Medication-related Osteonecrosis Of The Jaw Research Articles

A retrospective study on odontogenic and non-odontogenic medication-related osteonecrosis of the jaw: Potential differences in clinical features and treatment outcomes

Background/purposeLocal infections, such as periodontal disease or apical lesions, and invasive dental procedures, such as tooth extraction, are thought to trigger medication-related osteonecrosis of the jaw (MRONJ) development. However, some cases of MRONJ develop without any obvious odontogenic triggers. We conducted a retrospective study to clarify the characteristics of non-odontogenic MRONJ. Materials and methodsWe retrospectively reviewed data of 229 patients with mandibular MRONJ who underwent surgery. Based on imaging findings, we classified MRONJ as odontogenic MRONJ involving a dental infection and non-odontogenic MRONJ with no dental involvement. Clinical and imaging findings and treatment outcomes of both types of MRONJ were compared. ResultsOverall, 193 patients were classified as having odontogenic MRONJ and 36 as having non-odontogenic MRONJ. Non-odontogenic MRONJ was slightly more common among patients with malignancies who received denosumab; however, the difference was not significant. Univariate and multivariate analyses showed that patients with MRONJ with non-odontogenic triggers had significantly poorer treatment outcomes than their counterparts. ConclusionNon-odontogenic MRONJ exists without the involvement of odontogenic infection as a cause of MRONJ. Compared with that in odontogenic MRONJ, the treatment outcome in non-odontogenic MRONJ is poor. Further studies are required to clarify the true nature of non-odontogenic MRONJ.

Prediction of Medication-Related Osteonecrosis of the Jaw (MRONJ) in Patients Receiving Anti-resorptive Therapy Using Machine Learning Models

BackgroundMedication-related osteonecrosis of the jaw (MRONJ) is a serious complication associated with the use of antiresorptive agents, impacting patient quality of life and treatment outcomes. Predictive modeling may aid in a better understanding of MRONJ development. PurposeThe study aimed to evaluate machine learning (ML)-based models for predicting MRONJ in patients receiving antiresorptive therapy.Study Design, Setting, Sample: This retrospective in silico study analyzed electronic medical records from Thammasat University Hospital, covering the period from January 2012 to December 2022. The sample included subjects receiving antiresorptive therapy, excluding those with a history of radiation therapy or metastatic jaw disease. Predictor VariablesThe primary predictor variable was the predicted probability of MRONJ development from the ML models. Outcome VariablesThe outcome variable was MRONJ status coded as present or absent based on chart review. CovariatesCovariates included demographic data, MRONJ occurrence, location and staging of MRONJ, comorbidities, diseases related to antiresorptive agents, types of antiresorptive agents, therapy duration, concurrent medications, blood calcium levels, and dental factors. AnalysesModel performance was assessed via accuracy, sensitivity, specificity, positive and negative predictive values, and the area under the receiver operating characteristic curve (AUROC). Additionally, univariate and multivariate Cox regression analyses were conducted to identify factors significantly associated with MRONJ development. P ≤ 0.05 was statistically significant. ResultsThe study analyzed data from 5,305 subjects with a mean age of 75 ± 11.1 years, predominantly female. MRONJ was observed in 81 cases (1.5%), with a median time to development of 33 months (IQR = 3). Among the six models tested, the best-performing model had an accuracy of 0.95 and an AUROC of 0.89–0.90. Significant predictors identified through Cox regression included metabolic syndrome (HR = 14.064, 95% CI = 1.111–178.067, P = 0.041) and patients receiving intravenous pamidronate (HR = 5.932, 95% CI = 1.755–20.051, P = 0.004), indicating their strong association with MRONJ development. Conclusions and RelevanceML-based predictive and time-to-event models effectively predict MRONJ risk, aiding in the strategic prevention and management for patients undergoing antiresorptive therapy.

