RARE DISEASE
Osteonecrosis of the jaw
Osteonecrosis of the jaw
Osteonecrosis of the jaw
Drug discovery
1
drug
With orphan designation
Overview
Osteonecrosis of the jaw (ONJ) is a rare but serious condition characterized by exposed, non-healing jawbone due to impaired vascular supply, often associated with antiresorptive (bisphosphonates, denosumab) or antiangiogenic therapies. It typically manifests as pain, exposed bone (>8 weeks), and infection, with highest incidence in oncology patients receiving high-dose IV therapy. Management involves staged approaches, emphasizing early diagnosis and multidisciplinary care to prevent progression [1][3][9][14].
Burden
Significantly impacts quality of life, causing chronic pain, dysphagia, and disfigurement [9][14].
Incidence rises with prolonged antiresorptive use: ~1% at 1 year, 3% at 3 years in cancer patients [10], reaching 9% in metastatic breast cancer cohorts [14].
Treatment costs and morbidity escalate in advanced stages due to complex surgical needs and prolonged antimicrobial therapy [4][7][12].
Therapies
Conservative: Antibiotics (e.g., penicillin, clindamycin), chlorhexidine rinses, and analgesia for early stages (0–2) [8][12][15].
Surgical: Debridement or resection for advanced non-responsive cases (stage 3), often combined with platelet-rich fibrin or laser therapy [7][16].
Preventive: Pre-therapy dental evaluation, minimally invasive procedures (e.g., root canals over extractions), and smoking cessation [1][5][9].
Categories: rare bone diseases, rare systemic and rheumatological diseases
Research Papers
2,056 drug discovery papers about Osteonecrosis of the jaw, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,056 drug discovery papers about Osteonecrosis of the jaw, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-05-04 | Denosumab Therapy in Dental Practice: Awareness, Risk Factors and Preventive Strategies.
Denosumab is increasingly prescribed for osteoporosis and metastatic bone disease, leading to a parallel rise in reports of medication-related osteonecrosis of the jaw (MRONJ). Although the condition was first associated with bisphosphonate therapy, emerging evidence indicates that denosumab-associated MRONJ presents distinct epidemiological, clinical and management challenges. Despite an expanding body of research, awareness of MRONJ risk among general dental practitioners remains inconsistent, contributing to preventable adverse outcomes. This narrative review consolidates current knowledge on MRONJ in denosumab-treated patients by examining epidemiology, pathophysiology, clinical features, established risk factors and evidence-based preventive strategies. Numerous guidelines consistently emphasise early dental assessment, optimisation of oral health prior to the first denosumab dose and timely communication between physicians and dental clinicians. A planned dental intervention may be safer when coordinated around the denosumab dosing schedule, particularly by utilising a "window of opportunity" during periods of the waning drug effect. This review also synthesises practical recommendations for routine dental care, pretreatment evaluation, risk stratification and management of established MRONJ. A clinical decision-making flowchart is proposed to assist dental practitioners in evaluating treatment needs, assessing patient risk and planning interventions with minimal disruption to systemic therapy. Taken together, understanding the unique characteristics of denosumab-associated MRONJ is essential for reducing morbidity and improving patient outcomes. Strengthening collaboration between dental practitioners and medical prescribers, along with early identification of vulnerable patients, remains the cornerstone of prevention.
2026-04-09 | The use of denosumab in rare bone diseases in adults: a systematic review from the ECTS Rare Bone Disease Action Group.
Rare bone diseases may display a disrupted RANKL-RANK-Osteoprotegerin pathway causing increased osteoclastogenesis and enhanced bone resorption. Although bisphosphonates are commonly used, they often fall short of desired outcomes. Denosumab, an anti-RANKL antibody, provides a promising alternative by swiftly and strongly suppressing bone turnover (faster and more potent suppression of bone resorption than bisphosphonates), though its effects are reversible upon discontinuation. The use of denosumab has been highlighted, especially in pediatric cases but not substantially in adults. A targeted evidence search was conducted to retrieve studies reporting denosumab use in rare bone diseases in adults. Denosumab administration may lead to pain reduction, lesion reduction or bone formation. Treatment dosage, schedules and duration varied, however, a dose of 120 mg dosed monthly or 3 monthly for almost one year reached the desired treatment effect in most patients. Denosumab is generally well tolerated in adults, with mild common side effects such as (asymptomatic) hypocalcemia and hypophosphatemia. Serious adverse effects such as osteonecrosis of the jaw or atypical femoral fractures are rarely reported. Main concerns regard rebound effect after denosumab discontinuation, with disease recurrence in some cases. Zoledronic acid after discontinuation of denosumab might be advisable, but is seldom reported. Denosumab is a feasible treatment in adults with rare bone diseases when managed by multidisciplinary teams with knowledge of both the underlying disease and potential surgeries as well as the medical site of treatment. Denosumab discontinuation management is paramount to prevent recurrence and severe complications. The paucity of data supports the need for data collection through rare disease registries for future pertinent evidence-based recommendations.
2026-04-06 | Combined Effects of Romosozumab and Zoledronate on the Development of Osteonecrosis of the Jaw.
This study aimed to assess the occurrence of medication-related osteonecrosis of the jaw (MRONJ) in mice following the sequential administration of romosozumab and zoledronate and to confirm their inhibitory effects on osteoclast differentiation in vitro. Thirty-five female C57BL/6 mice were divided into three groups: romosozumab followed by zoledronate (ROM+ ZOL), saline followed by zoledronate (ZOL), and control (Con) group receiving saline. After drug administration, the maxillary first molars were extracted. Bone healing and necrosis were evaluated using micro-computed tomography, histomorphometry, and immunohistochemistry. To investigate the mechanism underlying the in vivo study results, the effects of romosozumab and zoledronate were evaluated by analysing tartrate-resistant acid phosphatase staining and actin ring formation after differentiation of RAW 264.7 cells. The ROM+ZOL group exhibited more severe bone necrosis than the ZOL and Con groups. The ROM+ZOL group demonstrated a lower bone volume fraction and a reduction in the number of sclerostin-positive cells, suggesting enhanced osteonecrosis when romosozumab was administered before zoledronate. Moreover, both zoledronate and romosozumab effectively suppressed osteoclast differentiation and function in vitro. Sequential administration of romosozumab followed by zoledronate may exacerbate the risk of MRONJ, underscoring the need for careful consideration in clinical applications.
2026-03-12 | Atypical femoral fracture and jaw osteonecrosis under high doses of denosumab, healed with the aid of low dose of denosumab: a case report.
Atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ) are rare but serious complications associated with long-term use of antiresorptive therapies such as denosumab. Denosumab discontinuation to allow for bone healing is not possible because of the high risk of spontaneous multiple vertebral fractures. We present a case of concurrent AFF and ONJ in a patient previously treated with denosumab 120mg monthly. The patient was managed with a low-dose denosumab regimen tailored according to bone turnover marker monitoring, resulting in successful bone union and resolution of ONJ.
2026-02-27 | Clinical characteristics of osteonecrosis of the jaw related to denosumab: a 5-year retrospective cohort study.
This study aimed to investigate the clinical characteristics, treatment outcomes, and factors influencing treatment success in patients with denosumab (Dmab)-related osteonecrosis of the jaw (DRONJ). This retrospective cohort study included the patients who were diagnosed with DRONJ and treated at the authors' affiliated hospital, between August 2019 and August 2024. The patients were divided into the three groups; Group 1, low-dose Dmab; Group 2, transition from bisphosphonates (BPs) to low-dose Dmab; Group 3, high-dose Dmab. Differences in clinical characteristics among the groups were compared. Surgical outcomes were classified into three categories: complete healing, partial healing, and no healing. "Treatment success" was defined as the combined proportion of complete and partial healing. A total of 178 DRONJ patients were included in this study. Most of DRONJ occurred in osteoporosis patients. In patients treated with lowdose Dmab, prior BP use resulted in the development of MRONJ within a shorter period after Dmab administration but did not affect disease severity or treatment outcomes. Overall postoperative healing outcomes were favorable at 3 months after DRONJ treatment. The overall treatment success rate was 81.5%; Group 1, 85.0%; Group 2, 82.8%; Group 3, 53.8%, P=0.027). Multiple regression analysis demonstrated that Dmab dosage was a significant factor influencing treatment success, whereas age, treatment duration, lesion location, and DRONJ stage were not (odds ratio, 5.13; 95% confidence interval, 1.19-22.14; P=0.028). The earlier onset in the BP to Dmab transition group may be attributable to the cumulative duration of antiresorptive therapy. Patients treated with high-dose Dmab demonstrated poorer prognosis and more frequent recurrence after MRONJ treatment compared with those treated with low-dose Dmab or BP to Dmab transition therapy. herefore, these findings need to be considered for treatment of DRONJ.
small molecules
2026-07-31 | [Role and mechanism of methyltransferase-like 3 in promoting macrophage NLRP3 inflammatory responses in medication-related osteonecrosis of the jaw].
Objective: To investigate the role and mechanism of methyltransferase-like 3 (METTL3) in regulating macrophage inflammatory responses and the derelopment of medication-related osteonecrosis of the jaw (MRONJ) at the single-cell level. Methods: Single-cell RNA sequencing was used to construct an immune atlas of zoledronic acid (ZA)-induced bisphosphonate-related osteonecrosis of the jaw(BRONJ)-like lesions in mice. Key epigenetic regulators were screened by bioinformatic analysis, and key genes were predicted using virtual knockdown analysis. METTL3 expression in vivo and in vitro was validated by immunohistochemical staining and Western blotting. In vitro knockdown and overexpression experiments were performed to clarify the regulatory effect of METTL3 on NLRP3 inflammasome activation in macrophages. Results: The single-cell atlas showed that ZA treatment significantly induced the recruitment of specific pro-inflammatory macrophage subsets in extraction sockets, accompanied by marked activation of inflammation-related pathways. Bioinformatic screening indicated that NLRP3 inflammasome-related genes served as a central bridge linking inflammatory responses to RNA processing and modification. Pseudotime trajectory and virtual knockdown analyses further suggested that METTL3 functioned as a key node in maintaining the pro-inflammatory state of macrophages. In vivo and in vitro experiments confirmed that ZA significantly induced METTL3 upregulation at both tissue and cellular levels, accompanied by an increase in global m6A levels. Functional assays showed that METTL3 knockdown markedly suppressed NLRP3 inflammasome activation, whereas METTL3 overexpression exerted the opposite effect. Conclusions: This study reveals the critical role of METTL3 as a positive regulator in promoting macrophage NLRP3 inflammatory responses in MRONJ pathogenesis. METTL3 is expected to provide clues for targeted therapy research on modulating local immune dysregulation and promoting bone repair in MRONJ.
