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Objective: This article reviews the literature and evidence of the association of medication-related osteonecrosis of the jaw with tumor necrosis factor-α inhibition., Methods: A systematic review was performed using electronic databases (PubMed, MEDLINE, and Embase) using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Key terms were used in the search. No restrictions were placed on publication status. Selection criteria comprised all levels of available evidence. Articles in the English language were selected up to and including July 2020. Reference lists of relevant studies were searched for additional articles. Articles were selected on the basis of inclusion and exclusion criteria. Findings from eligible studies were extracted by one reviewer and confirmed by a second. Disagreements were settled through discussion., Results: The initial search of the key terms yielded 2107 articles. There were 1192 articles remaining after removal of duplicates and addition of 6 articles that were hand-selected from among reference lists of relevant studies. There were 12 eligible articles after screening. The full texts were read, and 5 articles were included on the basis of inclusion and exclusion criteria., Conclusions: Further research is required to determine an association of medication-related osteonecrosis of the jaw and tumor necrosis factor-α inhibition., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Medication-related osteonecrosis of the jaw is an oral complication in cancer patients being treated with either antiresorptive or antiangiogenic drugs. The first reports of MRONJ were published in 2003. Hundreds of manuscripts have been published in the medical and dental literature describing the complication, clinical and radiographic signs and symptoms, possible pathophysiology, and management. Despite this extensive literature, the pathobiological mechanisms by which medication-related osteonecrosis of the jaw develops have not yet been fully delineated. The aim of this manuscript is to present current knowledge about the complication ragarding to the definition, known risk factors, and clinical management recommendations. Based on this current state of the science, we also propose research directions that have potential to enhance the management of future oncology patients who are receiving these agents., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: The reporting of osteonecrosis of the jaw (ONJ) related to anticancer agents without known antiresorptive properties (non-antiresorptives), such as antiangiogenics, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, immune checkpoint inhibitors, and cytotoxic chemotherapy is increasing., Objective: To review characteristics of ONJ in cancer patients receiving non-antiresorptives., Methods: A systematic review of the literature between 2009 and 2017 was conducted by the Bone Study Group of MASCC/ISOO., Results: Of 6249 articles reviewed and from personal communication, 42 ONJ cases related to non-antiresorptives were identified. No gender predilection was noted. Median age was 60 years and ONJ stage 2 was most common, with predilection for posterior mandible. Exposed bone, pain, and infection were common at diagnosis. In comparison to bone targeting agents (BTAs), radiology, histology, and management were similar, with medication often discontinued. Delayed diagnosis (median 8 weeks) was noted. Important differences included earlier time to ONJ onset (median 20 weeks), absence of trigger event (40%), and greater likelihood of healing and shorter healing time (median 8 weeks) as compared to BTA-related ONJ. Gastrointestinal cancers predominated, followed by renal cell carcinomas compared to breast, followed by prostate cancers in BTA-related ONJ, reflecting different medications., Conclusions: Data about non-antiresorptive-related ONJ is sparse. This type of ONJ may have better prognosis compared to the BTA-related ONJ, suggested by greater likelihood of healing and shorter healing time. However, the delay in diagnosis highlights the need for more education. This is the first attempt to characterize ONJ associated with different non-antiresorptives, including BRAF and immune checkpoint inhibitors.