Local Single-Dose Teriparatide Administration for BRONJ Prevention: Insights from a Rat Model Study.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) presents significant clinical challenges with uncertain treatment outcomes. Teriparatide, a fragment of human parathyroid hormone, shows potential in prevention strategies for BRONJ. This study investigates the impact of a single local dose of teriparatide on BRONJ prevention in an animal model. BRONJ was induced on 26 male Wistar rats via intraperitoneal injections of 0.06mg/kg Zoledronic acid weekly for four weeks. Following tooth extraction under general anesthesia, rats were divided into two groups: one received teriparatide via Gelatamp in the tooth socket and the other as a local injection in the vestibule. Control groups received the treatment without teriparatide. Histopathological assessments for bone remodeling, osteoclast number, inflammation, angiogenesis, and necrosis were performed after four weeks. Histopathological analysis indicated a significant improvement in bone remodeling and new bone formation in both treatment groups compared to controls, with notably better outcomes in the injection group (p = 0.01). Necrosis in the Gelatamp group was significantly higher in the control group than in the treatment group (p = 0.01), and bone formation was significantly higher in the injection group compared to the Gelatamp group (p = 0.03). Local administration of teriparatide significantly enhances bone remodeling and reduces necrosis, suggesting a potential role in the prevention of BRONJ. These findings support further clinical investigation into teriparatide as a preventive strategy against BRONJ.

Insights into Medication-Induced Osteonecrosis of the Jaw Through the Application of Salivary Proteomics and Bioinformatics.

Long-term treatment with bisphosphonates is accompanied by an increased risk of medication-related osteonecrosis of the jaw (MRONJ). Currently, no clinically useful biomarkers for the predictive diagnosis of MRONJ are available. To investigate the potential key proteins involved in the pathogenesis of MRONJ, a proteomic LC-MS/MS analysis of saliva was performed. Differentially expressed proteins (DEPs) were analyzed using BiNGO, ClueGO, cytoHubba, MCODE, KEGG, and ReactomeFI software packages using Cytoscape platforms. In total, 1545 DEPs were identified, including 43 up- and 11 down-regulated with a 1.5-fold cut-off value and adj. p-value < 0.05. The analysis provided a panel of hub genes, including APOA2, APOB, APOC2, APOC3, APOE, APOM, C4B, C4BPA, C9, FGG, GC, HP, HRG, LPA, SAA2-SAA4, and SERPIND1. The most prevalent terms in GO of the biological process were macromolecular complex remodeling, protein-lipid complex remodeling, and plasma lipoprotein particle remodeling. DEPs were mainly involved in signaling pathways associated with lipoproteins, the innate immune system, complement, and coagulation cascades. The current investigation advanced our knowledge of the molecular mechanisms underlying MRONJ. In particular, the research identified the principal salivary proteins that are implicated in the onset and progression of this condition.

Knowledge Level of Physicians Prescribing Bisphosphonates: Prevention and Treatment of Medication-Related Osteonecrosis of the Jaw

Introduction: Medication-related osteonecrosis of the jaw (MRONJ) is an important uncommon complication. Due to its complexity, its prevention requires a multidisciplinary approach, involving physicians and dental clinicians. Materials and Methods: This study aimed to assess the knowledge level of physicians prescribing bisphosphonates in Tehran, Iran, about dental considerations in such patients and the prevention and treatment of MRONJ in 2019. This descriptive, cross-sectional study evaluated 100 physicians (rheumatologists, endocrinologists, oncologists, and orthopedists) practicing in Tehran. A questionnaire comprising a demographic section and knowledge questions regarding dental considerations in patients taking bisphosphonates was administered among the physicians. The frequency of qualitative variables such as gender, type of specialty, and physicians’ responses to each question was calculated, and the knowledge scores were analyzed separately based on the physicians’ specialty types using one-way ANOVA followed by Tukey’s test for pairwise comparisons. The effect of different variables on knowledge scores was analyzed by simple regression. Results: The mean knowledge score of physicians was 5.19±1.78 (range 2-8). The mean knowledge score of oncologists was significantly higher than that of endocrinologists (5.88 versus 4.52, P=0.03). No other significant differences were noted. Work experience (P=0.04), age (P=0.02), orthopedics specialty (P=0.05), and oncology specialty (P=0.006) had significant effects on the knowledge score. Conclusion: Considering acquiring about 50% of the total score, physicians seem to have limited knowledge about dental considerations in patients taking bisphosphonates.