2026-07-29 | Advanced biomaterial-based approaches for medication-related osteonecrosis of the jaw.
Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating adverse effect linked to anti-resorptive and anti-angiogenic therapies, with an incidence of 4.34 % (6.22 % in oncology patients and 0.59 % in osteoporosis patients) based on a pooled analysis of 92 observational studies (2015-2020), characterized by persistent bone exposure and poor healing. Conventional treatment modalities often yield suboptimal outcomes, with recurrence and procedural morbidity. In recent years, biomaterial-based strategies have emerged as promising alternatives by targeting MRONJ's complex pathophysiology, including imbalances in bone remodeling, impaired angiogenesis, immune dysregulation, and infection. This review highlights advances in functional biomaterials for bisphosphonate sequestration, restoration of osteo-angiogenic homeostasis, and immune modulation. These platforms have shown efficacy in promoting tissue regeneration while reducing systemic toxicity. However, clinical translation is limited by biosafety, scalability, and regulatory hurdles, such as instability in the oral environment and mismatched scaffold degradation rates. Future efforts should prioritize multifunctional, intelligent, and patient-specific biomaterials, alongside the establishment of standardized preclinical models and clinical trials. Combinatory strategies have great potential for synergistic treatment and addressing the multiple pathological factors of MRONJ. By integrating materials engineering with mechanistic understanding, this review synthesizes current evidence to highlight the transformative potential of biomaterials for MRONJ prevention and therapy.
2026-07-26 | Pharmacological effects of PTH1R agonists on jaw bone fracture, periodontitis, orthodontic treatment and MRONJ: a view from dosing regimen settings.
Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) are endogenous ligands of PTH type I receptor (PTH1R), which are essential for skeletal development and homeostasis. Since the intermittent application of these molecules to organisms exerts bone anabolic effects, they are used pharmacologically to increase bone mass and stimulate bone formation. Teriparatide, an N-terminal 34 amino acid fragment of human PTH, and abaloparatide, a derivative of the N-terminal 34 amino acid of human PTHrP, have been pharmaceutically developed and clinically applied to treat severe osteoporosis and are categorized as PTH1R agonists. An increasing number of clinical and preclinical studies have demonstrated that PTH1R agonists can be used in dental medicine, including jaw bone regeneration and orthodontic treatment, periodontitis, and the management of medication-related osteonecrosis of the jaw (MRONJ). However, it is unclear whether the mandibular bone responds pharmacologically to PTH1R agonists in the same way as other trunk bones, such as the limb and axial bones. Compared with studies using long and vertebral bones, the beneficial effects of PTH1R agonists on the mandibular bone appear to require higher doses and longer treatment durations. Clinical application of PTH1R agonists in dental medicine may result in promising outcomes. However, dosing regimens and the timing of their application should be further investigated with knowledge of the biological uniqueness of the mandibular bone.
2026-07-20 | Sequential Anabolic and Antiresorptive Treatment Promotes Medication-Related Osteonecrosis of the Jaw in Mice.
To investigate the effects of sequential administration of romosozumab and denosumab on post-extraction socket healing and osteonecrosis development in a murine tooth extraction model. Forty female mice were randomly assigned to four groups: control (Ctrl), romosozumab (Rm), denosumab (Dmab), and sequential romosozumab followed by denosumab (Rm + Dmab). After drug administration, bilateral maxillary first molars were extracted. Extraction socket healing was evaluated by micro-computed tomography, histological analysis, and immunohistochemistry for receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin. The Rm + Dmab group exhibited significantly less new bone formation and more necrotic bone in the extraction sockets than the other groups, accompanied by a marked reduction in osteoclast numbers. The Dmab-only group showed a lower RANKL/OPG ratio. No significant differences in sclerostin expression were observed among groups. Sequential administration of romosozumab followed by denosumab severely impaired extraction socket healing and induced osteonecrotic lesions in mice, resembling medication-related osteonecrosis of the jaw (MRONJ). These findings suggest that such sequential antiresorptive therapy may increase the risk of MRONJ in patients undergoing dental extractions.
2026-06-12 | Vitamin D Deficiency as a Context-Dependent Modifier of Osteonecrosis of the Jaw.
Osteonecrosis of the jaw (ONJ) is a multifactorial disorder characterized by impaired bone remodeling, vascular compromise, immune dysregulation, and mucosal barrier disruption. Although these mechanisms have been extensively investigated, they are often discussed separately, limiting an integrated understanding of ONJ pathogenesis. Vitamin D has emerged as a biologically relevant factor across these interconnected pathways, yet its role in ONJ remains incompletely defined. This narrative and hypothesis-generating review synthesizes current mechanistic, preclinical, observational, and clinical evidence regarding vitamin D biology and ONJ and proposes a vitamin D-centered vulnerability model in which vitamin D deficiency acts as a context-dependent modifier rather than a primary causal driver. Mechanistically, vitamin D deficiency may impair osteoblast function and mineralization, disrupt angiogenic responses, promote pro-inflammatory immune signaling, and compromise mucosal integrity, collectively creating a microenvironment susceptible to impaired healing and osteonecrosis. These effects are likely to vary across clinical settings, particularly in patients receiving antiresorptive or antiangiogenic therapies. Clinical and epidemiological studies have reported associations between low vitamin D status and increased ONJ risk or severity, while some observational studies suggest that vitamin D supplementation may be associated with improved outcomes in selected populations. However, current human evidence remains predominantly observational and subject to substantial heterogeneity and residual confounding, and direct randomized evidence is lacking. Overall, this framework provides an integrated perspective linking vitamin D biology to ONJ-related pathogenic processes and may support future mechanistic research, risk stratification, and supportive multidisciplinary management strategies. Nevertheless, the proposed model should be interpreted cautiously as hypothesis-generating and requires further validation in well-designed prospective studies and randomized controlled trials.
proteins
2026-07-29 | Should Teriparatide Be Part of Our Clinical Armamentarium in the Management of Medication-Related Osteonecrosis of the Jaw? A Systematic Review and Meta-Analysis.
Medication-related osteonecrosis of the jaw (MRONJ) is a severe and potentially debilitating drug reaction. Adjunctive treatments including pentoxifylline, tocopherol, and teriparatide (TPTD) have been studied, but TPTD's efficacy remains unclear. This systematic review and meta-analysis aims to consolidate and evaluate high-quality evidence on TPTD in managing MRONJ. An electronic search strategy was performed on 3 databases (Pubmed, Embase, and Cochrane CENTRAL). Search terms include ("Teriparatide" OR "TPTD" OR "Recombinant Parathyroid Hormone" OR "Recombinant PTH") AND ("Medication-Related Osteonecrosis of the Jaw" OR "MRONJ" OR "BRONJ"). No publication date range was utilized. Inclusion criteria include randomized controlled trials, case-control studies, and cohort studies. All systematic reviews, case reports, case series, animal studies, editorials, non-English publications, or studies relating to osteoradionecrosis were excluded. Each study was screened independently, followed by final study selection after discussion with all authors. Primary meta-analysis used Cox proportional hazards regression with pseudo-individual-subject data reconstructed from published Kaplan-Meier curves (Guyot method) and a Tierney events + P value derivation for one study without Kaplan-Meier data. A sensitivity analysis pooled odds ratios (ORs) at the 6-month clinical response endpoint. Primary outcomes include improvement in MRONJ clinical staging. Secondary outcomes include time to improvement, adverse effects, radiographic evaluation, and presence of serum markers. After review of 162 studies, 5 (3.1%) studies were included in the systematic review with 3 (1.9%) studies included in the meta-analysis (n = 101 subjects). A three-study Cox hazard ratio (HR) meta-analysis yielded a pooled HR of 5.35 (95% CI, 3.14 to 9.13, P < .0001, I2 = 0%) favoring TPTD. Subgroup analyses by dosing regimen showed directionally consistent effects (daily pooled HR = 12.52; 95% CI, 5.75 to 27.23; weekly pooled HR = 8.09; 95% CI, 3.59 to 18.26; both I2 = 0%), and an OR-based sensitivity analysis at the 6-month binary healing endpoint was directionally concordant (pooled OR = 14.26; 95% CI, 2.83 to 71.77). Adjunctive TPTD shows improvement of MRONJ staging and time to healing compared to conventional treatments alone, but the magnitude of the impact remains unclear. Additional evidence, including studies evaluating dosing regimens and subject segmentation by MRONJ staging, is warranted.
2026-07-11 | Pharmacological and surgical predictors of postoperative healing in medication-related osteonecrosis of the jaw: A retrospective multicenter cohort study.
