Cases Of Medication-related Osteonecrosis Of The Jaw Research Articles

A Multi-Center Observation Study on Medication-Related Osteonecrosis of the Jaw (MRONJ) in Patients with Osteoporosis, and Other Non-Malignant Bone Diseases, in Northwestern Italy over 16 Years.

To assess the number of new cases of Medication-Related Osteonecrosis of the Jaw (MRONJ) among patients with osteoporosis and other non-malignant bone diseases in Northwestern Italy between 2007 and 2022. MRONJ cases were collected from referral centers in a population of 4.5 million. We analysed the number of new MRONJ cases per year, type of disease, administered drugs, duration of therapy (when available), and onset time of disease. We analysed 198 cases (out of 1071 total MRONJ cases); diseases included osteoporosis (87%), rheumatoid arthritis (5%), their association (4%), Paget's disease, and other various diseases (4%). Patients received bisphosphonates alone (74%), or denosumab alone (6%), or a sequence of different drugs (20%). The number of new cases increased over five years from 2 (2003-2007) to 51 (2008-2012), 65 (2013-2017), and 79 (2018-2022), and the percentage increased from 1% to 14%, 20%, and 29% of the total cases. The number of new MRONJ cases per year among patients with non-malignant diseases is rapidly increasing all around the world, though underestimation cannot be excluded. In this study, we describe epidemiological and clinical characteristics of patients, and the drug most frequently involved in MRONJ cases in our region over a long period, allowing a comprehensive view of the progression of the disease. Greater collaboration among specialists is needed for correct and early diagnosis to improve measures potentially reducing disease incidence and to limit quality of life deterioration in patients with osteoporosis and other non-malignant diseases.

Platelet-Rich Plasma in the Prevention and Treatment of Medication-Related Osteonecrosis of the Jaw: A Systematic Review and Meta-Analysis.

Medication-related osteonecrosis of the jaw (MRONJ) is a significant complication associated with bisphosphonates, impacting jaw osteoclasts, and causing altered bone remodelling. Prevention involves stabilizing systemic pathology, considering antiresorptive therapies, and exploring platelet-rich fibrin (PRF) for wound healing and tissue regeneration. The study aims to assess the efficacy of PRF in MRONJ treatment and highlight research gaps for more robust investigations. Following PRISMA and MOOSE guidelines, this systematic review and meta-analysis included English publications from 2013 to 2023, employing a systematic search in databases such as MEDLINE, Scopus, and Web of Science. Quality assessment used the Cochrane Collaboration's tool and the NOS, with the main meta-analysis concentrating on PRF-treated MRONJ cases, assessing resolution rates, and prioritizing healing outcomes and infection absence as primary endpoints. The study, encompassing 11 articles and 480 participants with MRONJ, demonstrated that in stage 1 procedures, PRF significantly outperformed conventional medical treatments (OR: 2.93, 95% CI: 1.54-5.59, P=0.001), particularly at the mandible site (OR: 1.65, 95% CI: 0.86-3.17, P=0.13). PRF also exhibited significantly superior healing outcomes compared with conventional medical treatments (OR: 4.45, 95% CI: 1.58-12.53, P=0.005), supporting its consideration as a valuable alternative in specific MRONJ management scenarios. This study highlights PRF's effectiveness in early MRONJ interventions and specific anatomic sites, despite acknowledged limitations, emphasizing the need for further research, and supporting its consideration in MRONJ surgical management.

Pathogenesis of Medication-Related Osteonecrosis of the Jaw: Odontogenic Infection-Preceding Type and Osteonecrosis-Preceding Type.

Introduction Medication-related osteonecrosis of the jaw (MRONJ) develops from odontogenic infection. However, there are also some cases of MRONJ developing from sites with no teeth, no root canal lesions, or no periodontal disease. This study aimed to retrospectively review radiographic images of MRONJ cases and examine the differences in characteristics between MRONJ suspected to be related to dental infection (odontogenic MRONJ) and MRONJ that occurred without dental involvement or of unknown cause (non-odontogenic MRONJ). Materials and methods One hundred and forty-five patients were diagnosed with MRONJat Kansai Medical University Hospital and Kansai Medical University Medical Center. The following variables were investigated: sex, age, primary disease, MRONJ site, body mass index, smoking habit, diabetes, corticosteroids, type of antiresorptive agent, administration period, CT findings (separation of sequestrum, osteolysis, periosteal reaction, and osteosclerosis), trigger, leukocytes, neutrocytes, neutrophil-lymphocyte ratio, serum albumin, and serum creatinine levels. Results In the univariate analysis, significant differences between odontogenic and non-odontogenic MRONJs were found in patients whose primary disease was malignancy, receiving denosumab (DMB), and with short administration period of antiresorptive agent, no osteolysis, periosteal reaction, and serum creatinine level. In multivariate analysis, non-odontogenic MRONJ was significantly more common in patients with no osteolysis and with periosteal reaction. Conclusion Non-odontogenic MRONJ tends to occur more frequently in patients treated with high-dose DMB, and there were significantly more cases of non-osteolytic MRONJ without radiographic evidence of osteolysis or with periosteal reactions.