Objectives: The objectives of this study were to define the incidence, pain, and healing in cancer patients treated with intravenous bisphosphonates., Study Design: The study included long-term follow-up of 99 bisphosphonate-using patients (group A) and conservative treatment of 67 patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ, group B) using 3 antibiotic schemes and oral hygiene., Results: The frequency of zoledronic acid single-agent use was 85.9% and 69.8% in group A and B, respectively. Median follow-up was 13 months (group A) and 16 months (group B). Two patients in group A developed BRONJ (2%). Of those with BRONJ in group B who completed follow-up, healing occurred in 14.9% (7/47) and pain subsided in 80.9% (38/47). Healing was significant in patients who received pamidronate followed by zoledronic acid (P = .023) and with BRONJ stages 0 and stage I (P = .003)., Conclusions: This case series suggests that oral hygiene and conservative antibiotic therapy play a role in healing and pain alleviation in BRONJ. Oral hygiene and follow-up may decrease incidence of BRONJ., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Bisphosphonate-associated osteonecrosis (BON) is a complication that almost exclusively affects the jaw bones. The clinical presentation of BON often mimics that of other conditions, such as routine dental disease, osteoradionecrosis or avascular necrosis; therefore, diagnosis can be difficult. As this complication has only been recognized within the past 10 years, management strategies for patients with BON are poorly defined. Physicians must choose between continuing the bisphosphonate therapy (to reduce the risk of skeletal complications in patients with metastatic bone disease or osteoporosis) and discontinuing the drug (to possibly improve the odds for tissue healing). A conservative or aggressive management strategy must be chosen with limited evidence that the outcome of either strategy will be successful. BON is most prevalent in patients with cancer using intravenous nitrogen-containing bisphosphonates. The pathobiology of this complication is not fully understood and the diagnosis relies on the clinical manifestations of the condition. Future research should focus on the pathobiological mechanisms involved in the development of BON, which could help explain why this complication affects only a small number of those who use bisphosphonates, and also suggest strategies for prevention and management.

Purpose: This systematic review aims to examine the prevalence of bisphosphonate osteonecrosis (BON) in the cancer population, prevention and treatment protocols, and quality of life issues., Methods: A search of MEDLINE/PubMed and EMBASE form October 2003 to December 31, 2008 was conducted with the objective of identifying publications that contained original data regarding BON., Results: A total of 28 publications fulfilled inclusion criteria, but only 22 were used for prevalence analysis. No randomized controlled clinical trials, meta-analysis, or quality of life papers were found that contained information regarding either prevalence or treatment protocols for the management of BON. The overall weighted prevalence of BON included a sample of 39,124 patients with a mean weighted prevalence of 6.1%. The weighted prevalence was 13.3% for studies with documented follow-up with a sample size of 927 individuals. The weighted prevalence in studies with undocumented follow-up was 0.7% in a sample of 8,829 chart reviews. Epidemiological studies evaluated a total of 29,368 individual records, and the weighted BON prevalence was 1.2%., Conclusions: High-quality studies are needed to accurately characterize the prevalence of BON, and to determine effective treatment protocols.

Bisphosphonate osteonecrosis (BON) is a relatively recent adverse drug event that affects the oral cavity almost exclusively. It has been reported in individuals with metastatic breast, prostate, and lung cancer as well as in multiple myeloma. It has also been reported in a small subset of individuals who have been treated with bisphosphonate therapy for osteoporosis and Paget's disease of bone. Published studies to date have been characterized by relatively small sample sizes. Based on these studies, incidence appears to range between 0.1% and 11% depending on the population being studied and a number of other co-factors that have not been completely understood. The pathobiology of BON has not been fully elucidated and risk factors involved in the process need confirmation. Patients with this complication have altered quality of life and can suffer from discomfort and pain. Management is difficult and, while many treatment protocols have been proposed, at best they have only had partial success. This review of literature discusses a number of issues involving BON, with focus on the definition, possible association of BON and bisphosphonate therapy, pathobiology of BON and several additional research questions that need further investigation.

Background: and Overview. In 2005, the American Dental Association (ADA) Council on Scientific Affairs convened an expert panel to develop clinical recommendations for dentists treating patients who are receiving oral bisphosphonate therapy. The Journal of the American Dental Association published the resulting report in 2006. This 2008 advisory statement is the first of projected periodic updates of the 2006 clinical recommendations., Conclusion: This 2008 advisory statement concludes, on the basis of a review of the current literature, that for patients receiving bisphosphonate therapy, the risk of developing bisphosphonate-associated osteonecrosis (BON) of the jaw apparently remains low. It also newly concludes that current screening and diagnostic tests are unreliable for predicting a patient's risk of developing the condition. This statement updates the 2006 recommendations regarding general dentistry, management of periodontal diseases, implant placement and maintenance, oral and maxillofacial surgery, endodontics, restorative dentistry and prosthodontics, and orthodontics.