Failure to achieve postoperative healing after surgical treatment of medication-related osteonecrosis of the jaw (MRONJ) remains a clinical challenge. We aimed to investigate the independent predictors of postoperative nonhealing and to evaluate the impact of regenerative adjuncts. In a multicenter surgical cohort (2019-2025) of 531 patients with MRONJ, pharmacological, lesion level, and surgical factors were assessed using univariable testing, elastic net regularization for variable selection, and multivariable logistic regression. Postoperative nonhealing was defined as the need for additional surgical intervention or failure to achieve complete mucosal coverage, accompanied by clinical or radiographic evidence of persistent or progressive disease. Kaplan-Meier analysis was used to estimate nonhealing-free survival. The overall postoperative nonhealing rate was 18.5% (98/531). In the multivariable models, high-dose antiresorptive therapy (odds ratio [OR]: 2.94, 95% confidence interval [CI]: 1.70-5.06) and multiple-site lesions (OR: 2.29, 95% CI: 1.09-4.67) were independent risk factors for postoperative nonhealing, whereas intraoperative bone morphogenetic protein (BMP) use was associated with a lower risk of postoperative nonhealing (OR: 0.32, 95% CI: 0.20-0.52). The number needed to treat to prevent one postoperative nonhealing event was 5.3 (95% CI: 3.9-8.7) for BMP, and the number needed to harm was 4.4 (95% CI: 3.0-8.5) for high-dose therapy. Solitary maxillary lesions showed an insignificant protective effect. Antiangiogenic agents were associated with postoperative nonhealing in the univariate and elastic net analyses, but not in the final multivariable model. Neither treatment duration nor preoperative drug holiday was independently associated with postoperative nonhealing. The elastic net model showed acceptable discrimination (area under the curve [AUC]: 0.724), and the Kaplan-Meier curves were consistent with these findings. Postoperative nonhealing after surgical management of MRONJ was mainly associated with systemic pharmacological burden and lesion extent, whereas BMP application was associated with improved postoperative healing. These findings support further investigation of regenerative adjuncts and risk-adapted surgical management strategies.
2026-05-22 | Synergistic application of concentrated growth factor and bone perforation technique in bisphosphonate-related-osteonecrosis of the jaw.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication caused by the deposition of bisphosphonates in bone tissue, particularly after invasive dental procedures. Its pathogenesis is closely related to impaired bone remodeling and insufficient blood supply. Optimizing treatment strategies for BRONJ remains a significant clinical challenge. This study aims to evaluate the therapeutic effects of concentrated growth factor (CGF) combined with the bone perforation technique in the treatment of BRONJ. A rat model of BRONJ was established and divided into four groups: Non-treated group (N), Bone perforation group (B), CGF group (C), and CGF + Bone perforation group (C + B). Bone repair was evaluated at 2 and 4 weeks post-treatment through micro-computed tomography (Micro-CT), histological analysis (HE and TRAP staining), Western blot, immunofluorescence staining, and qRT-PCR (RUNX2, ALP). HE staining at 2 weeks postoperatively showed abundant empty lacunae with inflammation in the N and B groups, while the C and C + B groups exhibited reduced necrotic bone and new bone formation. At 4 weeks, the C + B group achieved complete epithelial healing with no residual necrotic bone. Quantitative histomorphometry revealed that the TRAP-positive area was 0.32% in the C group and 0.27% in C + B groups, significantly higher than that in the N group 0.12%(p < 0.001). PCR analyses revealed that, at 2 weeks, ALP expression was highest in the C group compared to all other groups (N, B, and C + B) (p < 0.001), whereas RUNX2 expression showed no significant difference between the C and C + B groups but was significantly higher than that in the N and B groups (p < 0.01). At 4 weeks, the C + B group exhibited the highest ALP and RUNX2 expression, significantly exceeding all other groups (N, B, and C). Western blot analyses demonstrated that at 2 weeks post-surgery, ALP and RUNX2 protein expression was higher in the C group than in all other groups (p < 0.05). At 4 weeks, ALP expression was higher in the C and C + B groups compared to the other groups (p < 0.001). RUNX2 expression was highest in the C + B group (p < 0.001). Our results demonstrate that CGF significantly promotes BRONJ repair, while the bone perforation technique improves early blood supply but has limited long-term therapeutic effects. The combined application of CGF and bone perforation exerts a synergistic effect in enhancing osteogenesis and optimizing bone repair outcomes. Future studies with larger sample sizes and longer follow-up periods are warranted to verify these findings.
2026-03-10 | Regenerative and surgical strategies for medication-related osteonecrosis of the jaw (MRONJ): a systematic review
Aim: Medication-related osteonecrosis of the jaw (MRONJ) challenges clinicians with its complex pathology and high risk of complications. Methods: We searched seven databases - PubMed, Scopus, Web of Science, Cochrane Library, Embase, CINAHL, and Google Scholar - and adapted the search strings for each database to optimize retrieval of relevant studies. We then systematically reviewed the included studies to identify the most effective treatments for promoting MRONJ healing. Results: A total of 329 records were identified through database searches across seven electronic databases. After removal of 45 duplicates, 284 records were screened. Following title and abstract screening and full-text assessment, 13 studies met the eligibility criteria and were included in the qualitative synthesis. The included studies consisted primarily of randomized controlled trials and retrospective cohort studies investigating surgical, pharmacological, and adjunctive therapeutic strategies for MRONJ management. Risk-of-bias assessment using the RoB 2.0 and ROBINS-I (Risk of Bias in Non-randomised Studies - of Interventions) tools showed that most studies presented low to moderate risk of bias, although some methodological concerns were identified. Surgical interventions were commonly associated with improved clinical healing, while adjunctive therapies such as bone morphogenetic protein-2 and teriparatide showed promising outcomes in selected cases. Follow-up periods ranged from 1 month to 2 years, and outcome measures included clinical, radiological, and histological evaluations. Conclusion: MRONJ treatment is diverse and multifaceted. Such inferences were made to varying degrees in previous investigations, illustrating the limitations for clinical use, revealing the need for further studies to clarify both the efficacy and optimal use of the interventions in diverse clinical settings.
2026-02-15 | The effectiveness of different treatment methods in the treatment and prevention of medication-related osteonecrosis of the jaw: A systematic review and Bayesian network meta-analysis.
The treatment strategies and efficacy of medication-related osteonecrosis of the jaw (MRONJ) are controversial, and there is a lack of unified clinical treatment standards. We used a Bayesian network meta-analysis method to evaluate the clinical efficacy of different intervention methods. We searched for clinical controlled trials published from January 2010 to May 2025 in PubMed, the Cochrane Library, Web of Science, and Embase. We assessed the quality of the included studies using the NOS quality assessment and the Cochrane risk of bias tool. We conducted a network meta-analysis (NMA) using R Studio and ranked the treatment modalities for each outcome measure using SUCRA. A total of 19 studies were included, involving 1064 MRONJ patients and 12 different intervention measures. The meta-analysis results showed that the included interventions improved healing rates compared to conventional surgical treatment [RR = 1.44, 95 % CI (1.20, 1.71), P < 0.001]; and reduced the incidence of MRONJ in high-risk populations [RR = 0.10, 95 % CI (0.04, 0.29), P < 0.001]. The network meta-analysis results showed that the top three wound healing rates in the probability-weighted ranking were: BMP-2 + L-PRF (89.3 %) > Hyperbaric oxygen (84.1 %) > YAG laser + LLLT (67.8 %) CONCLUSION: Based on the meta-analysis results, we found that the intervention methods included in the study were effective compared to conventional surgical treatment and prevented the incidence of MRONJ in high-risk populations. The SUCRA value showed that BMP-2 + L-PRF significantly improved the healing rate of MRONJ patients and may have good clinical application prospects.
cell therapies
2026-08-09 | Individualized 3D-Printed Titanium Mesh-Assisted Alveolar Reconstruction and Implant Rehabilitation Following MRONJ Resection: A Case Report.
Medication-related osteonecrosis of the jaw is a severe complication of antiresorptive therapy that often necessitates complex reconstructive surgery. This report describes a case of implant-supported rehabilitation using a customized 3D-printed titanium mesh for an extensive mandibular defect resulting from medication-related osteonecrosis of the jaw. A 58-year-old woman with stage-3 medication-related osteonecrosis of the jaw after zoledronate therapy underwent segmental mandibulectomy and reconstruction with a free iliac crest graft. Nine months later, a customized titanium mesh was placed to protect the planned 9.5-11 mm augmentation. Cone beam computed tomography confirmed mineralized regeneration within the mesh. The mesh was removed after achieving 9.5 mm vertical and 11 mm horizontal alveolar augmentation, and 4 implants were placed with high primary stability (insertion torque ≥ 40 N cm). At 6 months, resonance frequency analysis values ranged from 75 to 84, allowing delivery of a splinted fixed prosthesis. At 12 months of loading, the peri-implant tissues remained normal with stable radiographic bone levels and satisfactory function. Combining customized 3D-printed titanium mesh with guided implant placement supports stable bone regeneration and prosthetic rehabilitation in patients with medication-related osteonecrosis of the jaw. However, outcomes depend on medication history, therapy timing, and unresolved drug-related factors, underscoring the need for a multidisciplinary approach with individualized treatment and proactive complication care.
2026-07-31 | [A retrospective study of pedicled flaps for repair of oral mucosal defects in patients with medication-related osteonecrosis of the jaw].
Objective: To investigate the clinical efficacy of pedicled flaps for repairing oral mucosa defects in medication-related osteonecrosis of the jaw (MRONJ), and to analyze the indications for different types of pedicled flaps. Methods: The clinical data of 158 MRONJ patients who met the inclusion criteria and were admitted to the Department of Maxillofacial Trauma and Orthognathic Surgery, Hospital of Stomatology, Air Force Medical University from January 2019 to December 2024 were retrospectively analyzed, including 74 males (46.8%) and 84 females (53.2%).The mean age was (59.2±10.7) years (range, from 20 to 87 years old). According to the method of soft tissue repair, the patients were divided into direct suture group (61 cases) and pedicled tissue flap group (97 cases, including 80 cases of buccal fat pad flap and 17 cases of submental island flap). The rate of secondary operation was compared between the two groups. Multivariate binary Logistic regression and subgroup analysis were used to evaluate the efficacy and influencing factors of pedicled tissue flaps, and the comparison between the buccal fat pad flap and submental island flap was performed. Results: The median follow-up time was 36 months. Univariate analysis showed that the secondary operation rate was 68.9% (42/61) in the direct suture group, which was significantly higher than 16.5% (16/97) in the pedicled tissue flap group (P<0.001). After adjusting for confounding factors such as age and lesion location, multivariate Logistic regression analysis showed that pedicled tissue flap was an independent protective factor against the risk of secondary surgery (OR=0.049, P<0.001). Stage 3 disease was an independent risk factor for secondary surgery (OR=8.455, P=0.002). Subgroup analysis showed that the secondary operation rate of pedicled tissue flap was significantly lower than that of direct suture in stage 3 group, mandibular group,<65 years group, male group and female group (all P<0.05). There was no significant difference among stage 2 group, maxillary group and≥65 years group (all P>0.05), but the trend of protection was the same. The secondary operation rate was 17.5% (14/80) in the buccal fat pad flap group and 2/17 in the submental island flap group. There was no significant difference between the two groups (P=0.730). Conclusions: The use of pedicled tissue flap for repairing oral mucosal wounds can significantly reduce the risk of secondary surgery for MRONJ, and the effect is superior to direct suture. Buccal fat pad flap is the first choice for maxillary and retromolar mucosal defects, and submental island flap can be used for large mandibular mucosal defects.