Preliminary Analysis of Incidence, Risk Factors, and Management of Medication-Related Osteonecrosis of the Jaw in Cancer Patients

BackgroundMedication-related osteonecrosis of the jaw (MRONJ) is a severe complication associated with antiresorptive and antiangiogenic therapies commonly used to manage bone metastasis and improve bone density in cancer patients. This study aimed to investigate MRONJ's incidence, risk factors, and outcomes of MRONJ in patients receiving these therapies. MethodsA retrospective cohort study was conducted involving 98 patients who had received antiresorptive or antiangiogenic medications for at least one year. Data were collected from the electronic health records, focusing on demographics, medication details, comorbidities, dental history, and MRONJ status. Logistic regression analysis was used to identify predictors of MRONJ, and Kaplan-Meier survival analysis was used to assess treatment outcomes, comparing surgical and conservative management approaches. ResultsThe incidence of MRONJ was 21.4% among the study cohort. Logistic regression identified prolonged medication duration (odds ratio [OR] =2.5; p=0.01), comorbidities (OR=3.2; p=0.003), and prior dental procedures (OR=2.1; p=0.02) as significant predictors of MRONJ. Kaplan-Meier analysis showed that surgical intervention resulted in longer survival (median 24.5 Â months) than conservative management (median 12.8 months; p<0.01). Despite the high rates of healing (71.4%) and pain management success (85.7%), a recurrence rate of 23.8% indicated MRONJ’s chronic nature of MRONJ. ConclusionThis study underscores the importance of early identification and interdisciplinary management of MRONJ risk factors, particularly in patients with prolonged antiresorptive or antiangiogenic therapy. Surgical intervention appears beneficial; however, high recurrence rates emphasize the need for vigilant monitoring and patient-specific treatment strategies.

Major considerations of maxillary/mandible osteonecrosis caused by bisphosphonates in the dental implant scenario: a systematic review

Introduction: The literature has shown that several patients with a history of bisphosphonate treatment appear to be at risk for medication-related osteonecrosis of the jaw (MRONJ) osteonecrosis of the jaw. Objective: It was analyzing the use of BP associated with dentistry. Because it is a possible alternative for the reduction of loss and increase in bone density, as well as for the possibility of osteonecrosis, which requires therapeutic and preventive measures in the involvement of invasive practices such as dental implants. Methods: The PRISMA Platform systematic review rules were followed. The search was carried out from April to June 2024 in the Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: 85 articles were founded, and 54 articles were evaluated and 30 were included in this systematic review. Considering the Cochrane tool for risk of bias, the global assessment resulted in 24 studies with a high risk of bias and 18 studies that did not meet GRADE and AMSTAR-2. Most studies showed homogeneity in their results, with X2 =81.9% &gt;50%. It was concluded that osteoporosis is a metabolic condition that affects alveolar bone density, but does not present problems for the installation of osseointegrated implants, as long as there is sufficient bone mass in the region where the tooth will be implanted. It suggests to the dental surgeons the knowledge of the diagnosis so that it makes a careful evaluation, directing the professional to observe the quality of the bone through routine image examinations. Further, alendronate sodium is used to decrease bone resorption, the drug should be considered as an adjunctive therapeutic agent for the treatment of osteoporosis.

Evaluation of the Awareness and Knowledge Levels of Dentists Regarding Bisphosphonates and Bisphosphonate-Related Jaw Necrosis