Clinical status of established MRONJ in oncology patients continuing bone-modifying agents.

The continuation of bone-modifying agents (BMAs) in patients with established medication-related osteonecrosis of the jaw (MRONJ) is a common concern among dentists and oncologists. There is little evidence supporting or refuting the continued use of BMAs or drug holidays and their impact on established MRONJ. This paper evaluates the outcome of continued BMAs use on the patient's MRONJ status. A retrospective review of 29 oncology patients undergoing active cancer care for either metastatic disease or multiple myeloma was conducted. Data on demographics, oncological status, BMA history and MRONJ status were collected. In total, 90% of patients were judged to have healed or stable MRONJ while continuing BMAs. Most patients (69%) continued the same BMA regime (three- or four-weekly) that they were on before developing MRONJ. The average number of BMAs doses received after an MRONJ diagnosis was 12 (range 1-48). Three patients (10.3%) were found to have MRONJ progression, with two patients developing new sites of necrosis. This real-world dataset suggests that the majority of MRONJ cases remain stable and will not worsen with the continuation of BMAs.

Effect of Antiresorptive Drugs on Osseointegrated Dental Implants: A Systematic Review.

Background: This systematic review aimed to evaluate the impact of antiresorptive drug therapy on osseointegrated dental implants and the association with medication-related osteonecrosis of the jaw (MRONJ). Methods: A systematic search, including a computer search of several databases with specific keywords, a reference search, and a manual search of four key maxillofacial journals were performed. Relevant articles were then evaluated and those that fulfilled the five predetermined criteria were chosen to enter the final review. A total of 445 implants in 135 subjects were included in the eight studies analyzed in the final review. Results: The failure rate of dental implants after antiresorptive medication in the included studies was 23%, with 83% of failures attributed to MRONJ. The average time from antiresorptive drug initiation to MRONJ development was approximately 34 months, ranging from 3 months to 16 years. The majority of MRONJ cases were classified as stage 2, and all sites showed either complete healing or substantial mucosal coverage after treatment. Conclusions: This review highlights the significant impact of antiresorptive drugs on osseo- integrated implants, with MRONJ identified as a leading cause of implant failure. The potential role of peri-implantitis as a trigger for MRONJ is emphasized. Regular monitoring and maintaining good periodontal health, especially within the first three years of antiresorptive drug therapy initiation, are crucial for implant success. Physicians and dentists should provide comprehensive information to patients prescribed with antiresorptive drugs, emphasizing the need for an awareness of the risks of MRONJ in the context of osseointegrated implants. A longer term of follow-up is recommended to identify and manage MRONJ around dental implants in an early manner.

Medication-Related Osteonecrosis of the Jaw – 2024 Update

As the global number of patients with osteoporosis and malignant diseases such as breast cancer, multiple myeloma, and prostate cancer increases every year, there is an associated rise in the use of antiangiogenic medications and antiresorptive medications. With increasing frequencies in the use of antiangiogenic and antiresorptive medications, there is an associated increase in the number of medication-related osteonecrosis of the jaw (MRONJ) cases reported from patients. MRONJ has emerged as a significant comorbidity in cancer patients treated with antiangiogenics or high doses of potent antiresorptive agents, such as bisphosphonates (BPs) or denosumab. MRONJ first emerged from BP-treated cancer patients who presented with a spectrum of dental problems, including delayed wound healing following a dental extraction or oral surgery, exposed bone, soft tissue infection and inflammation, anesthesia, paresthesia, odontalgia, sinus pain, and aching bone pain in the mandible, which continues to be a significant source of problems for dentists, physicians, and patients today. A significant number of MRONJ cases secondary to osteoporosis have also been reported in osteoporotic patients receiving antiresorptive medications. The American Association of Oral and Maxillofacial Surgeons (AAOMS) has established diagnostic standards for MRONJ based on pharmacological history, clinical signs, and radiographic findings. However, as the expertise and knowledge base for MRONJ continues to evolve, revisions and refinements for MRONJ pathogenesis and treatment strategies are necessary to reflect the current research status of the disease correctly. This review highlights current scientific information associated with MRONJ to identify and summarize preventative measures, and treatment interventions for reading the impact of this debiliating disorders.