2026-07-31 | [Research progress of mesenchymal stem cells in the treatment of medication-related osteonecrosis of the jaw].
Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication characterized primarily by jawbone necrosis, induced by bisphosphonates or other targeted agents for systemic diseases. With the advancement of systemic anticancer therapies, the survival of patients with advanced malignancies has been prolonged, leading to an annual increase in the number of patients with MRONJ. However, there is currently no effective treatment for MRONJ worldwide. Recent studies have indicated that mesenchymal stem cells exhibit significant potential for osteogenic and angiogenic differentiation, proliferation, immunomodulation, and anti-inflammatory effects, thereby providing a novel therapeutic strategy for medication-related osteonecrosis of the jaw. This article reviews the research on mesenchymal stem cell therapy for MRONJ, providing a reference for its clinical research and treatment.
2026-06-01 | Human Amniotic Membrane as Adjuvant Therapy in Medication-Related Osteonecrosis of the Jaw: A Scoping Review
Background: Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication characterized by progressive destruction of the maxillary and mandibular bones in patients receiving antiresorptive or antiangiogenic agents. Despite evolving clinical guidelines, its management remains controversial and nonstandardized. Human amniotic membrane (HAM) has emerged as a promising adjuvant therapy due to its immunomodulatory, anti-inflammatory, and regenerative properties. Objective: To identify and synthesize available evidence on the effectiveness of HAM as an adjuvant treatment in promoting wound healing in patients diagnosed with MRONJ. Methods: A scoping review was conducted following the PRISMA-ScR framework. Searches were performed in PubMed/MEDLINE, Scopus, and Web of Science using MeSH terms and free-text keywords including “amniotic membrane,” “amnion,” “bisphosphonate-associated osteonecrosis,” and “medicationrelated osteonecrosis of the jaw,” combined with Boolean operators. Searches were limited to primary human studies published within the past five years. Results: A total of 25 records were identified; after deduplication and screening, 3 primary studies were included comprising a total of 39 patients across various MRONJ stages. Across all studies, 83.8% of patients achieved complete mucosal wound closure, and 84.6% reported a significant reduction in pain perception. No adverse events, recurrences, or infectious complications were reported. Conclusions: HAM represents a viable, versatile, and effective adjuvant intervention in the surgical management of MRONJ. It promotes soft-tissue healing, reduces pain and infection, and favorably impacts patient prognosis and quality of life. Randomized controlled trials with larger samples and standardized protocols are warranted.
2026-05-20 | Mesenchymal stem cell therapy for treatment of medication related osteonecrosis of the jaw (MRONJ): A systematic review.
Medication-related osteonecrosis of the jaw (MRONJ) is a significant adverse effect associated with antiresorptive and antiangiogenic therapies. Therapies utilizing mesenchymal stem cells (MSCs) represent a promising regenerative strategy; however, conventional management methods have shown limited effectiveness. This systematic review aimed to evaluate the effectiveness of MSC-based interventions in preventing and treating MRONJ. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify studies published from 2011 to 2024. Studies examining MSCs therapy in the context of MRONJ were incorporated according to predefined inclusion and exclusion criteria. Seventeen studies (6 clinical, 11 preclinical) met inclusion criteria. Preclinical models demonstrated that MSCs enhance angiogenesis and bone regeneration, providing mechanistic support for human application. Clinically, 80-90% of patients achieved complete mucosal healing with radiographic evidence of bone regeneration. However, due to species differences in oral microbiome and immunity, animal findings require confirmation in human trials. This review integrates human clinical data with mechanistic insights from preclinical studies. Human evidence shows promising mucosal and bone regeneration, while animal studies elucidate underlying mechanisms-particularly angiogenesis and immunomodulation. Given that animal models cannot replicate the human oral immune environment, these findings should be interpreted as hypothesis-generating. MSC therapy represents a biologically sound but experimental strategy, warranting confirmation through randomized controlled trials.
other
2025-12-11 | The Mitigating Effect and Mechanism of Polydeoxyribonucleotide Against Zoledronic Acid-Induced Growth Suppression of Human Gingival Fibroblasts.
Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, is widely used to treat osteoporosis and bone metastases. However, its clinical application is limited by adverse effects, notably bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is associated with cytotoxicity in oral mucosal cells. Polydeoxyribonucleotide (PDRN), a salmon sperm-derived DNA polymer with regenerative and anti-inflammatory properties, has shown therapeutic potential in tissue repair; however, its ability to mitigate ZA-induced cytotoxicity remains poorly understood. Here, we investigated the molecular mechanisms of ZA-induced toxicity in HGF-1 cells, a human gingival fibroblast line, and evaluated the protective effects of PDRN. ZA treatment (50 µM, 48 h) significantly inhibited HGF-1 cell growth, accompanied by reduced phosphorylation of protein kinase B (PKB) and signal transducer and activator of transcription 3 (STAT-3), along with increased phosphorylation of TANK-binding kinase 1 (TBK1). TBK1 silencing restored cell growth under ZA exposure, whereas silencing PKB or STAT-3 further suppressed cell growth even without ZA. Co-treatment with PDRN (100 µg/mL) effectively prevented and reversed ZA-induced HGF-1 cytotoxicity. Mechanistically, PDRN inhibited ZA-induced TBK1 phosphorylation and partially restored PKB phosphorylation, though it did not reverse the reduction in p-STAT-3. Additionally, ZA significantly elevated intracellular reactive oxygen species (ROS) levels at 8 h, which were attenuated by PDRN. The antioxidant N-acetylcysteine (NAC) similarly reduced ZA-induced ROS and p-TBK1 levels and improved cell growth, although it had limited effects on p-PKB at 8 h. Importantly, delayed PDRN treatment following ZA exposure reversed ZA-induced cell growth inhibition and TBK1 activation in a dose- and time-dependent manner. In summary, these findings demonstrate that ZA suppresses HGF-1 cell growth through ROS production, TBK1 activation, and inhibition of PKB and STAT-3, whereas PDRN counteracts these effects primarily by suppressing TBK1 activation and oxidative stress.
2025-09-02 | Rethinking Osteonecrosis of the Jaw: Could Cellular Senescence Be the Missing Link Between ORN and MRONJ?
Osteonecrosis of the jaw (ONJ) is a series bone diseases characteristic with similar diagnostic criteria and clinical manifestations. Phossy jaws, medication-related osteonecrosis of the jaw (MRONJ), and osteoradionecrosis (ORN) are major subtypes of ONJ. Though subtypes of ONJ are considered different diseases in clinical practice, similar diagnostic criteria, clinical presentation, and features prompt the possibility that there is a common pathogenesis mechanism for ONJ subtypes. Current pathogenic theories fail to fully explain the delayed onset, persistent progression, and stimulus-independent nature of ONJ. Here, we propose that cellular senescence could be a common pathogenesis mechanism of ONJ. Radiation, antiresorptive agents, and trauma induce persistent DNA damage and activate the DNA damage response, leading to irreversible senescence in jawbone cells. This model explains key clinical observations and offers a rationale for the failure of stimulus withdrawal to reverse disease progression. We outline future directions to validate this hypothesis. If confirmed, this hypothesis may unify ONJ subtypes under a single pathogenic framework and open avenues for targeted interventions.
2024-10-16 | Genetic Background of Medication-Related Osteonecrosis of the Jaw: Current Evidence and Future Perspectives.
Medication-related osteonecrosis of the jaw (MRONJ) is a rare side effect of antiresorptive drugs that significantly hinders the quality of life of affected patients. The disease develops in the presence of a combination of factors. Important pathogenetic factors include inflammation, inhibition of bone remodeling, or genetic predisposition. Since the first description of this rare side effect in 2003, a growing body of data has suggested a possible role for genetic factors in the disease. Several genes have been suggested to play an important role in the pathogenesis of MRONJ such as SIRT1, VEGFA, and CYP2C8. With the development of molecular biology, newer methods such as miRNA and gene expression studies have been introduced in MRONJ, in addition to methods that can examine the base sequence of the DNA. Describing the complex genetic background of MRONJ can help further understand its pathophysiology as well as identify new therapeutic targets to better manage this adverse drug reaction.
2024-07-09 | Inflammation Can Be a High-Risk Factor for Mucosal Nonunion of MRONJ by Regulating SIRT1 Signaling When Treated with an Oncologic Dose of Zoledronate.
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. 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. 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. 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.