Bisphosphonates are used in the treatment of osteoporosis, bone metastases, and metabolic bone diseases. Long-term use of bisphosphonates increases the risk of osteonecrosis in patients undergoing dental surgery. This study aimed to evaluate dentists’ knowledge about bisphosphonates and bisphosphonate-related osteonecrosis of the jaw (BRONJ) and their treatment approaches in patients using oral and intravenous bisphosphonates. In this study, a 25-question questionnaire was applied to dentists working in different institutions regarding their knowledge and experience about bisphosphonates and BRONJ, and treatment approaches for different surgical procedures in patients using bisphosphonates. The obtained data were statistically analyzed and evaluated. In total, 90.5% of the dentists identified osteoporosis, 79.8% identified bone metastases, 52.4% identified osteitis deformans, and 39.3% identified multiple myeloma as conditions in which bisphosphonates are used, thus answering correctly in a significant proportion. When participants were asked about treatment options according to the stages of BRONJ, participation in the “I’m not sure” option increased as the stages progressed, indicating that dentists were not sufficiently familiar with the treatments for different stages of BRONJ. In total, 88.5% of the participants stated that when they see an exposed bone area in patients they examine, they consider bisphosphonate use as a possible cause. There was a statistically significant difference between dentists with and without prior BRONJ experience regarding their ages (P=0.039) and years of practice (P=0.001). There was a statistically significant difference between dentists with and without BRONJ experience regarding whether they inquired about bisphosphonate use (P=0.001). It was found that dentists have serious deficiencies in knowledge regarding bisphosphonates, their side effects, and treatment approaches for patients using bisphosphonates. Increasing dentists’ knowledge and awareness of this issue would help reduce the risk of developing BRONJ.

Comparison of the Effects of Four Laser Wavelengths on Medication-Related Osteonecrosis of the Jaw (MRONJ) in a Murine Model: An In Vivo Photobiomodulation Study.

Background: This study aims to investigate the effectiveness of lasers at various wavelengths in treating medication-related osteonecrosis of the jaw (MRONJ) using biochemical, clinical scoring, micro CT analysis, and histopathological methods. The study follows the ARRIVE guidelines to ensure robust and transparent research. Methods: In our study, there were 6 groups, including one SHAM group, one CONTROL group, and four experimental groups, with 8 rats in each individual group. Each rat received antiresorptive drug intraperitoneally for 4 weeks and then had the left second molar in the mandible extracted. All animals were sacrificed at the end of the 12th week. In the experimental groups, lasers at wavelengths of 405nm, 445nm, 660nm, and 808nm were applied to the animals. Parameters such as serum vitamin D levels, bone density and bone volume at the extraction site, new bone formation, dead bone count, inflammatory cell count, and epithelial regeneration were examined. Additionally, clinical scoring was conducted after sacrifice. The laser parameters included power density, area, time, fluence, and mode (continuous wave), and the light was administered using a fiber with a Gaussian profile. Statistical analyses were performed with the NCSS (Number Cruncher Statistical System) 2007 Statistical Software (Utah, USA) package program. The results were evaluated at the p<0.05 significance level. Results: According to the results obtained from our study, new bone formation in all experimental groups was significantly higher than in the SHAM and CONTROL groups. Furthermore, the 660nm and 808nm wavelengths increased serum vitamin D levels significantly. The most successful outcomes were observed in clinical scoring, dead bone count, epithelial cell regeneration, and bone density in the 660nm and 808nm wavelength groups. Conclusions: The combined use of lasers at 660nm and 808nm wavelengths may yield successful results in treating MRONJ.

Retrospective analysis of medication-related osteonecrosis of the jaw at a maxillofacial prosthetics clinic

Purpose: Medication-related osteonecrosis of the jaw (MRONJ) poses significant challenges in patient care because of its complex etiology, clinical manifestations, and management. This study aims to provide an overview of patients with MRONJ treated at our clinic over the past 12 years, highlighting incidence, clinical characteristics, and prosthetic treatment outcomes. Materials and Methods: The study included patients with MRONJ who visited our clinic between January 2012 and April 2024. Data on demographic characteristics, lesion location, clinical presentation, primary diseases, prosthetic management and medications were collected from health records. Results: This retrospective analysis of cases of MRONJ over 12 years at a maxillofacial prosthetics clinic reveals a rising prevalence of the condition, particularly in the elderly, with treatments for breast and prostate cancer emerging as prominent risk factors. Distinct medication-specific effects on distribution of lesions suggest variation in pathogenic mechanisms, which require tailored treatment strategies. Management strategies encompass a spectrum of interventions from conservative measures to prosthetic rehabilitation, highlighting the importance of interdisciplinary collaboration and personalized care. Conclusion: The rising incidence of MRONJ, especially among elderly patients, indicates the need for enhanced preventive measures and interdisciplinary care. Breast and prostate cancer treatments are significant risk factors, necessitating tailored monitoring. Effective prosthetic management is crucial for improving oral function and quality of life in MRONJ patients.