More than half of all serious adverse reactions are identified 7 or more years after a drug receives approval from the US Food and Drug Administration (FDA). In 2002, 9 months after the intravenous bisphosphonate zoledronic acid received regulatory approval for marketing, the FDA received reports of nine patients with cancer, who were treated with zoledronic acid, who unexpectedly developed osteonecrosis of the jaw. During the next 2 years, three oral surgeons described 104 patients with cancer with osteonecrosis of the jaw in the medical literature and identified intravenous bisphosphonate therapy as being common to the care of these patients. In subspecialty medical, radiology, and dental journals, case reports and case series described clinical features of osteonecrosis of the jaw in patients with cancer who were treated with bisphosphonates. Manufacturer-sponsored epidemiological studies reported the first estimates of the incidence of this toxic effect, ranging from 0.1% to 1.8%. By contrast, independent epidemiological efforts from clinicians and the International Myeloma Foundation reported incidence estimates between 5% and 10%. Between 2003 and 2005, warnings about the risks of bisphosphonate-associated osteonecrosis were disseminated by national regulatory agencies, the manufacturers of bisphosphonates, and the International Myeloma Foundation. From 2006, independent clinical recommendations for diagnosis, prevention, and treatment of this toxic effect have been disseminated by manufacturers, national regulatory authorities, the International Myeloma Foundation, and medical specialty organisations. Furthermore, independent efforts by pharmaceutical manufacturers, dental and medical professionals, a non-profit organisation (the International Myeloma Foundation), patients, and regulatory authorities has led to the rapid identification and dissemination of safety information for this serious adverse reaction. Better coordination of safety-related pharmacovigilance initiatives is now needed.

Bisphosphonate osteonecrosis, BON, was recently described in the literature. Lack of scientific evidence explaining the pathophysiologic mechanisms involved in the development of this oral complication has generated uncertainties about proper management of patients treated with a bisphosphonate. This manuscript discusses the dental management of two breast cancer patients treated with intravenous bisphosphonates as part of their cancer management and who developed oral disease. Clinical management decisions will be presented as well as the treatment outcomes.

A breast cancer patient with skeletal metastases was treated with only one i.v. dose of ibandronate in March of 2005 and subsequent doses of oral ibandronate 50 mg daily. One year after the i.v. infusion, the patient complained of oral pain under her lower denture. After several negative attempts from her dentist to control the pain and adjust the denture, the patient was diagnosed with bisphosphonate-associated osteonecrosis (BON) of the mandible. The use of ibandronate, a potent bisphosphonate, is increasing worldwide. Prescribing oncologists should be aware of the potential for the development of new cases of BON in a similar fashion as with zoledronic acid.

Background: Osteoporosis is a common disease in middle-aged and older Americans. The risk of sustaining fractures is a concern, and mortality rates after hip or vertebral fractures are high. Oral health maintenance for adults with osteoporosis is important., Types of Studies Reviewed: The authors conducted a MEDLINE search of the medical and dental literature with the objective of reviewing osteoporosis, its effect on public health in the population in the United States and the implications in providing dental care for these patients. They selected studies by performing a content search with National Library of Medicine medical subject headings (epidemiology, public health impact, treatment, adverse drug reactions, cost-effectiveness of osteoporosis therapy, oral health, periodontal disease, adverse drug reactions, bisphosphonates and osteonecrosis of the jaw). They then performed a study design search with a filter so that only randomized clinical trials were included., Results: Osteoporosis and related fractures are more common than coronary disease, stroke and breast cancer. Fractures resulting from osteoporosis can affect a patient's quality of life severely, and fractures result in functional impairment and increased health care cost and mortality. Medical management of osteoporosis includes diet control, with appropriate intake of calcium and vitamin D, weight-bearing exercise, discontinuation of tobacco and alcohol intake, and use of medications, including selective estrogen receptor modulators, calcitonin, anabolic agents and bisphosphonates. Bisphosphonates have been associated with the development of osteonecrosis of the jaws., Clinical Implications: Oral health maintenance is important in patients with osteoporosis. Bisphosphonate therapy or other medical treatment for these people should be discontinued only after consultation with the patient's physician.