2023-11-13 | Exosome-targeted delivery of METTL14 regulates NFATc1 m6A methylation levels to correct osteoclast-induced bone resorption
Abstract Osteoporosis has a profound influence on public health. First-line bisphosphonates often cause osteonecrosis of the jaw meanwhile inhibiting osteoclasts. Therefore, it is important to develop effective treatments. The results of this study showed that the increased level of NFATc1 m6A methylation caused by zoledronic acid (ZOL), with 4249A as the functional site, is highly correlated with the decreased bone resorption of osteoclasts. Upstream, METTL14 regulates osteoclast bone absorption through the methylation functional site of NFATc1. Downstream, YTHDF1 and YTHDF2 show antagonistic effects on the post-transcriptional regulation of NFATc1 after the m6A methylation level is elevated by METTL14. In this study, meRIP-Seq, luciferase reporter assays, meRIP and other methods were used to elucidate the NFATc1 regulatory mechanism of osteoclasts from the perspective of RNA methylation. In addition, EphA2 overexpression on exosomes is an effective biological method for targeted delivery of METTL14 into osteoclasts. Importantly, this study shows that METTL14 released by exosomes can increase the m6A methylation level of NFATc1 to inhibit osteoclasts, help postmenopausal osteoporosis patients preserve bone mass, and avoid triggering osteonecrosis of the jaw, thus becoming a new bioactive molecule for the treatment of osteoporosis.
antibodies
2026-05-04 | Denosumab Therapy in Dental Practice: Awareness, Risk Factors and Preventive Strategies.
Denosumab is increasingly prescribed for osteoporosis and metastatic bone disease, leading to a parallel rise in reports of medication-related osteonecrosis of the jaw (MRONJ). Although the condition was first associated with bisphosphonate therapy, emerging evidence indicates that denosumab-associated MRONJ presents distinct epidemiological, clinical and management challenges. Despite an expanding body of research, awareness of MRONJ risk among general dental practitioners remains inconsistent, contributing to preventable adverse outcomes. This narrative review consolidates current knowledge on MRONJ in denosumab-treated patients by examining epidemiology, pathophysiology, clinical features, established risk factors and evidence-based preventive strategies. Numerous guidelines consistently emphasise early dental assessment, optimisation of oral health prior to the first denosumab dose and timely communication between physicians and dental clinicians. A planned dental intervention may be safer when coordinated around the denosumab dosing schedule, particularly by utilising a "window of opportunity" during periods of the waning drug effect. This review also synthesises practical recommendations for routine dental care, pretreatment evaluation, risk stratification and management of established MRONJ. A clinical decision-making flowchart is proposed to assist dental practitioners in evaluating treatment needs, assessing patient risk and planning interventions with minimal disruption to systemic therapy. Taken together, understanding the unique characteristics of denosumab-associated MRONJ is essential for reducing morbidity and improving patient outcomes. Strengthening collaboration between dental practitioners and medical prescribers, along with early identification of vulnerable patients, remains the cornerstone of prevention.
2026-04-09 | The use of denosumab in rare bone diseases in adults: a systematic review from the ECTS Rare Bone Disease Action Group.
Rare bone diseases may display a disrupted RANKL-RANK-Osteoprotegerin pathway causing increased osteoclastogenesis and enhanced bone resorption. Although bisphosphonates are commonly used, they often fall short of desired outcomes. Denosumab, an anti-RANKL antibody, provides a promising alternative by swiftly and strongly suppressing bone turnover (faster and more potent suppression of bone resorption than bisphosphonates), though its effects are reversible upon discontinuation. The use of denosumab has been highlighted, especially in pediatric cases but not substantially in adults. A targeted evidence search was conducted to retrieve studies reporting denosumab use in rare bone diseases in adults. Denosumab administration may lead to pain reduction, lesion reduction or bone formation. Treatment dosage, schedules and duration varied, however, a dose of 120 mg dosed monthly or 3 monthly for almost one year reached the desired treatment effect in most patients. Denosumab is generally well tolerated in adults, with mild common side effects such as (asymptomatic) hypocalcemia and hypophosphatemia. Serious adverse effects such as osteonecrosis of the jaw or atypical femoral fractures are rarely reported. Main concerns regard rebound effect after denosumab discontinuation, with disease recurrence in some cases. Zoledronic acid after discontinuation of denosumab might be advisable, but is seldom reported. Denosumab is a feasible treatment in adults with rare bone diseases when managed by multidisciplinary teams with knowledge of both the underlying disease and potential surgeries as well as the medical site of treatment. Denosumab discontinuation management is paramount to prevent recurrence and severe complications. The paucity of data supports the need for data collection through rare disease registries for future pertinent evidence-based recommendations.
2026-04-06 | Combined Effects of Romosozumab and Zoledronate on the Development of Osteonecrosis of the Jaw.
This study aimed to assess the occurrence of medication-related osteonecrosis of the jaw (MRONJ) in mice following the sequential administration of romosozumab and zoledronate and to confirm their inhibitory effects on osteoclast differentiation in vitro. Thirty-five female C57BL/6 mice were divided into three groups: romosozumab followed by zoledronate (ROM+ ZOL), saline followed by zoledronate (ZOL), and control (Con) group receiving saline. After drug administration, the maxillary first molars were extracted. Bone healing and necrosis were evaluated using micro-computed tomography, histomorphometry, and immunohistochemistry. To investigate the mechanism underlying the in vivo study results, the effects of romosozumab and zoledronate were evaluated by analysing tartrate-resistant acid phosphatase staining and actin ring formation after differentiation of RAW 264.7 cells. The ROM+ZOL group exhibited more severe bone necrosis than the ZOL and Con groups. The ROM+ZOL group demonstrated a lower bone volume fraction and a reduction in the number of sclerostin-positive cells, suggesting enhanced osteonecrosis when romosozumab was administered before zoledronate. Moreover, both zoledronate and romosozumab effectively suppressed osteoclast differentiation and function in vitro. Sequential administration of romosozumab followed by zoledronate may exacerbate the risk of MRONJ, underscoring the need for careful consideration in clinical applications.
2026-03-12 | Atypical femoral fracture and jaw osteonecrosis under high doses of denosumab, healed with the aid of low dose of denosumab: a case report.
Atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ) are rare but serious complications associated with long-term use of antiresorptive therapies such as denosumab. Denosumab discontinuation to allow for bone healing is not possible because of the high risk of spontaneous multiple vertebral fractures. We present a case of concurrent AFF and ONJ in a patient previously treated with denosumab 120mg monthly. The patient was managed with a low-dose denosumab regimen tailored according to bone turnover marker monitoring, resulting in successful bone union and resolution of ONJ.
2026-02-27 | Clinical characteristics of osteonecrosis of the jaw related to denosumab: a 5-year retrospective cohort study.
This study aimed to investigate the clinical characteristics, treatment outcomes, and factors influencing treatment success in patients with denosumab (Dmab)-related osteonecrosis of the jaw (DRONJ). This retrospective cohort study included the patients who were diagnosed with DRONJ and treated at the authors' affiliated hospital, between August 2019 and August 2024. The patients were divided into the three groups; Group 1, low-dose Dmab; Group 2, transition from bisphosphonates (BPs) to low-dose Dmab; Group 3, high-dose Dmab. Differences in clinical characteristics among the groups were compared. Surgical outcomes were classified into three categories: complete healing, partial healing, and no healing. "Treatment success" was defined as the combined proportion of complete and partial healing. A total of 178 DRONJ patients were included in this study. Most of DRONJ occurred in osteoporosis patients. In patients treated with lowdose Dmab, prior BP use resulted in the development of MRONJ within a shorter period after Dmab administration but did not affect disease severity or treatment outcomes. Overall postoperative healing outcomes were favorable at 3 months after DRONJ treatment. The overall treatment success rate was 81.5%; Group 1, 85.0%; Group 2, 82.8%; Group 3, 53.8%, P=0.027). Multiple regression analysis demonstrated that Dmab dosage was a significant factor influencing treatment success, whereas age, treatment duration, lesion location, and DRONJ stage were not (odds ratio, 5.13; 95% confidence interval, 1.19-22.14; P=0.028). The earlier onset in the BP to Dmab transition group may be attributable to the cumulative duration of antiresorptive therapy. Patients treated with high-dose Dmab demonstrated poorer prognosis and more frequent recurrence after MRONJ treatment compared with those treated with low-dose Dmab or BP to Dmab transition therapy. herefore, these findings need to be considered for treatment of DRONJ.
small molecules
2026-07-31 | [Role and mechanism of methyltransferase-like 3 in promoting macrophage NLRP3 inflammatory responses in medication-related osteonecrosis of the jaw].
Objective: To investigate the role and mechanism of methyltransferase-like 3 (METTL3) in regulating macrophage inflammatory responses and the derelopment of medication-related osteonecrosis of the jaw (MRONJ) at the single-cell level. Methods: Single-cell RNA sequencing was used to construct an immune atlas of zoledronic acid (ZA)-induced bisphosphonate-related osteonecrosis of the jaw(BRONJ)-like lesions in mice. Key epigenetic regulators were screened by bioinformatic analysis, and key genes were predicted using virtual knockdown analysis. METTL3 expression in vivo and in vitro was validated by immunohistochemical staining and Western blotting. In vitro knockdown and overexpression experiments were performed to clarify the regulatory effect of METTL3 on NLRP3 inflammasome activation in macrophages. Results: The single-cell atlas showed that ZA treatment significantly induced the recruitment of specific pro-inflammatory macrophage subsets in extraction sockets, accompanied by marked activation of inflammation-related pathways. Bioinformatic screening indicated that NLRP3 inflammasome-related genes served as a central bridge linking inflammatory responses to RNA processing and modification. Pseudotime trajectory and virtual knockdown analyses further suggested that METTL3 functioned as a key node in maintaining the pro-inflammatory state of macrophages. In vivo and in vitro experiments confirmed that ZA significantly induced METTL3 upregulation at both tissue and cellular levels, accompanied by an increase in global m6A levels. Functional assays showed that METTL3 knockdown markedly suppressed NLRP3 inflammasome activation, whereas METTL3 overexpression exerted the opposite effect. Conclusions: This study reveals the critical role of METTL3 as a positive regulator in promoting macrophage NLRP3 inflammatory responses in MRONJ pathogenesis. METTL3 is expected to provide clues for targeted therapy research on modulating local immune dysregulation and promoting bone repair in MRONJ.
2026-07-29 | Advanced biomaterial-based approaches for medication-related osteonecrosis of the jaw.