The effect of cold atmospheric plasma on viability of osteoblasts and expression of RANKL and OPG genes in medium with bisphosphonates.

Medication-related osteonecrosis of the jaw is a rare but severe complication with challenging treatment protocols. Cold atmospheric plasma (CAP) has shown promising effects in wound healing, cell proliferation and viability. This study investigated the effect of CAP on osteoblasts in a culture medium containing bisphosphonates. Pilot study was designed to determine the optimal setting of CAP. MG-63 cells were exposed to zoledronic acid at a concentration of 10 micromolar for 72h. Study groups with the best MTT assay results, were chosen for assessing OPG and RANKL genes by RT-PCR. Cell viability was significantly higher in groups 9kV.1mm.90s, 10kV.1mm.60s, and 12kV.1mm.60s (P < 0.05). Expression of RANKL in these groups was significantly lower than the positive control group (medium culture without zoledronic and plasma treatment) and higher than the BP group (culture with zoledronic without plasma treatment), except for the 12kV.1mm.60s group, which did not differ significantly from the positive control group (P > 0.05). OPG decreased in all test groups compared to BP (p < 0.05), except for the 12kV.1mm.60s group, which did not significantly differ from BP (P > 0.05). RANKL/OPG ratio in groups 9kV.1mm.90s and 12kV.1mm.60s significantly increased compared to BP (P < 0.05).CAP treatment may enhance the viability of osteoblasts exposed to bisphosphonates, increase their activity levels, enhance osteoclast activity, and improve bone turnover rates.

Clinical and Radiographic Features of Peri-Implant Medication-Related Osteonecrosis of the Jaw: ARetrospective Study.

This study aimed to analyze the factors affecting the occurrence of peri-implant medication-related osteonecrosis of the jaw (PI-MRONJ) in patients using anti-resorptive drugs (ARDs) on different implant position, inclinations, and types of prosthesis. The data of 75 patients with bone necrosis that progressed around the implant between 2018 and 2022 were retrospectively examined to identify the factors influencing PI-MRONJ. Data, including patient demographics (age, sex, smoking status, concomitant disease, time of ARD therapy, dose of ARDs, and parafunctional habits) and implant-specific information (type of prosthesis, angle of insertion), were extracted from medical and dental records. Tilted implants with an angle ≥ 5.1° relative to the occlusal plane of the prosthesis had a stronger association with PI-MRONJ in comparison to non-tilted implants (inclination was < 5°). Additionally, the boundary of the area of osteonecrosis around the fixture was larger for the splinted implant-supported crowns than for the single implant supported crowns). In patients taking anti-resorptive medications the inclination of the implant was associated with the occurrence of PI-MRONJ. Further studies are required to confirm the clinical findings.

High-dose denosumab (Xgeva®) Associated Medication-Related Osteonecrosis of the Jaws (MRONJ): incidence and clinical characteristics in a retrospective analysis of 1278 patients.

High-dose denosumab (Xgeva®) is increasingly used for treating bone metastasis and various malignant diseases but carries the risk of medication-related osteonecrosis of the jaw (MRONJ). This study aimed to evaluate the incidence, risk factors, and clinical outcomes of MRONJ in patients treated with high-dose denosumab. A retrospective review was performed on 1278 patients who received high-dose denosumab at Severance Hospital, Seoul, South Korea, from September 2014 to February 2023. Data on the incidence of MRONJ, patient demographics, primary diseases, and treatment outcomes were analyzed. Among the 1278 patients (average age 64.72years; 728 males and 550 females) treated, 34 developed MRONJ, with a 2.66% incidence rate. The average age of those with MRONJ was 68.32years, and they received more Xgeva® injections on average (13.62) compared to the overall cohort. Factors such as age and the frequency of injections were significantly associated with the risk of MRONJ. Notably, the incidence of MRONJ did not significantly differ between those who underwent oral surgery and those with spontaneous MRONJ, especially if oral surgery occurred within 1month of injection. Surgical interventions have shown higher recovery rates in advanced MRONJ stages. This study confirmed a significant MRONJ incidence of 2.66% among high-dose denosumab recipients, highlighting the importance of careful patient selection, monitoring, and education, particularly in older and long-term treatment patients, to mitigate the risk of MRONJ.

