osteoporosis treatments. While inflammation is recognized as a potential disruptor of mucosal healing processes associated with ZA, prior research has overlooked the influence of varying ZA dosages on tissue adaptability. Therefore, a deeper understanding of the specific mechanisms by which inflammation exacerbates ZA-induced MRONJ, particularly when inflammation acts as a risk factor, remains crucial.
UNASSIGNED: Cell proliferation and migration of human oral keratinocytes (HOK) was analyzed after treatment with different doses of ZA and/or lipopolysaccharide (LPS) to assess their possible effect on mucosal healing of extraction wounds. Mouse periodontitis models were established using LPS, and histological changes in extraction wounds were observed after the administration of oncologic dose ZA. Hematoxylin and eosin (HE) staining and immunofluorescence were used to evaluate mucosal healing.
UNASSIGNED: In vitro, LPS did not exacerbate the effects of osteoporosis therapeutic dose of ZA on the proliferation and migration of HOK cells, while aggravated these with the oncologic dose of ZA treatment by inducing mitochondrial dysfunction and oxidative stress via regulating SIRT1 expression. Furthermore, SIRT1 overexpression can alleviate this process. In vivo, local injection of LPS increased the nonunion of mucous membranes in MRONJ and decreased the expression of SIRT1, PGC-1α, and MnSOD.
UNASSIGNED: Inflammation aggravates oncologic dose of ZA-induced mitochondrial dysfunction and oxidative stress via a SIRT1-dependent pathway, enhancing the risk of impaired mucosal healing in MRONJ. Our study implies that inflammation becomes a critical risk factor for MRONJ development at higher ZA concentrations. Elucidating the mechanisms of inflammation as a risk factor for mucosal non-healing in MRONJ could inform the development of SIRT1-targeted therapies.

OBJECTIVE: Use of numerous medications such as tyrosine kinase inhibitors (sunitinib), monoclonal antibodies (bevacizumab), fusion proteins (aflibercept), mTOR inhibitors (everolimus), radiopharmaceuticals (radium 223), selective estrogen receptor modulators (raloxifene), and immunosuppressants (methotrexate and corticosteroids) has been reported to be a risk factor for development of medication-related osteonecrosis of the jaws till date. This study aimed to evaluate the preventive effect of low-level laser therapy (LLLT) and gaseous ozone on the onset of MRONJ following tooth extraction.
METHODS: A total of 40 male Wistar rats were randomly allocated into 4 groups of 10 rats each. The groups laser (L), ozone (O), and control (C) received weekly intraperitoneal injections of zoledronic acid (0.06 mg/kg), while group sham (S) received saline solution for 4 weeks. After the 4th injection, all subjects underwent mandibular first molar extraction and adjunctive laser or ozone was applied according to the groups. All the rats were sacrificed at 4 postoperative weeks for comparative histomorphometric evaluation of bone healing in extraction sites.
RESULTS: Laser and ozone groups demonstrated significantly higher bone formation compared to control group (p < 0.05), while no significant difference was found between laser and ozone groups (p = 1.00). Furthermore, the greatest bone formation was observed with the sham group (p < 0.05).
CONCLUSIONS: Findings of the current study support that adjunctive LLLT and ozone therapy following tooth extraction may help prevent MRONJ and improve bone healing in subjects under zoledronic acid therapy.
CONCLUSIONS: Since the introduction in 2003, great effort has been devoted to developing a certain management protocol for MRONJ. Several publications have appeared in recent years documenting promising results of adjunctive LLLT and ozone application in treatment of MRONJ. However, experimental data are limited on this regard and the present study, for the first time, aimed to evaluate and compare the effects of LLLT and ozone in prevention of MRONJ.