Medication-related osteonecrosis of the jaw (MRONJ) is a debilitating adverse effect linked to anti-resorptive and anti-angiogenic therapies, with an incidence of 4.34 % (6.22 % in oncology patients and 0.59 % in osteoporosis patients) based on a pooled analysis of 92 observational studies (2015-2020), characterized by persistent bone exposure and poor healing. Conventional treatment modalities often yield suboptimal outcomes, with recurrence and procedural morbidity. In recent years, biomaterial-based strategies have emerged as promising alternatives by targeting MRONJ's complex pathophysiology, including imbalances in bone remodeling, impaired angiogenesis, immune dysregulation, and infection. This review highlights advances in functional biomaterials for bisphosphonate sequestration, restoration of osteo-angiogenic homeostasis, and immune modulation. These platforms have shown efficacy in promoting tissue regeneration while reducing systemic toxicity. However, clinical translation is limited by biosafety, scalability, and regulatory hurdles, such as instability in the oral environment and mismatched scaffold degradation rates. Future efforts should prioritize multifunctional, intelligent, and patient-specific biomaterials, alongside the establishment of standardized preclinical models and clinical trials. Combinatory strategies have great potential for synergistic treatment and addressing the multiple pathological factors of MRONJ. By integrating materials engineering with mechanistic understanding, this review synthesizes current evidence to highlight the transformative potential of biomaterials for MRONJ prevention and therapy.
2026-07-26 | Pharmacological effects of PTH1R agonists on jaw bone fracture, periodontitis, orthodontic treatment and MRONJ: a view from dosing regimen settings.
Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) are endogenous ligands of PTH type I receptor (PTH1R), which are essential for skeletal development and homeostasis. Since the intermittent application of these molecules to organisms exerts bone anabolic effects, they are used pharmacologically to increase bone mass and stimulate bone formation. Teriparatide, an N-terminal 34 amino acid fragment of human PTH, and abaloparatide, a derivative of the N-terminal 34 amino acid of human PTHrP, have been pharmaceutically developed and clinically applied to treat severe osteoporosis and are categorized as PTH1R agonists. An increasing number of clinical and preclinical studies have demonstrated that PTH1R agonists can be used in dental medicine, including jaw bone regeneration and orthodontic treatment, periodontitis, and the management of medication-related osteonecrosis of the jaw (MRONJ). However, it is unclear whether the mandibular bone responds pharmacologically to PTH1R agonists in the same way as other trunk bones, such as the limb and axial bones. Compared with studies using long and vertebral bones, the beneficial effects of PTH1R agonists on the mandibular bone appear to require higher doses and longer treatment durations. Clinical application of PTH1R agonists in dental medicine may result in promising outcomes. However, dosing regimens and the timing of their application should be further investigated with knowledge of the biological uniqueness of the mandibular bone.
2026-07-20 | Sequential Anabolic and Antiresorptive Treatment Promotes Medication-Related Osteonecrosis of the Jaw in Mice.
To investigate the effects of sequential administration of romosozumab and denosumab on post-extraction socket healing and osteonecrosis development in a murine tooth extraction model. Forty female mice were randomly assigned to four groups: control (Ctrl), romosozumab (Rm), denosumab (Dmab), and sequential romosozumab followed by denosumab (Rm + Dmab). After drug administration, bilateral maxillary first molars were extracted. Extraction socket healing was evaluated by micro-computed tomography, histological analysis, and immunohistochemistry for receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin. The Rm + Dmab group exhibited significantly less new bone formation and more necrotic bone in the extraction sockets than the other groups, accompanied by a marked reduction in osteoclast numbers. The Dmab-only group showed a lower RANKL/OPG ratio. No significant differences in sclerostin expression were observed among groups. Sequential administration of romosozumab followed by denosumab severely impaired extraction socket healing and induced osteonecrotic lesions in mice, resembling medication-related osteonecrosis of the jaw (MRONJ). These findings suggest that such sequential antiresorptive therapy may increase the risk of MRONJ in patients undergoing dental extractions.
2026-06-12 | Vitamin D Deficiency as a Context-Dependent Modifier of Osteonecrosis of the Jaw.
Osteonecrosis of the jaw (ONJ) is a multifactorial disorder characterized by impaired bone remodeling, vascular compromise, immune dysregulation, and mucosal barrier disruption. Although these mechanisms have been extensively investigated, they are often discussed separately, limiting an integrated understanding of ONJ pathogenesis. Vitamin D has emerged as a biologically relevant factor across these interconnected pathways, yet its role in ONJ remains incompletely defined. This narrative and hypothesis-generating review synthesizes current mechanistic, preclinical, observational, and clinical evidence regarding vitamin D biology and ONJ and proposes a vitamin D-centered vulnerability model in which vitamin D deficiency acts as a context-dependent modifier rather than a primary causal driver. Mechanistically, vitamin D deficiency may impair osteoblast function and mineralization, disrupt angiogenic responses, promote pro-inflammatory immune signaling, and compromise mucosal integrity, collectively creating a microenvironment susceptible to impaired healing and osteonecrosis. These effects are likely to vary across clinical settings, particularly in patients receiving antiresorptive or antiangiogenic therapies. Clinical and epidemiological studies have reported associations between low vitamin D status and increased ONJ risk or severity, while some observational studies suggest that vitamin D supplementation may be associated with improved outcomes in selected populations. However, current human evidence remains predominantly observational and subject to substantial heterogeneity and residual confounding, and direct randomized evidence is lacking. Overall, this framework provides an integrated perspective linking vitamin D biology to ONJ-related pathogenic processes and may support future mechanistic research, risk stratification, and supportive multidisciplinary management strategies. Nevertheless, the proposed model should be interpreted cautiously as hypothesis-generating and requires further validation in well-designed prospective studies and randomized controlled trials.
proteins
2026-07-29 | Should Teriparatide Be Part of Our Clinical Armamentarium in the Management of Medication-Related Osteonecrosis of the Jaw? A Systematic Review and Meta-Analysis.
Medication-related osteonecrosis of the jaw (MRONJ) is a severe and potentially debilitating drug reaction. Adjunctive treatments including pentoxifylline, tocopherol, and teriparatide (TPTD) have been studied, but TPTD's efficacy remains unclear. This systematic review and meta-analysis aims to consolidate and evaluate high-quality evidence on TPTD in managing MRONJ. An electronic search strategy was performed on 3 databases (Pubmed, Embase, and Cochrane CENTRAL). Search terms include ("Teriparatide" OR "TPTD" OR "Recombinant Parathyroid Hormone" OR "Recombinant PTH") AND ("Medication-Related Osteonecrosis of the Jaw" OR "MRONJ" OR "BRONJ"). No publication date range was utilized. Inclusion criteria include randomized controlled trials, case-control studies, and cohort studies. All systematic reviews, case reports, case series, animal studies, editorials, non-English publications, or studies relating to osteoradionecrosis were excluded. Each study was screened independently, followed by final study selection after discussion with all authors. Primary meta-analysis used Cox proportional hazards regression with pseudo-individual-subject data reconstructed from published Kaplan-Meier curves (Guyot method) and a Tierney events + P value derivation for one study without Kaplan-Meier data. A sensitivity analysis pooled odds ratios (ORs) at the 6-month clinical response endpoint. Primary outcomes include improvement in MRONJ clinical staging. Secondary outcomes include time to improvement, adverse effects, radiographic evaluation, and presence of serum markers. After review of 162 studies, 5 (3.1%) studies were included in the systematic review with 3 (1.9%) studies included in the meta-analysis (n = 101 subjects). A three-study Cox hazard ratio (HR) meta-analysis yielded a pooled HR of 5.35 (95% CI, 3.14 to 9.13, P < .0001, I2 = 0%) favoring TPTD. Subgroup analyses by dosing regimen showed directionally consistent effects (daily pooled HR = 12.52; 95% CI, 5.75 to 27.23; weekly pooled HR = 8.09; 95% CI, 3.59 to 18.26; both I2 = 0%), and an OR-based sensitivity analysis at the 6-month binary healing endpoint was directionally concordant (pooled OR = 14.26; 95% CI, 2.83 to 71.77). Adjunctive TPTD shows improvement of MRONJ staging and time to healing compared to conventional treatments alone, but the magnitude of the impact remains unclear. Additional evidence, including studies evaluating dosing regimens and subject segmentation by MRONJ staging, is warranted.
2026-07-11 | Pharmacological and surgical predictors of postoperative healing in medication-related osteonecrosis of the jaw: A retrospective multicenter cohort study.
Failure to achieve postoperative healing after surgical treatment of medication-related osteonecrosis of the jaw (MRONJ) remains a clinical challenge. We aimed to investigate the independent predictors of postoperative nonhealing and to evaluate the impact of regenerative adjuncts. In a multicenter surgical cohort (2019-2025) of 531 patients with MRONJ, pharmacological, lesion level, and surgical factors were assessed using univariable testing, elastic net regularization for variable selection, and multivariable logistic regression. Postoperative nonhealing was defined as the need for additional surgical intervention or failure to achieve complete mucosal coverage, accompanied by clinical or radiographic evidence of persistent or progressive disease. Kaplan-Meier analysis was used to estimate nonhealing-free survival. The overall postoperative nonhealing rate was 18.5% (98/531). In the multivariable models, high-dose antiresorptive therapy (odds ratio [OR]: 2.94, 95% confidence interval [CI]: 1.70-5.06) and multiple-site lesions (OR: 2.29, 95% CI: 1.09-4.67) were independent risk factors for postoperative nonhealing, whereas intraoperative bone morphogenetic protein (BMP) use was associated with a lower risk of postoperative nonhealing (OR: 0.32, 95% CI: 0.20-0.52). The number needed to treat to prevent one postoperative nonhealing event was 5.3 (95% CI: 3.9-8.7) for BMP, and the number needed to harm was 4.4 (95% CI: 3.0-8.5) for high-dose therapy. Solitary maxillary lesions showed an insignificant protective effect. Antiangiogenic agents were associated with postoperative nonhealing in the univariate and elastic net analyses, but not in the final multivariable model. Neither treatment duration nor preoperative drug holiday was independently associated with postoperative nonhealing. The elastic net model showed acceptable discrimination (area under the curve [AUC]: 0.724), and the Kaplan-Meier curves were consistent with these findings. Postoperative nonhealing after surgical management of MRONJ was mainly associated with systemic pharmacological burden and lesion extent, whereas BMP application was associated with improved postoperative healing. These findings support further investigation of regenerative adjuncts and risk-adapted surgical management strategies.