Extracellular vesicles from mouse bone marrow macrophages-derived osteoclasts treated with zoledronic acid contain miR-146a-5p and miR-322-3p, which inhibit osteoclast function

Medication-related osteonecrosis of the jaw (MRONJ) is an intractable form of osteonecrosis of the jaw that rarely occurs in patients using bone resorption inhibitors such as bisphosphonates (BPs). Then, extracellular vesicles (EVs) carry various signaling molecules, such as mRNAs, microRNAs (miRNAs), and proteins, and have attracted attention as intercellular communication tools. Recently, the role of EVs in communication between osteoclasts and surrounding bone cells has been confirmed. This study aimed to elucidate the effects of EVs derived from osteoclasts treated with zoledronic acid (ZA), one of the BPs on osteoclast function. EVs were isolated by ultracentrifugation of the culture supernatant of osteoclasts treated with ZA, and miRNAs were extracted from these EVs. Tartrate-resistant acid phosphatase staining of the ZA treated osteoclasts showed reduced osteoclastogenesis. In addition, pit assay showed that ZA significantly decreased the bone resorption capacity of osteoclasts. miRNA-seq analysis identified 11 upregulated and 5 downregulated differentially expressed genes (DEGs) in the miRNA of EVs derived from ZA-treated osteoclasts compared to EVs derived from osteoclasts not treated with ZA. qRT-PCR analysis confirmed the amount of these specific miRNAs, with miR-146a-5p, and miR-322-3p being significantly upregulated by ZA. Overexpression of miR-146a-5p in osteoclasts inhibited osteoclastogenesis and decreased the mRNA expression of osteoclast markers. In addition, Traf6 was identified as a candidate target gene of miR-146a-5p in several miRNA databases. Indeed, the overexpression of miR-146a-5p decreased the expression level of Traf6 in osteoclasts. Additionally, overexpression of miR-322-3p in the pre-osteoblast, MC3T3-E1 cells, resulted in a significant increase in the mRNA expression levels of Sp7. Our data indicate that BPs attenuate osteoclastogenesis by simultaneously altering the characteristics of osteoclast-derived EVs. Overexpression of miR-146a-5p and miR-322-3p influences osteoclast differentiation, and Traf6 is a target gene of miR-146a-5p. On the other hand, Overexpression of miR-322-3p affects osteoblast differentiation. We suggest that ZA-treated osteoclast-derived EVs may play an important role in osteoclast function and bone resorption.

Zoledronate interrupts pre-osteoclast-induced angiogenesis via SDF-1/CXCR4 pathway

IntroductionIn this study, we tested the hypothesis that pre-osteoclast signaling is key in triggering post-traumatic angiogenesis in alveolar bone via the SDF-1/CXCR4 pathway. Interruption of osteoclast differentiation through zoledronate (Zol) disrupts the crosstalk between pre-osteoclasts and endothelial cells, hindering the initial angiogenic reaction following dental trauma. This disruption could therefore play a role in the pathogenesis of medication-related osteonecrosis of the jaw (MRONJ). MethodsThe effect of zoledronate on the expression of SDF1 was tested in pre-osteoclasts (POC) in vitro. Then, we tested the effect of pre-osteoclast conditioned medium on HUVEC cell differentiation, migration, tube-formation, and CXCR4 expression and activity in-vitro. Lastly, we quantified the effect of zoledronate treatment on post-traumatic vascular perfusion of alveolar bone, using microCT-angiography and immunohistochemistry. ResultsSDF-1 mRNA expression decreased in Zol-treated POCs (p = 0.02). Flow-Cytometry analysis showed a decrease in CXCL-12+ (SDF-1α) expressing POCs with Zol treatment (p = 0.0058). On the other hand, CXCR4 mRNA expression was significantly inhibited in Zol-treated HUVECs (p = 0.0063). CXCR4 protein expression and activity showed a corresponding dose-dependent downregulation HUVEC surface treated with conditioned media from POC treated with Zol (p = 0.008 and 0.03, respectively). Similar inhibition was observed of HUVEC migration (p = 0.0012), and tube formation (p < 0.0001), effects that were reversed with SDF-1. Finally, there was a significant reduction of CD31+ HUVECs in Alveolar bone of Zol-treated rats (p = 0.0071), confirmed by significantly lower percentage of blood vessel volume (p = 0.026), and marginally lower vessel number (p = 0.062) in the alveolar bone. ConclusionPre-osteoclasts play a crucial role in the initial angiogenic response in alveolar bone following dental extraction. Disruption of this process may be a predisposing factor to osteonecrosis.

