American Association of Oral and Maxillofacial Surgeons' Position Paper on Medication-Related Osteonecrosis of the Jaws-2022 Update.

Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaws (MRONJ) - formerly referred to as bisphosphonate-related osteonecrosis of the jaws (BRONJ)-were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007, 2009 and 2014. The position papers were developed by a committee appointed by the AAOMS Board of Trustees and comprising clinicians with extensive experience in caring for these patients, as well as clinical and basic science researchers. The knowledge base and experience in addressing MRONJ continues to evolve and expand, necessitating modifications and refinements to the previous position papers. Three members of the AAOMS Committee on Oral, Head, and Neck Oncologic and Reconstructive Surgery (COHNORS) and three authors of the 2014 position paper were appointed to serve as a working group to analyze the current literature and revise the guidance as indicated to reflect current knowledge in this field. This update contains revisions to diagnosis and management strategies and highlights the current research status. AAOMS maintains that it is vitally important for this information to be disseminated to other relevant healthcare professionals and organizations.

Case-Based Review of Osteonecrosis of the Jaw (ONJ) and Application of the International Recommendations for Management From the International Task Force on ONJ.

Osteonecrosis of the jaw (ONJ) has been associated with antiresorptive therapy in both oncology and osteoporosis patients. This debilitating condition is very rare and advances in diagnosis and management may now effectively reduce the risk of its development and offer valuable treatment options for affected patients. This paper provides a case-based review of ONJ and application of the International Task Force on ONJ (referred to as the "Task Force") recommendations for the diagnosis and management of ONJ. The Task Force was supported by 14 international societies and achieved consensus from representatives of these multidisciplinary societies on key issues pertaining to the diagnosis and management of ONJ. The frequency of ONJ in oncology patients receiving oncology doses of bisphosphonate (BP) or denosumab is estimated at 1%-15%, and the frequency in the osteoporosis patient population receiving much lower doses of BP or denosumab is estimated at 0.001%-0.01%. Although the diagnosis of ONJ is primarily clinical, imaging may be helpful in confirming the diagnosis and staging. In those with multiple risk factors for ONJ for whom major invasive oral surgery is being planned, interruption of BP or denosumab therapy (in cancer patients) is advised, if possible, before surgery, until the surgical site heals. Major oral surgery in this context could include multiple extractions if surgical extractions are required, not simple forceps extractions. ONJ development may be reduced by optimizing oral hygiene and postoperatively using topical and systemic antibiotics as appropriate. Periodontal disease should be managed before starting oncology doses of BP or denosumab. Local debridement may be successful in disease unresponsive to conservative therapy. Successful surgical intervention has been reported in those with stage 3 disease; less severe disease is best managed conservatively. Teriparatide may be helpful in healing ONJ lesions and may be considered in osteoporosis patients at a high fracture risk in the absence of contraindications. Resumption of BP or denosumab therapy following healing of ONJ lesions is recommended, and there have not been reports of subsequent local recurrence.

Disease Stage and Mode of Therapy Are Important Determinants of Treatment Outcomes for Medication-Related Osteonecrosis of the Jaw.

PURPOSE: The treatment of patients with medication-related osteonecrosis of the jaw (MRONJ) is challenging. The purpose of the present study was to estimate the frequency and identify the factors associated with clinical improvement during treatment. PATIENTS AND METHODS: We designed and implemented a retrospective cohort study and enrolled a sample of subjects diagnosed with MRONJ between 2004 and 2015. The primary predictor variables were a set of heterogeneous variables grouped into the following categories: demographic (age and gender) and clinical (location of necrosis, therapy duration, medication type, disease stage, and treatment type). The primary outcome variable was the treatment outcome, defined as stable or worse and improved or healed. The descriptive, bivariate, and multiple logistic statistics were computed, and statistical significance was defined as P < .05. RESULTS: The sample included 337 subjects with a mean age of 68.9 years. Of the 337 subjects, 256 were women (76%). A total of 143 patients (42.2%) experienced spontaneous necrosis. Twenty-four (7.1%) had had exposure to targeted antiangiogenic agents. Those with stage 1 or 2 disease were more likely to have better outcomes than those with stage 3 disease (stage 1, adjusted odds ratio [OR] 3.4, P = .005; stage 2, adjusted OR 2.2, P = .03). Treatment type was a significant variable. Subjects undergoing surgery were 28 times more likely to have a positive outcome than those receiving nonoperative therapy (adjusted OR 28.7, P < .0001). CONCLUSIONS: Subjects with MRONJ who presented with less severe disease or who underwent operative treatment were most likely to have improvement or complete healing of their MRONJ-related lesions.

American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update.

Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaw (MRONJ) were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007 and 2009. The position papers were developed by a special committee appointed by the board and composed of clinicians with extensive experience in caring for these patients and basic science researchers. The knowledge base and experience in addressing MRONJ has expanded, necessitating modifications and refinements to the previous position paper. This special committee met in September 2013 to appraise the current literature and revise the guidelines as indicated to reflect current knowledge in this field. This update contains revisions to diagnosis, staging, and management strategies and highlights current research status. The AAOMS considers it vitally important that this information be disseminated to other relevant health care professionals and organizations.

Development and Standardization of an Osteoradionecrosis Classification System in Head and Neck Cancer: Implementation of a Risk-Based Model.

PURPOSE: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. METHODS: Consecutive patients with head and neck cancer (HNC) treated with curative-intent intensity-modulated radiation therapy (IMRT) (≥45 Gy) from 2011 to 2017 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared with 15 existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). RESULTS: ORN was identified in 219 of 2,732 (8%) consecutive patients with HNC. Factors associated with high risk of ORN were oral cavity or oropharyngeal primaries, received IMRT dose ≥60 Gy, current/ex-smokers, and/or stage III to IV periodontal condition. The ORN rate for high-risk versus low-risk patients was 12.7% versus 3.1% (P < .001) with an AUC of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, ClinRad, was proposed on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. CONCLUSION: We identified risk factors for ORN and proposed a novel ORN classification system on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN and may facilitate clinical care and clinical trials.

Prevention and Management of Osteoradionecrosis in Patients With Head and Neck Cancer Treated With Radiation Therapy: ISOO-MASCC-ASCO Guideline.

PURPOSE: To provide evidence-based recommendations for prevention and management of osteoradionecrosis (ORN) of the jaw secondary to head and neck radiation therapy in patients with cancer. METHODS: The International Society of Oral Oncology-Multinational Association for Supportive Care in Cancer (ISOO-MASCC) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library databases were searched for randomized controlled trials and observational studies, published between January 1, 2009, and December 1, 2023. The guideline also incorporated systematic reviews conducted by ISOO-MASCC, which included studies published from January 1, 1990, through December 31, 2008. RESULTS: A total of 1,539 publications were initially identified. There were 487 duplicate publications, resulting in 1,052 studies screened by abstract, 104 screened by full text, and 80 included for systematic review evaluation. RECOMMENDATIONS: Due to limitations of available evidence, the guideline relied on informal consensus for some recommendations. Recommendations that were deemed evidence-based with strong evidence by the Expert Panel were those pertaining to best practices in prevention of ORN and surgical management. No recommendation was possible for the utilization of leukocyte- and platelet-rich fibrin or photobiomodulation for prevention of ORN. The use of hyperbaric oxygen in prevention and management of ORN remains largely unjustified, with limited evidence to support its practice.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

Metastatic cancer identified in osteonecrosis specimens of the jaws in patients receiving intravenous bisphosphonate medications.

PURPOSE: The aim of the present study was to investigate the microscopic presence of metastatic cancer in jaw specimens clinically and histologically diagnosed as having osteonecrosis in patients receiving intravenous bisphosphonate medications. PATIENTS AND METHODS: A retrospective cohort multicenter study was designed. Patients from the University of Tennessee Medical Center, New York University Medical Center, and New York Center for Orthognathic and Maxillofacial Surgery were enrolled who had been treated with intravenous bisphosphonate medications for an underlying diagnosis of cancer and who had been clinically diagnosed with bisphosphonate-related osteonecrosis of the jaws (BRONJ). The institutional review boards approved the present study. The primary predictor variable was the clinical presence of BRONJ. The primary outcome variable was the microscopic presence of metastatic cancer in the osteonecrotic jaw specimens. RESULTS: A total of 744 sites of BRONJ were clinically diagnosed. Of these sites, 552 (74%) were diagnosed in patients who had received intravenous bisphosphonate medications. Of these 552 sites, 357 (65%) underwent microscopic evaluation through biopsy, sequestrectomy, or resection with curative intent. Of the 357 sites of BRONJ subjected to microscopic analysis, 19 (5.3%) sites were diagnosed with 20 cancers in 16 patients. CONCLUSIONS: Albeit rare, the presence of cancer in a BRONJ specimen represents 1 explanation for the development of osteonecrosis in patients exposed to intravenous bisphosphonate medications in whom a clinical diagnosis of BRONJ has been applied. Additional molecular information is needed to provide an explanation for this observation.

Absence of exposed bone following dental extraction in beagle dogs treated with 9 months of high-dose zoledronic acid combined with dexamethasone.