Treatment of medication-related osteonecrosis of the jaw with cell therapy.

Introduction: Medication-related osteonecrosis of the jaw (MRONJ) poses a significant challenge considering the absence of a "gold standard" treatment. Cell-based therapy and tissue engineering offer promising therapeutic alternatives. This study aimed to harness the regenerative properties of adipose-tissue stromal vascular fraction (AT-SVF) and leukocyte-platelet-rich fibrin (L-PRF) for MRONJ treatment. AT-SVF contains mesenchymal stromal cells (MSC) and endothelial progenitor cells (EPC), which promote bone formation, while the L-PRF scaffold can serve as a three-dimensional scaffold for the AT-SVF and support tissue healing through growth factor release. Materials and methods: The protocol involved applying autologous AT-SVF within an L-PRF matrix following surgical debridement. Age, gender, body mass index, comorbidities, underlying oncological condition, prescribed antiresorptive treatment: BP or DMB, antiresorptive treatment duration, antiresorptive treatment potential discontinuation, number of MRONJ lesion, MRONJ location, MRONJ stage, MRONJ trigger factor were assessed for each patient. Patients underwent the procedure and were monitored for a minimum of 6months based on clinical, biological and medical imaging criteria. Results: Nine patients, with a total of ten MRONJ lesions, participated in the study. Six patients were female, and three were male, with a mean age of 68 ± 8years. Four patients had multiple myeloma (MM), three had metastatic breast cancer, and two had metastatic prostate cancer. Seven MRONJ cases were classified as stage II, and three were classified as stage III. Soft tissue completely healed within a month after treatment in nine cases, with no clinical improvement observed in the remaining case. During follow-up, no sign of MRONJ recurrence was observed. Tridimensional medical imaging revealed bone healing 6months after the surgical procedure. Immunophenotyping confirmed the presence of MSC and EPC in the AT-SVF: 12,6 ± 4,5% CD31+, 20.5 ± 7,8% CD34+, 34,4 ± 7,3% CD146+ and 54,6 ± 7,4% CD45+. Conclusion: This prospective study introduces a potential new treatment approach for MRONJ using autologous AT-SVF within an L-PRF scaffold. Our results are encouraging and suggest the need for further investigation with a larger patient cohort to better understand the underlying mechanisms.

Prevention and management of drug-induced osteonecrosis of the jaws using platelet-rich fibrin: A clinical feasibility study.

Although a standard treatment guideline has not been established to date, various treatment modalities have been described in the literature based on the staging of medication-related osteonecrosis of the jaw (MRONJ). The aim of this case series was to describe the outcomes of surgical intervention of MRONJ cases with the adjunctive use of platelet-rich fibrin (PRF). Thirteen patients under therapy with zoledronic acid, seven of them underwent surgical removal of necrotic bone with debridement, followed by placement of three to four PRF membranes and achieving primary closure. In six patients, PRF was used preventively to avoid MRONJ. The surgical treatment outcomes were successful in all patients, with a follow-up range of 12-48 months. In the presented cases, the intraoral evaluation showed excellent soft tissue healing except for one patient secondary wound healing was reported. Additionally, there was no recurrence of bone exposure in all cases. PRF membranes were comparatively effective in postsurgical pain control. The use of PRF could represent a valuable adjunct in the surgical management for advanced stages of MRONJ cases. This clinical case series describes the use of PRF membranes as a valuable adjunct in the surgical management of MRONJ patients, especially when treating advanced MRONJ cases. Moreover, PRF demonstrates usefulness in preventing such difficult complications from occurring.

