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.

暂无摘要。

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.

BACKGROUND: It is well-known that oral surgical procedures pose a high risk for medication-related osteonecrosis of the jaw in patients taking bisphosphonates. Although some position papers and guidelines have been published with regard to its treatment, few studies have investigated prevention methods. This study investigates the effectiveness of methenolone enanthate, an anabolic steroid, for the prevention of medication-related osteonecrosis of the jaw.
METHODS: Thirty-six Wistar rats were divided into three groups. Two experimental groups, Z and ZM, took zoledronic acid for 6 weeks prior to extraction of the left maxillary first molar. The Group ZM also was given methenolone enanthate continuously for 1 week before and 4 weeks after the extraction. The control group was not given any medication. The rats were euthanized 5 weeks after extraction. The extraction socket was evaluated clinically for bone exposure and histologically for inflammation, hyperemia, collagen fibers, epithelialization, number of osteoclasts, and empty lacunae.
RESULTS: Six rats died during the experimental research. The bone exposure rate, mean numbers of attached osteoclasts (in 40× magnification), and empty lacunae (in 100× magnification) were 0%, 4%, and 0.8% in Group C; 75%, 1%, and 8% in Group Z; and 10%, 2.1%, and 3% in Group ZM, respectively. Significant differences exist between all groups regarding the number of empty lacunae. There were significant differences between Group C/ZM and Group Z in terms of bone exposure rate, inflammation, hyperemia, collagen fiber organization, and epithelialization.
CONCLUSIONS: In our tested preclinical model, methenolone enanthate has shown potential for preventing medication-related osteonecrosis of the jaw.

Macrophages are important regulators of bone remodeling, and M1 polarization is observed in the setting of medication-related osteonecrosis of the jaws (MRONJ). Here, we characterize the phenotype of macrophages during early stages of MRONJ development in zoledronate (ZA)-treated mice with periodontal disease and explore the role of rosiglitazone, a drug that has been reported to lower the M1/M2 macrophage ratio, in MRONJ burden. Mice received ZA, and experimental periodontal disease (EPD) was induced around their second left maxillary molar. The mice were euthanized 1, 2, or 4 wk later. Micro-computed tomography and histologic and immunohistochemical analyses were carried out. In a separate experiment, mice were treated with ZA in the absence or presence of rosiglitazone, EPD was induced for 5 wk, and the MRONJ burden was assessed. An M1 predilection was noted in ZA versus vehicle (Veh) mice at 1, 2, or 4 wk after ligature placement. M1 cells were found to be positive for MMP-13, and their presence coincided with disruption of the surrounding collagen network in ZA mice. Rosiglitazone caused a reversal in the M1/M2 polarization in Veh and ZA mice. Rosiglitazone did not cause significant radiographic changes 5 wk after EPD in Veh or ZA animals. Importantly, percentage osteonecrosis and bone exposure were decreased in the rosiglitazone-treated versus nontreated ZA sites 5 wk after EPD. Our data point to an important role of M1 macrophage polarization with an overexpression of MMP-13 in the early phases of MRONJ development and provide insight into the use of interventional approaches promoting an M2 phenotype as a preventative means to alleviate MRONJ burden.

暂无摘要。

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.

Osteonecrosis of the jaw (ONJ) is a relatively rare side effect after prolonged use of bisphosphonates, which are drugs used to treat bone resorption in osteoporosis and certain cancers. This study introduces a novel ONJ model in rats by combining exposure to bisphosphonates, oral surgery, and bacterial inoculation. Potential ONJ preventive effects of polyguanidine (GuaDex) or antibiotics were evaluated. The study consisted of twenty-four male Wistar rats were divided into four groups. Groups 1 to 3 were given weekly doses of i.v. Zoledronic acid (ZA), four weeks before and two weeks after an osteotomy procedure on their left mandibular first molar. Group 4 was a negative control. Streptococcus gordonii bacteria were introduced into the osteotomy pulp chamber and via the food for seven days. On day eight, the rats were given different treatments. Group 1 was given a GuaDex injection into the osteotomy socket, Group 2 was given an intramuscular (i.m.) injection of clindamycin, Group 3 (positive control) was given an i.m. injection of saline, and Group 4 was given an i.m. injection of saline. Blood samples were taken two weeks after the osteotomy procedure, after which the rats were euthanized. Bone healing, bone mineral density, histology, and blood status were analyzed. The results showed that Group 1 (GuaDex) had no ONJ, extensive ongoing bone regeneration, active healing activity, vascularization, and no presence of bacteria. Group 2 (clindamycin) showed early stages of ONJ, avascular areas, and bacteria. Group 3 showed stages of ONJ, inflammatory infiltrates, defective healing, and bacterial presence, and Group 4 had normal healing activity and no bacterial presence. Conclusion: ZA treatment and bacterial inoculation after tooth extraction inhibited bone remodeling/healing and induced ONJ characteristic lesions in the rats. Only GuaDex apparently prevented ONJ development, stimulated bone remodeling, and provided an antimicrobial effect.

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.