Exosomes from Adipose-Derived Mesenchymal Stromal Cells Prevent Medication-Related Osteonecrosis of the Jaw by Inhibiting Macrophage M1 Polarization and Pyroptosis.

Exosomes from mesenchymal stromal cells (MSCs) can prevent the development of medication-related osteonecrosis of the jaw (MRONJ) by promoting tooth socket wound healing; however, the exact mechanism remains to be clarified. In this study, our aim was to explore the mechanisms of exosomes derived from adipose-derived mesenchymal stromal cells (ADSCs) in preventing MRONJ by focusing on macrophage M1 polarization and pyroptosis. The MRONJ model was established by theadministration of zoledronate and tooth extraction. Exosomes isolated from the supernatant of ADSCs were mixed with hydrogel and locally injected into the extraction site after tooth extraction. Stereoscope observations, micro computed tomography (microCT), and histological analysis were used to assess tooth socket wound healing. The results showed that exosomes could effectively avoid MRONJ via accelerating gingival wound healing and tooth socket bone regeneration. Mechanistically, zoledronate triggered the NF-κB signaling pathway and promoted p65 transferring into the nucleus in macrophages, resulting in macrophage M1 polarization and pyroptosis-mediated tissue inflammation, while exosomes could reduce macrophage pyroptosis and pro-inflammation cytokines release by suppressing the NF-κB/NLRP3/IL-1β axis. Additionally, IL-1RA derived from exosomes plays a key role in preventing MRONJ. Pyroptosis-related and inflammatory-related processes were upregulated in MRONJ patients further confirmed by assessing MRONJ gingival samples and healthy gingival tissues. ADSCs-derived exosomes could effectively promote tooth socket healing and prevent MRONJ by inhibiting M1 macrophage activation and pyroptosis by blocking the NF-κB/NLRP3/IL-1β axis.

Innovative Use of Limberg Flap for MRONJ Reconstruction.

Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication associated with bisphosphonate therapy, characterized by necrotic bone exposure in the maxillofacial region. This case report details the surgical management of a 68-year-old female patient with a history of cancer and bisphosphonate-related osteonecrosis. After the initial sequestrectomy, the patient developed a purulent discharge, necessitating soft tissue reconstruction using a Limberg flap. The surgical procedure involved meticulous debridement and flap placement, resulting in successful healing and resolution of symptoms. This case highlights the importance of tailored management strategies for MRONJ and the potential benefits of the Limberg flap in reconstructive surgery, addressing a notable gap in the literature regarding its application in this context.

Does an Osteoporosis-like Condition Jeopardize the Osseointegration Process around Dental Implants Placed in Animal Models? A Systematic Review.