2026-05-22 | Synergistic application of concentrated growth factor and bone perforation technique in bisphosphonate-related-osteonecrosis of the jaw.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication caused by the deposition of bisphosphonates in bone tissue, particularly after invasive dental procedures. Its pathogenesis is closely related to impaired bone remodeling and insufficient blood supply. Optimizing treatment strategies for BRONJ remains a significant clinical challenge. This study aims to evaluate the therapeutic effects of concentrated growth factor (CGF) combined with the bone perforation technique in the treatment of BRONJ. A rat model of BRONJ was established and divided into four groups: Non-treated group (N), Bone perforation group (B), CGF group (C), and CGF + Bone perforation group (C + B). Bone repair was evaluated at 2 and 4 weeks post-treatment through micro-computed tomography (Micro-CT), histological analysis (HE and TRAP staining), Western blot, immunofluorescence staining, and qRT-PCR (RUNX2, ALP). HE staining at 2 weeks postoperatively showed abundant empty lacunae with inflammation in the N and B groups, while the C and C + B groups exhibited reduced necrotic bone and new bone formation. At 4 weeks, the C + B group achieved complete epithelial healing with no residual necrotic bone. Quantitative histomorphometry revealed that the TRAP-positive area was 0.32% in the C group and 0.27% in C + B groups, significantly higher than that in the N group 0.12%(p < 0.001). PCR analyses revealed that, at 2 weeks, ALP expression was highest in the C group compared to all other groups (N, B, and C + B) (p < 0.001), whereas RUNX2 expression showed no significant difference between the C and C + B groups but was significantly higher than that in the N and B groups (p < 0.01). At 4 weeks, the C + B group exhibited the highest ALP and RUNX2 expression, significantly exceeding all other groups (N, B, and C). Western blot analyses demonstrated that at 2 weeks post-surgery, ALP and RUNX2 protein expression was higher in the C group than in all other groups (p < 0.05). At 4 weeks, ALP expression was higher in the C and C + B groups compared to the other groups (p < 0.001). RUNX2 expression was highest in the C + B group (p < 0.001). Our results demonstrate that CGF significantly promotes BRONJ repair, while the bone perforation technique improves early blood supply but has limited long-term therapeutic effects. The combined application of CGF and bone perforation exerts a synergistic effect in enhancing osteogenesis and optimizing bone repair outcomes. Future studies with larger sample sizes and longer follow-up periods are warranted to verify these findings.
2026-03-10 | Regenerative and surgical strategies for medication-related osteonecrosis of the jaw (MRONJ): a systematic review
Aim: Medication-related osteonecrosis of the jaw (MRONJ) challenges clinicians with its complex pathology and high risk of complications. Methods: We searched seven databases - PubMed, Scopus, Web of Science, Cochrane Library, Embase, CINAHL, and Google Scholar - and adapted the search strings for each database to optimize retrieval of relevant studies. We then systematically reviewed the included studies to identify the most effective treatments for promoting MRONJ healing. Results: A total of 329 records were identified through database searches across seven electronic databases. After removal of 45 duplicates, 284 records were screened. Following title and abstract screening and full-text assessment, 13 studies met the eligibility criteria and were included in the qualitative synthesis. The included studies consisted primarily of randomized controlled trials and retrospective cohort studies investigating surgical, pharmacological, and adjunctive therapeutic strategies for MRONJ management. Risk-of-bias assessment using the RoB 2.0 and ROBINS-I (Risk of Bias in Non-randomised Studies - of Interventions) tools showed that most studies presented low to moderate risk of bias, although some methodological concerns were identified. Surgical interventions were commonly associated with improved clinical healing, while adjunctive therapies such as bone morphogenetic protein-2 and teriparatide showed promising outcomes in selected cases. Follow-up periods ranged from 1 month to 2 years, and outcome measures included clinical, radiological, and histological evaluations. Conclusion: MRONJ treatment is diverse and multifaceted. Such inferences were made to varying degrees in previous investigations, illustrating the limitations for clinical use, revealing the need for further studies to clarify both the efficacy and optimal use of the interventions in diverse clinical settings.
2026-02-15 | The effectiveness of different treatment methods in the treatment and prevention of medication-related osteonecrosis of the jaw: A systematic review and Bayesian network meta-analysis.
The treatment strategies and efficacy of medication-related osteonecrosis of the jaw (MRONJ) are controversial, and there is a lack of unified clinical treatment standards. We used a Bayesian network meta-analysis method to evaluate the clinical efficacy of different intervention methods. We searched for clinical controlled trials published from January 2010 to May 2025 in PubMed, the Cochrane Library, Web of Science, and Embase. We assessed the quality of the included studies using the NOS quality assessment and the Cochrane risk of bias tool. We conducted a network meta-analysis (NMA) using R Studio and ranked the treatment modalities for each outcome measure using SUCRA. A total of 19 studies were included, involving 1064 MRONJ patients and 12 different intervention measures. The meta-analysis results showed that the included interventions improved healing rates compared to conventional surgical treatment [RR = 1.44, 95 % CI (1.20, 1.71), P < 0.001]; and reduced the incidence of MRONJ in high-risk populations [RR = 0.10, 95 % CI (0.04, 0.29), P < 0.001]. The network meta-analysis results showed that the top three wound healing rates in the probability-weighted ranking were: BMP-2 + L-PRF (89.3 %) > Hyperbaric oxygen (84.1 %) > YAG laser + LLLT (67.8 %) CONCLUSION: Based on the meta-analysis results, we found that the intervention methods included in the study were effective compared to conventional surgical treatment and prevented the incidence of MRONJ in high-risk populations. The SUCRA value showed that BMP-2 + L-PRF significantly improved the healing rate of MRONJ patients and may have good clinical application prospects.
cell therapies
2026-08-09 | Individualized 3D-Printed Titanium Mesh-Assisted Alveolar Reconstruction and Implant Rehabilitation Following MRONJ Resection: A Case Report.
Medication-related osteonecrosis of the jaw is a severe complication of antiresorptive therapy that often necessitates complex reconstructive surgery. This report describes a case of implant-supported rehabilitation using a customized 3D-printed titanium mesh for an extensive mandibular defect resulting from medication-related osteonecrosis of the jaw. A 58-year-old woman with stage-3 medication-related osteonecrosis of the jaw after zoledronate therapy underwent segmental mandibulectomy and reconstruction with a free iliac crest graft. Nine months later, a customized titanium mesh was placed to protect the planned 9.5-11 mm augmentation. Cone beam computed tomography confirmed mineralized regeneration within the mesh. The mesh was removed after achieving 9.5 mm vertical and 11 mm horizontal alveolar augmentation, and 4 implants were placed with high primary stability (insertion torque ≥ 40 N cm). At 6 months, resonance frequency analysis values ranged from 75 to 84, allowing delivery of a splinted fixed prosthesis. At 12 months of loading, the peri-implant tissues remained normal with stable radiographic bone levels and satisfactory function. Combining customized 3D-printed titanium mesh with guided implant placement supports stable bone regeneration and prosthetic rehabilitation in patients with medication-related osteonecrosis of the jaw. However, outcomes depend on medication history, therapy timing, and unresolved drug-related factors, underscoring the need for a multidisciplinary approach with individualized treatment and proactive complication care.
2026-07-31 | [A retrospective study of pedicled flaps for repair of oral mucosal defects in patients with medication-related osteonecrosis of the jaw].
Objective: To investigate the clinical efficacy of pedicled flaps for repairing oral mucosa defects in medication-related osteonecrosis of the jaw (MRONJ), and to analyze the indications for different types of pedicled flaps. Methods: The clinical data of 158 MRONJ patients who met the inclusion criteria and were admitted to the Department of Maxillofacial Trauma and Orthognathic Surgery, Hospital of Stomatology, Air Force Medical University from January 2019 to December 2024 were retrospectively analyzed, including 74 males (46.8%) and 84 females (53.2%).The mean age was (59.2±10.7) years (range, from 20 to 87 years old). According to the method of soft tissue repair, the patients were divided into direct suture group (61 cases) and pedicled tissue flap group (97 cases, including 80 cases of buccal fat pad flap and 17 cases of submental island flap). The rate of secondary operation was compared between the two groups. Multivariate binary Logistic regression and subgroup analysis were used to evaluate the efficacy and influencing factors of pedicled tissue flaps, and the comparison between the buccal fat pad flap and submental island flap was performed. Results: The median follow-up time was 36 months. Univariate analysis showed that the secondary operation rate was 68.9% (42/61) in the direct suture group, which was significantly higher than 16.5% (16/97) in the pedicled tissue flap group (P<0.001). After adjusting for confounding factors such as age and lesion location, multivariate Logistic regression analysis showed that pedicled tissue flap was an independent protective factor against the risk of secondary surgery (OR=0.049, P<0.001). Stage 3 disease was an independent risk factor for secondary surgery (OR=8.455, P=0.002). Subgroup analysis showed that the secondary operation rate of pedicled tissue flap was significantly lower than that of direct suture in stage 3 group, mandibular group,<65 years group, male group and female group (all P<0.05). There was no significant difference among stage 2 group, maxillary group and≥65 years group (all P>0.05), but the trend of protection was the same. The secondary operation rate was 17.5% (14/80) in the buccal fat pad flap group and 2/17 in the submental island flap group. There was no significant difference between the two groups (P=0.730). Conclusions: The use of pedicled tissue flap for repairing oral mucosal wounds can significantly reduce the risk of secondary surgery for MRONJ, and the effect is superior to direct suture. Buccal fat pad flap is the first choice for maxillary and retromolar mucosal defects, and submental island flap can be used for large mandibular mucosal defects.