Medication-related osteonecrosis of the jaw without osteolysis on computed tomography: a retrospective and observational study

Medication-related osteonecrosis of the jaw (MRONJ) is a refractory osteonecrosis caused by antiresorptive agents such as bisphosphonate and denosumab (DMB). In MRONJ surgery, computed tomography (CT) is generally used to determine the extent of bone resection. However, in some recent MRONJ cases, no abnormal findings were detected on CT. Therefore, we aimed to clarify the characteristics of MRONJ without osteolysis. This retrospective and observational study included 18 patients diagnosed with MRONJ between October 2020 and October 2022 at Department of Dentistry and Oral Surgery, Kansai Medical University Medical Center. In four of 18 patients with MRONJ, no abnormal findings such as osteolysis, separation of sequestrum, and periosteal reaction were observed on CT images at the first visit. All four patients with non-osteolytic MRONJ had malignant tumors and received high-dose DMB, and in the four patients there were no preceding dental infections such as apical lesions or periodontal disease and the trigger of MRONJ was unknown. Surgery was performed in three of the four patients. The extent of bone resection was determined using magnetic resonance imaging and intraoperative gross findings. In the future, it is necessary to establish a method for diagnosing non osteolytic MRONJ and determining the extent of bone resection.

Radiographic Evaluation of Medication-Related Osteonecrosis of the Jaw (MRONJ) With Different Primary Cancers and Medication Therapies.

Medication-related osteonecrosis of the jaw (MRONJ) is a condition that affects the jaws and is characterized by exposed bone in the oral cavity that persists for more than eight weeks despite treatment. Additional criteria include that the patient should have a current or past history of antiresorptive drugsand/or in combination with antiangiogenic drugs, absence of metastasis, and no previous radiotherapy to the affected area. The radiographic features of MRONJ in most instances do not have any specific radiographic features. This is because standard radiographs usually show no stark abnormalities in the early stages of the disease. The study aimed to evaluate if any specific radiographic patterns are associated with primary cancers and between medications. The study is an observational case series. A total of 50 cases of possible osteonecrosisfrom June 2010 to June 2013 archives of the Department of Oral and Maxillofacial Radiology were assessed. Based on the history, 12 cases that had a history of medication use that could lead to medication-related osteonecrosis of the jaw (MRONJ) were selected. Cone beam computed tomography (CBCT) scans of these 12 cases were evaluated using the CBCT reconstruction program InVivo Dental version 6 (Anatomage Inc., San Jose, CA, USA). The number of areas showing sequestration, the pattern of osteonecrosis, and the extent were assessed. Primary cancer and the type of medication were also assessed to identify if certain cancers or drugs showed any distinctive pattern of osteonecrosis. Reconstructed panoramic images and true three-dimensional (3D) multi-planar images were assessed to study the condition. An oral and maxillofacial radiology resident in training and a board-certified oral and maxillofacial radiologist assessed the images. Radiographic findings varied among the 12 cases and included generalized sclerosis, osteosclerosis with widened periodontal ligament (PDL) space, bony sequestra, and bony necrosis. However, no specific or distinctive radiographic patterns were observed in any of the cases, regardless of the type of primary cancer or medication used. It is challenging to radiographically distinguish between MRONJ cases with different primary cancer and/or medication. Future studies should include evaluating larger samples with varying primary cancers and medications and combination drug therapies. Cases in an advanced stage of MRONJ do not have distinctive features due to extensive destruction and superimposed infection;it may be valuable to evaluate patients in the early stages of MRONJ to better understand distinguishing radiographic patterns specific to certain primary cancers or medications.

Cooperation between physicians and dentists for osteonecrosis of the jaw: a 2022 Japanese survey.

A 2015 survey of the Japan Osteoporosis Society (JOS) on medication-related osteonecrosis of the jaw (MRONJ) revealed that cooperation between physicians and dentists was poor. Discontinuation of antiresorptive agents before tooth extraction was found to increase adverse events without preventing MRONJ. We compared this 2015 survey with a new survey conducted in 2022 to investigate cooperation between physicians and dentists for MRONJ. A web-based structured questionnaire including 13 key queries was sent to 3813 physicians who were members of JOS, and 1227 (32.2%) responses were received. Of the 1227 respondents, 909 (74.1%) had complied with a discontinuation request from a dentist before tooth extraction, although 25.4% of medications were not related to the incidence of MRONJ. Of these, 177 respondents reported 252 adverse events including 10 (1.3%) cases of MRONJ. The prevalence of fractures increased from 4.8% in 2015 to 8.2% in 2022. The rates of respondents who requested oral health care by a dentist before antiresorptive agent therapy and reported cooperation between physicians and dentists were 72.7% and 42.4% in 2022 compared with 32.9% and 24.8% in 2015, respectively. The rates of cooperation among the 47 prefectures in Japan were significantly different, ranging from 10.0 to 83.3% (p = 0.02). This study confirmed increased cooperation between physicians and dentists for MRONJ in Japan. However, a more equal distribution of cooperation across Japan is necessary to optimally manage MRONJ. Discontinuation of antiresorptive agents is no longer necessary because fractures during discontinuation continue to increase in Japan.