PURPOSE: Factors contributing to osteonecrosis of the jaw with anti-remodeling drug treatment are unclear. Epidemiologic and experimental studies have suggested the combination of bisphosphonates and dexamethasone results in osteonecrosis of the jaw more often than either agent alone. The goal of this study was to assess the combination of these 2 drugs in a large animal model previously shown to be susceptible to exposed bone in the oral cavity when treated with bisphosphonates. MATERIALS AND METHODS: Skeletally mature beagle dogs were untreated controls or treated with zoledronic acid (ZOL), dexamethasone (DEX), or ZOL plus DEX. ZOL and DEX were given at doses based on those used in humans. All animals underwent single molar extraction at 7 and 8 months after the start of the study. Extraction sites were obtained at month 9 for assessment of osseous healing using micro-computed tomography and histology. RESULTS: No animals were observed to have exposed bone after dental extraction, yet 1 animal treated with ZOL and 1 treated with ZOL plus DEX had severely disrupted extraction sites as viewed by computed tomography and histology. These 2 animals had an intense periosteal reaction that was less obvious but still present in all ZOL-treated animals and absent from untreated animals. There was no significant difference in bone volume within the socket among groups at 4 or 8 weeks after healing, yet the ratio of surface to volume was significantly higher in animals treated with ZOL plus DEX at 8 weeks compared with control animals. CONCLUSIONS: These findings suggest a more complex pathophysiology to osteonecrosis of the jaw than is implied by previous epidemiologic studies and those in rodents and raise questions about the potential role of DEX in its etiology.

Diagnosis and management of antiresorptive-related osteonecrosis of the jaw.

Antiresorptive medications have proven to be extremely efficacious in the treatment of disorders of bone remodeling and metabolism. However, the benefits of these agents have been offset to some degree by the occurrence of jaw necrosis in a subset of patients receiving these medications. This complication was first reported in 2004; since then there have been multiple retrospective, prospective, and case-controlled studies that have defined the diagnosis, associated risk factors, and treatment outcomes for this unique complication. The risk of developing this complication appears to be related to the potency of the antiresorptive, the duration of exposure, and dentoalveolar trauma. Stage-specific management strategies have been developed, as well as guidelines for evaluating the potential risks associated with this complication. Recent clinical, in vivo, and in vitro studies have made significant progress toward understanding anti-resorptive osteonecrosis of the jaw.

Pathophysiology of Medication-Related Osteonecrosis of the Jaw-A Minireview.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse effect of antiresorptive medications administered for control of osseous malignancy, osteoporosis, or other bone metabolic diseases. Despite being reported in the literature two decades ago, MRONJ etiology, pathophysiology, and progression remain largely unknown, and current nonoperative or operative treatment strategies are mostly empirical. Several hypotheses that attempt to explain the mechanisms of MRONJ pathogenesis have been proposed. However, none of these hypotheses alone is able to capture the complex mechanistic underpinnings of the disease. In this minireview, we aim to highlight key findings from clinical and translational studies and propose a unifying model for the pathogenesis and progression of MRONJ. We also identify aspects of the disease process that require further investigation and suggest areas for future research efforts toward calibrating methodologic approaches and validating experimental findings. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Development and Standardization of a Classification System for Osteoradionecrosis: Implementation of a Risk-Based Model.

Purpose: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. Methods: Consecutive head-and-neck cancer (HNC) patients treated with curative-intent IMRT (≥ 45Gy) in 2011-2018 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared to fifteen existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). Results: ORN was identified in 219 out of 2732 (8%) consecutive HNC patients. Factors associated with high-risk of ORN were: oral-cavity or oropharyngeal primaries, received IMRT dose ≥60Gy, current/ex-smokers, and/or stage III-IV periodontal disease. The ORN rate for high-risk vs low-risk patients was 12.7% vs 3.1% (p<0.001) with an area-under-the-receiver-operating-curve (AUC) of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, RadORN, was proposed based on vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. Conclusion: We identified risk factors for ORN, and proposed a novel ORN classification system based on vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN, and may facilitate clinical care and clinical trials.

Bisphosphonate osteonecrosis of the jaw: a historical and contemporary review.

The use of bisphosphonate drugs has been popularised in the late 20th century for the management of many conditions associated with abnormalities of bone turnover, particularly metastatic and haematogenous malignancy and osteopenia. The increase in indications for the use of bisphosphonates was supported by what was thought to be a very good safety profile. However in 2003 cases of osteonecrosis related to the use of bisphosphonates were first described. The pathogenesis, and with this the explanation of why it only appears to affect the maxillofacial skeleton, and the best way of managing this problem remains unknown. In this review we examine the process of identification of this pathology and the development of guidelines from medical societies and professional bodies on the management of patients before commencing bisphosphonate therapy, requiring dental treatment whilst on therapy, or with a diagnosis of bisphosphonate associated osteonecrosis of the jaws.

Bisphosphonate-related osteonecrosis of the jaw: diagnosis, prevention, and management.