Knowing that osteoporosis is a metabolic disease that could decrease dental implant success and survival, the purpose of this review was to gather information on the characteristics of implant osseointegration in animal models of induced osteoporosis. By pointing out the role of some factors that could improve the success rate in these situations, this study aimed to enhance the knowledge about this process that can be further translated to clinical designs. A systematic search in PubMed/Medline, Lilacs, Cochrane Library, Scopus and Web of Science was conducted to identify information between 2002 and 2023 regarding osseointegration of dental implants in animal models of induced osteoporosis. The following search strategy was utilized and adjusted to each database: (((dental implant) AND (Osseointegration)) AND (osteoporosis)) AND/OR (osteoporosis treatment). The inclusion criteria were animal studies in English, involving the placement of an osseointegrated implant in osteoporotic bone, and evaluating bone to implant contact (BIC) %. Exclusion criteria were studies in humans, in vitro studies, procedures involving any kind of bone graft and studies evaluating medication related osteonecrosis of the jaw. A standardized data extraction form was used to record data for each study, covering article title, date, authors, number of animals, purpose of study, type of analysis used by authors, follow-up, type of implant, test and control groups, intervention and conclusions. The risk of bias of the included studies was assessed using the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) Risk of Bias tool.20 Results: A total of 204 articles were found for evaluation and selection. All of the 43 selected studies evaluated the bone-implant contact (BIC) %. Other parameters such as bone to implant mechanical interface, bone area (BA) and bone volume (BV) ratio were also evaluated in some of the studies. There was a tendency for compromised results of implant osseointegration in the presence of osteoporosis. Modification of the implant surface, systemic and local use of anti-resorptive drugs and other substances, showed benefits for the implant success in osteoporotic sites. Still, no consensus among studies on the superiority of systemic medications in improving the process of peri-implant bone repair, was observed. Although it is possible to improve the osseointegration of implants in osteoporotic bone, either by using systemic or local factors, the metabolic bone syndrome caused by osteoporosis can jeopardize the osseointegration of dental implants.

Reporting MRONJ as an adverse drug reaction: an oral surgery survey.

Introduction Medication-related osteonecrosis of the jaw (MRONJ) is a significant adverse drug reaction associated with anti-angiogenic and anti-resorptive medications. The aim of this survey was to highlight the importance of reporting adverse drug reactions, including MRONJ.Methodology An electronic survey was disseminated to dentists working in the oral surgery department Birmingham Community Healthcare Trust in November 2021. The survey consisted of 14 open and closed questions relating to the identification and reporting of MRONJ as an adverse drug reaction.Results Although 97% of participants had seen a patient with MRONJ, only 19% had reported an adverse drug reaction to any medication. Interestingly, 27% of respondents felt that MRONJ should be classified as a 'post-operative complication' rather than an 'adverse drug reaction'. In total, 22% of participants were unaware of how to report an adverse drug reaction.Conclusion This survey acts as an important reminder to encourage both patients and dental professionals to report adverse drug reactions, including suspected MRONJ, to the Medicines and Healthcare products Regulatory Agency. Reporting aids accurate national data collection, highlights risk and supports ongoing research in this area.

Potential role of comprehensive dental care in preventing medication related osteonecrosis of the jaw (MRONJ): a single centre study

ObjectiveMedication-related osteonecrosis of the jaw bones (MRONJ) is a well-known complication of antiresorptive and antiangiogenic drugs. Since the first report, more occurrences of MRONJ have been described worldwide. Dental extraction has been described by many studies as one of the risk factors for MRONJ. Comprehensive dental care (CDC) is a preventive dental method provided to patients prior to drug commencement. This study aims to determine the association between CDC and MRONJ. Patients and methods. A retrospective analysis was performed on 75 medical records of patients on antiresorptive and/or antiangiogenic drugs between February 2018 and May 2021. Demographics and clinical and radiographic data were collected. Univariate and multivariate analyses were performed to determine the factors associated with MRONJ.ResultsOf the 75 patients who met the inclusion criteria, 11 (14.7%) developed MRONJ. Three out of 11 patients (27.2%) developed MRONJ spontaneously, while eight patients (72.8%) developed it after trauma from dentures or dental extractions. Following a binary logistic regression analysis, the lack of CDC was identified as a significant predictor of MRONJ. Patients who did not receive CDC had an odds ratio of 8.64 (95% confidence interval (CI): 1.27–58.62, p = 0.03). However, dental extraction did not show a statistically significant association with MRONJ in both the univariate and multivariate analyses.ConclusionCDC before treatment with antiresorptive and antiangiogenic drugs is a potentially effective preventive method for reducing MRONJ. Dental extraction was not a significant factor in relation to MRONJ.