Reports of osteonecrosis of the jaw (ONJ) in patients receiving long-term bisphosphonate therapy have appeared in the literature since 2003. This condition involves avascular necrotic bone in the area of maxilla or mandibula and there may be a secondary infection. Most cases of ONJ have been reported in cancer patients receiving the intravenous aminobisphosphonates zoledronic acid and pamidronate monthly or q 3 week; of note these are also the two most commonly used agents of this class. Risk factors for ONJ include a history of trauma, dental surgery or dental infection and intravenous bisphosphonate administration; in addition, the extent and duration of exposure to bisphosphonates also seem to correlate with the risk. Although a direct causal relationship with bisphosphonates cannot be assumed, these agents may possibly contribute to the development of ONJ by suppression of bone remodeling in the jaw which leads to increased rates of bone mineralisation and accumulation of microfractures. Clodronate, a non-aminobisphosphonate, appears to have a different mechanism of suppressing bone remodeling compared with aminobisphosphonates, and this may explain why few cases of ONJ have been reported with clodronate despite extensive use over the past 20 years; however, the potential of clodronate to reduce the risk of ONJ while providing equivalent clinical benefit to the aminobisphosphonates needs to be substantiated in controlled clinical trials. Use of bisphosphonate therapy should be carefully planned in patients with metastatic bone disease who have risk factors for ONJ, and appropriate preventive measures taken to avoid the development of this condition.

We present current knowledge of bisphosphonate-associated osteonecrosis, a new oral complication in oncology. It was first described in 2003, and hundreds of cases have been reported worldwide. The disorder affects patients with cancer on bisphosphonate treatment for multiple myeloma or bone metastasis from breast, prostate, or lung cancer. Bisphosphonate-associated osteonecrosis is characterised by the unexpected appearance of necrotic bone in the oral cavity. Osteonecrosis can develop spontaneously or after an invasive surgical procedure such as dental extraction. Patients might have severe pain or be asymptomatic. Symptoms can mimic routine dental problems such as decay or periodontal disease. Intravenous use of pamidronate and zoledronic acid is associated with most cases. Other risk factors include duration of bisphosphonate treatment (ie, 36 months and longer), old age in patients with multiple myeloma, and a history of recent dental extraction. We also discuss pathobiology, clinical features, management, and future directions for the disorder.

Background: This position paper addresses the prevention of bisphosphonate-associated osteonecrosis (BON) and the management of care of patients with cancer and/or osteoporosis who are receiving bisphosphonates and who have BON or are at risk of developing it., Methods: The authors reviewed the literature available on this newly described oral complication. Information of interest included bisphosphonates, the medications associated with this oral complication; the patient population at risk of developing BON and the diseases being treated with this class of medications; the clinical presentation of the oral lesions; guidelines for managing the care of patients who develop BON; the prevention of this complication based on current knowledge; and recommendations for routine dental treatment of patients receiving bisphosphonates., Results: There is strong evidence that bisphosphonate therapy is the common link in patients with BON. The pathobiological mechanism leading to BON may have to do with the inhibition of bone remodeling and decreased intraosseous blood flow caused by bisphosphonates. People at risk include patients with multiple myeloma and patients with cancer metastatic to bone who are receiving intravenous bisphosphonates, as well as patients taking bisphosphonates for osteoporosis. The risk of developing complications appears to increase with time of use of the medication. There are no guidelines based on evidence, and the clinical management of the oral complication is based on expert opinion., Conclusion: Prevention of BON is the best approach to management of this complication. Existing protocols to manage the care of patients who will receive radiation therapy or chemotherapy may be used until specific guidelines for BON are developed.