Bisphosphonate therapy has been considered standard therapy in the management and care of cancer patients with metastatic bone disease and patients with osteoporosis. The efficacy of these drugs is due to their ability to inhibit osteoclast-mediated bone resorption. However, the postmarketing experience with intravenous and, to a much lesser extent, oral bisphosphonates has raised concerns about potential side effects related to profound bone remodeling inhibition and osteonecrosis isolated to the jaws. We review the risk factors, incidence, pathogenesis, prevention strategies, and management of this new complication.

Diagnosis and Management of Lingual Nerve Injuries.

Injury to the lingual nerve is a well-recognized risk associated with certain routine dental and oral surgical procedures. The assessment and management of a patient with a traumatic lingual nerve neuropathy requires a logical and stepwise approach. The proper application and interpretation of the various neurosensory tests and maneuvers is critical to establishing an accurate diagnosis. The implementation of a surgical or nonsurgical treatment strategy is based not only on the established diagnosis, but also a multitude of variables including patient age, timing and nature of the injury, and the emotional or psychological impact.

Consequences to patients, clinicians, and manufacturers when very serious adverse drug reactions are identified (1997-2019): A qualitative analysis from the Southern Network on Adverse Reactions (SONAR).

BACKGROUND: Adverse drug/device reactions (ADRs) can result in severe patient harm. We define very serious ADRs as being associated with severe toxicity, as measured on the Common Toxicity Criteria Adverse Events (CTCAE)) scale, following use of drugs or devices with large sales, large financial settlements, and large numbers of injured persons. We report on impacts on patients, clinicians, and manufacturers following very serious ADR reporting. METHODS: We reviewed clinician identified very serious ADRs published between 1997 and 2019. Drugs and devices associated with reports of very serious ADRs were identified. Included drugs or devices had market removal discussed at Food and Drug Advisory (FDA) Advisory Committee meetings, were published by clinicians, had sales > $1 billion, were associated with CTCAE Grade 4 or 5 toxicity effects, and had either >$1 billion in settlements or >1,000 injured patients. Data sources included journals, Congressional transcripts, and news reports. We reviewed data on: 1) timing of ADR reports, Boxed warnings, and product withdrawals, and 2) patient, clinician, and manufacturer impacts. Binomial analysis was used to compare sales pre- and post-FDA Advisory Committee meetings. FINDINGS: Twenty very serious ADRs involved fifteen drugs and one device. Legal settlements totaled $38.4 billion for 753,900 injured persons. Eleven of 18 clinicians (61%) reported harms, including verbal threats from manufacturer (five) and loss of a faculty position (one). Annual sales decreased 94% from $29.1 billion pre-FDA meeting to $4.9 billion afterwards (p<0.0018). Manufacturers of four drugs paid $1.7 billion total in criminal fines for failing to inform the FDA and physicians about very serious ADRs. Following FDA approval, the median time to ADR reporting was 7.5 years (Interquartile range 3,13 years). Twelve drugs received Box warnings and one drug received a warning (median, 7.5 years following ADR reporting (IQR 5,11 years). Six drugs and 1 device were withdrawn from marketing (median, 5 years after ADR reporting (IQR 4,6 years)). INTERPRETATION: Because very serious ADRs impacts are so large, policy makers should consider developing independently funded pharmacovigilance centers of excellence to assist with clinician investigations. FUNDING: This work received support from the National Cancer Institute (1R01 CA102713 (CLB), https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-cancer-institute-nci; and two Pilot Project grants from the American Cancer Society's Institutional Grant Award to the University of South Carolina (IRG-13-043-01) https://www.cancer.org/ (SH; BS).

Lack of correlation between duration of osteonecrosis of the jaw and sequestra tissue morphology: what it tells us about the condition and what it means for future studies.

PURPOSE: More studies have begun to investigate properties of tissue obtained from patients with osteonecrosis of the jaw (ONJ). Because of the relatively low incidence of ONJ, these studies necessitate the use of specimens from patients who have had ONJ for various durations. The goal of this study was to determine if properties, specifically bone morphology assessed by microcomputed tomography, were influenced by the duration of ONJ. MATERIALS AND METHODS: Sequestra from 31 patients with confirmed ONJ for 3 weeks to 42 months before obtaining the tissue were scanned using microcomputed tomography to determine bone volume/tissue volume and bone surface/tissue volume. RESULTS: There was no significant correlation between the sequestra bone morphology (bone volume/tissue volume or bone surface/tissue volume) and the duration of ONJ. CONCLUSION: The findings indicated that studies should not be concerned about assessing tissue properties from patients who have had ONJ for different durations. In addition, the lack of difference in morphology with continued duration of ONJ suggests that most changes to bone tissue occur early in the disease progression.