2026-07-31 | [Research progress of mesenchymal stem cells in the treatment of medication-related osteonecrosis of the jaw].
Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication characterized primarily by jawbone necrosis, induced by bisphosphonates or other targeted agents for systemic diseases. With the advancement of systemic anticancer therapies, the survival of patients with advanced malignancies has been prolonged, leading to an annual increase in the number of patients with MRONJ. However, there is currently no effective treatment for MRONJ worldwide. Recent studies have indicated that mesenchymal stem cells exhibit significant potential for osteogenic and angiogenic differentiation, proliferation, immunomodulation, and anti-inflammatory effects, thereby providing a novel therapeutic strategy for medication-related osteonecrosis of the jaw. This article reviews the research on mesenchymal stem cell therapy for MRONJ, providing a reference for its clinical research and treatment.
2026-06-01 | Human Amniotic Membrane as Adjuvant Therapy in Medication-Related Osteonecrosis of the Jaw: A Scoping Review
Background: Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication characterized by progressive destruction of the maxillary and mandibular bones in patients receiving antiresorptive or antiangiogenic agents. Despite evolving clinical guidelines, its management remains controversial and nonstandardized. Human amniotic membrane (HAM) has emerged as a promising adjuvant therapy due to its immunomodulatory, anti-inflammatory, and regenerative properties. Objective: To identify and synthesize available evidence on the effectiveness of HAM as an adjuvant treatment in promoting wound healing in patients diagnosed with MRONJ. Methods: A scoping review was conducted following the PRISMA-ScR framework. Searches were performed in PubMed/MEDLINE, Scopus, and Web of Science using MeSH terms and free-text keywords including “amniotic membrane,” “amnion,” “bisphosphonate-associated osteonecrosis,” and “medicationrelated osteonecrosis of the jaw,” combined with Boolean operators. Searches were limited to primary human studies published within the past five years. Results: A total of 25 records were identified; after deduplication and screening, 3 primary studies were included comprising a total of 39 patients across various MRONJ stages. Across all studies, 83.8% of patients achieved complete mucosal wound closure, and 84.6% reported a significant reduction in pain perception. No adverse events, recurrences, or infectious complications were reported. Conclusions: HAM represents a viable, versatile, and effective adjuvant intervention in the surgical management of MRONJ. It promotes soft-tissue healing, reduces pain and infection, and favorably impacts patient prognosis and quality of life. Randomized controlled trials with larger samples and standardized protocols are warranted.
2026-05-20 | Mesenchymal stem cell therapy for treatment of medication related osteonecrosis of the jaw (MRONJ): A systematic review.
Medication-related osteonecrosis of the jaw (MRONJ) is a significant adverse effect associated with antiresorptive and antiangiogenic therapies. Therapies utilizing mesenchymal stem cells (MSCs) represent a promising regenerative strategy; however, conventional management methods have shown limited effectiveness. This systematic review aimed to evaluate the effectiveness of MSC-based interventions in preventing and treating MRONJ. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify studies published from 2011 to 2024. Studies examining MSCs therapy in the context of MRONJ were incorporated according to predefined inclusion and exclusion criteria. Seventeen studies (6 clinical, 11 preclinical) met inclusion criteria. Preclinical models demonstrated that MSCs enhance angiogenesis and bone regeneration, providing mechanistic support for human application. Clinically, 80-90% of patients achieved complete mucosal healing with radiographic evidence of bone regeneration. However, due to species differences in oral microbiome and immunity, animal findings require confirmation in human trials. This review integrates human clinical data with mechanistic insights from preclinical studies. Human evidence shows promising mucosal and bone regeneration, while animal studies elucidate underlying mechanisms-particularly angiogenesis and immunomodulation. Given that animal models cannot replicate the human oral immune environment, these findings should be interpreted as hypothesis-generating. MSC therapy represents a biologically sound but experimental strategy, warranting confirmation through randomized controlled trials.
other
2025-12-11 | The Mitigating Effect and Mechanism of Polydeoxyribonucleotide Against Zoledronic Acid-Induced Growth Suppression of Human Gingival Fibroblasts.
Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, is widely used to treat osteoporosis and bone metastases. However, its clinical application is limited by adverse effects, notably bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is associated with cytotoxicity in oral mucosal cells. Polydeoxyribonucleotide (PDRN), a salmon sperm-derived DNA polymer with regenerative and anti-inflammatory properties, has shown therapeutic potential in tissue repair; however, its ability to mitigate ZA-induced cytotoxicity remains poorly understood. Here, we investigated the molecular mechanisms of ZA-induced toxicity in HGF-1 cells, a human gingival fibroblast line, and evaluated the protective effects of PDRN. ZA treatment (50 µM, 48 h) significantly inhibited HGF-1 cell growth, accompanied by reduced phosphorylation of protein kinase B (PKB) and signal transducer and activator of transcription 3 (STAT-3), along with increased phosphorylation of TANK-binding kinase 1 (TBK1). TBK1 silencing restored cell growth under ZA exposure, whereas silencing PKB or STAT-3 further suppressed cell growth even without ZA. Co-treatment with PDRN (100 µg/mL) effectively prevented and reversed ZA-induced HGF-1 cytotoxicity. Mechanistically, PDRN inhibited ZA-induced TBK1 phosphorylation and partially restored PKB phosphorylation, though it did not reverse the reduction in p-STAT-3. Additionally, ZA significantly elevated intracellular reactive oxygen species (ROS) levels at 8 h, which were attenuated by PDRN. The antioxidant N-acetylcysteine (NAC) similarly reduced ZA-induced ROS and p-TBK1 levels and improved cell growth, although it had limited effects on p-PKB at 8 h. Importantly, delayed PDRN treatment following ZA exposure reversed ZA-induced cell growth inhibition and TBK1 activation in a dose- and time-dependent manner. In summary, these findings demonstrate that ZA suppresses HGF-1 cell growth through ROS production, TBK1 activation, and inhibition of PKB and STAT-3, whereas PDRN counteracts these effects primarily by suppressing TBK1 activation and oxidative stress.
2025-09-02 | Rethinking Osteonecrosis of the Jaw: Could Cellular Senescence Be the Missing Link Between ORN and MRONJ?
Osteonecrosis of the jaw (ONJ) is a series bone diseases characteristic with similar diagnostic criteria and clinical manifestations. Phossy jaws, medication-related osteonecrosis of the jaw (MRONJ), and osteoradionecrosis (ORN) are major subtypes of ONJ. Though subtypes of ONJ are considered different diseases in clinical practice, similar diagnostic criteria, clinical presentation, and features prompt the possibility that there is a common pathogenesis mechanism for ONJ subtypes. Current pathogenic theories fail to fully explain the delayed onset, persistent progression, and stimulus-independent nature of ONJ. Here, we propose that cellular senescence could be a common pathogenesis mechanism of ONJ. Radiation, antiresorptive agents, and trauma induce persistent DNA damage and activate the DNA damage response, leading to irreversible senescence in jawbone cells. This model explains key clinical observations and offers a rationale for the failure of stimulus withdrawal to reverse disease progression. We outline future directions to validate this hypothesis. If confirmed, this hypothesis may unify ONJ subtypes under a single pathogenic framework and open avenues for targeted interventions.
2024-10-16 | Genetic Background of Medication-Related Osteonecrosis of the Jaw: Current Evidence and Future Perspectives.
Medication-related osteonecrosis of the jaw (MRONJ) is a rare side effect of antiresorptive drugs that significantly hinders the quality of life of affected patients. The disease develops in the presence of a combination of factors. Important pathogenetic factors include inflammation, inhibition of bone remodeling, or genetic predisposition. Since the first description of this rare side effect in 2003, a growing body of data has suggested a possible role for genetic factors in the disease. Several genes have been suggested to play an important role in the pathogenesis of MRONJ such as SIRT1, VEGFA, and CYP2C8. With the development of molecular biology, newer methods such as miRNA and gene expression studies have been introduced in MRONJ, in addition to methods that can examine the base sequence of the DNA. Describing the complex genetic background of MRONJ can help further understand its pathophysiology as well as identify new therapeutic targets to better manage this adverse drug reaction.
2024-07-09 | Inflammation Can Be a High-Risk Factor for Mucosal Nonunion of MRONJ by Regulating SIRT1 Signaling When Treated with an Oncologic Dose of Zoledronate.
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. 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. 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. 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.
2023-11-13 | Exosome-targeted delivery of METTL14 regulates NFATc1 m6A methylation levels to correct osteoclast-induced bone resorption
Abstract Osteoporosis has a profound influence on public health. First-line bisphosphonates often cause osteonecrosis of the jaw meanwhile inhibiting osteoclasts. Therefore, it is important to develop effective treatments. The results of this study showed that the increased level of NFATc1 m6A methylation caused by zoledronic acid (ZOL), with 4249A as the functional site, is highly correlated with the decreased bone resorption of osteoclasts. Upstream, METTL14 regulates osteoclast bone absorption through the methylation functional site of NFATc1. Downstream, YTHDF1 and YTHDF2 show antagonistic effects on the post-transcriptional regulation of NFATc1 after the m6A methylation level is elevated by METTL14. In this study, meRIP-Seq, luciferase reporter assays, meRIP and other methods were used to elucidate the NFATc1 regulatory mechanism of osteoclasts from the perspective of RNA methylation. In addition, EphA2 overexpression on exosomes is an effective biological method for targeted delivery of METTL14 into osteoclasts. Importantly, this study shows that METTL14 released by exosomes can increase the m6A methylation level of NFATc1 to inhibit osteoclasts, help postmenopausal osteoporosis patients preserve bone mass, and avoid triggering osteonecrosis of the jaw, thus becoming a new bioactive molecule for the treatment of osteoporosis.
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Drug Discovery Landscape
1 orphan drug designation for Osteonecrosis of the jaw.
1 orphan drug designation for Osteonecrosis of the jaw.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant human platelet derived growth factor BB | proteins | FDA | 2007-02-01 | — | Luitpold Pharmaceuticals, Inc. |
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