Background: The current report presented 17 patients with cancer with bone metastases and 1 patient with osteopenia who received treatment with bisphosphonates and who subsequently developed osteonecrosis of the mandible and/or maxilla., Methods: The authors reviewed information on 18 patients who were referred to oral medicine or oral surgery specialists for evaluation and treatment of mandibular and/or maxillary bone necrosis from June 2002 to September 2004. To be included in the current review, patients must have been treated with either pamidronate or zoledronic acid to control or prevent metastatic disease, or with alendronate for osteoporosis. All patients with cancer had received chemotherapy while receiving bisphosphonate management., Results: The 17 patients with cancer were receiving active medical care for a malignancy. Cancer treatment included a variety of chemotherapeutic agents. They presented with metastatic disease to bone and were treated intravenously with the bisphosphonates pamidronate or zoledronic acid for a mean time of 25 months (range, 4-41 mos). There were 14 females and 4 males with a mean age of 62 years (range, 37-74 yrs). Malignancies included breast carcinoma (n = 10), multiple myeloma (n = 3), prostate carcinoma (n = 1), ovarian carcinoma (n = 1), prostate carcinoma/lymphoma (n = 1), and breast/ovarian carcinoma (n = 1). One female patient with osteopenia received alendronate. The most common clinical osteonecrosis presentations included infection and necrotic bone in the mandible. Associated events included dental extractions, infection, and trauma. Two patients appeared to develop disease spontaneously, without any clinical or radiographic evidence of local pathology. Despite surgical intervention, antibiotic therapy, hyperbaric oxygen therapy, and topical use of chemotherapeutic mouth rinses, most of the lesions did not respond well to therapy. Discontinuation of bisphosphonate therapy did not assure healing. However, 1 patient with cancer healed after discontinuation of bisphosphonate therapy for 4 months., Conclusions: The findings in the patient population combined with recent literature reports suggested that bisphosphonates may contribute to the pathogenesis of the oral lesions. The risk factors and precise mechanism involved in the formation of the osteonecrosis are not known. This condition represents a new oral complication in patients with cancer and can be termed bisphosphonate-associated osteonecrosis. Lesions in patients with osteoporosis are worrisome and need to be further evaluated.

The definition, pathobiology and risk factors of ONJ in cancer patients who receive BTAs are discussed in the recent ecancer module for osteonecrosis of the jaw (http://ecancer.org/education/module/276-osteonecrosis-of-the-jaw.php). ONJ prevention, early diagnosis and management are presented. The critical question of the performance of dental extraction, during BTA therapy, as indicated with the recent studies, is supported. The importance of the collaboration between dental and oncology professionals and the patients is highlighted and can be achieved through appropriate education. The ecancer modules are valuable tools for successful e-learning in medical oncology education, including ONJ. [ABSTRACT FROM AUTHOR]

Background. Tooth extraction in patients exposed to bisphosphonates (BPs) is considered a risk factor for osteonecrosis. The authors evaluated the time to mucosal healing and frequency of osteonecrosis after tooth extraction in participants exposed to BPs. Methods. The authors compared wound healing after tooth extraction in participants exposed to BPs with that in control participants who had not been exposed to BPs. Variables included age, sex, type of BP therapy (oral or intravenous), BP exposure time and C-terminal telopeptide (CTX) test results. The authors followed up patients weekly or biweekly until healing was complete. They used multivariable analyses to model time to healing in the presence of covariates, and estimates provided hazard ratios (HRs) and 95 percent confidence intervals (CIs) adjusted for all variables in the model. Results. The authors enrolled 53 participants with BP exposure and 39 control participants. Postextraction healing was significantly longer in participants exposed to BPs (P < .001) than it was in control participants. One patient (1.9 percent) developed osteonecrosis. A Cox proportional hazards model in which the authors controlled for age, sex and CTX values showed that BP exposure alone significantly (HR, 0.30; 95 percent confidence interval, 0.17-0.51) increased mucosal healing time. Conclusions. The study results showed that postextraction healing was impaired in patients exposed to BPs. CTX values were not associated with delayed healing after tooth extraction. Practical Implications. Postextraction healing was delayed in patients receiving BP therapy. However, the risk of developing osteonecrosis was low. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Regorafenib Also Can Cause Osteonecrosis of the Jaw," by L. Antonuzzo and colleagues in the 2016 issue.