Multicenter, retrospective population-based study on the incidence of medication-related osteonecrosis of the jaw in patients with breast cancer with bone metastases.

6588 Background: Antiresorptive therapy with bisphosphonates or denosumab is standard care for patients with primary or secondary osseous metastasized breast cancer. The most important toxicity of this class of drugs is medication-related osteonecrosis of the jaw (MRONJ). MRONJ represents a major medical burden and impairs quality of life. Based on recent studies, the risk of MRONJ occurrence ranges from 1% to 3%. The objective of this study was to assess the population-based incidence of MRONJ in breast cancer patients with bone metastases in Tyrol, Austria. Methods: This retrospective multicenter study was conducted between 2000 and 2020 at nine centers across Tyrol, Austria, including 8,860 patients with breast cancer. Depending on whether patients with bone metastases received denosumab, bisphosphonates or denosumab following bisphosphonates they were allocated to one of three groups. Data was collected using an electronic case report form (e-CRF) and managed via the web-based database AskiMed. MRONJ incidences with 95% confidence intervals and the differences between the median of cumulative incidences were calculated in patients treated with bisphosphonates and/or denosumab. Results: A total of 639 patients had bone metastasis and received antiresorptive therapy. MRONJ was diagnosed in 56 (8.8%) patients. Regarding the 292 (45.7%) patients treated with denosumab alone, the MRONJ incidence was 11.6% (95%CI 8.2%-15.9%). The group of patients treated with only bisphosphonates included 255 (39.9%) patients; their MRONJ incidence was 2.7% (95%CI 1.1%-5.6%). Of the 92 (14.4%) patients receiving both antiresorptive therapies consecutively, the MRONJ incidence was 16.3% (95%CI 9.4%-25.5%). Thus, a total of 49 (12.8%) MRONJ cases were detected in patients using denosumab alone as well as using the combination of denosumab following bisphosphonates. Patients treated with denosumab developed a MRONJ in median 60 months earlier than with bisphosphonates alone or followed by denosumab. The hazard ratio for MRONJ from start of therapy of denosumab compared to bisphosphonates alone or followed by denosumab was 7.9 (3.8-16.2; p-value < 0.0001). Conclusions: This study showed a substantially higher MRONJ incidence for denosumab alone or bisphosphonates followed by denosumab in the tyrolean cohort when compared to other recent studies. Future comparative real-world-evidence research provide explicit benefit-harm tradeoffs to inform treatment decision making.

Prevalence of Medication-Related Osteonecrosis of the Jaw in Osteoporotic Patients Treated with Antiresorptive Drugs at Pranangklao Tertiary Care Hospital in Nonthaburi Province, Thailand

Background: Medication-related osteonecrosis of the jaw (MRONJ) could disturb the quality of life of the patients. In Thailand, published data reporting the prevalence of MRONJ is scarce. Objective: To analyze the current situation regarding the occurrence of osteonecrosis of the jaw in osteoporotic patients taking antiresorptive drugs at Pranangklao Hospital in Nonthaburi Province, Thailand. Materials and Methods: Data regarding osteoporotic patients received antiresorptive drugs were collected retrospectively from the electronic medical records between January 2014 and June 2020. Data were analyzed using descriptive statistics. Results: The hospital database revealed that there were 1,188 patients that received antiresorptive drugs during the specified period. One thousand twenty-nine (86.62%) were prescribed with only one antiresorptive drug. Alendronate was the main drug among the four medications prescribed, which was used by 592 patients (49.83%). Mean antiresorptive drug exposure time was 1.52 years (SD 1.54) and median was 0.85 years. Among 49 patients who had tooth extraction after receiving oral bisphosphonate, two MRONJ cases were reported. Therefore, the prevalence of MRONJ among the 1,188 patients receiving antiresorptive drugs in the present study was 0.17%, and the prevalence of MRONJ among the 677 obtaining oral bisphosphonates was 0.295%. About 89% had comorbid diseases. The most common comorbid diseases were hypertension, followed by dyslipidemia, and diabetes mellitus. Furthermore, 17% had a history of corticosteroid drug administration. Conclusion: MRONJ cases were found in osteoporotic patients receiving oral bisphosphonates. The prevalence of MRONJ and contributing factors gave information essential for managing this unwanted condition. Keywords: Medication related osteonecrosis of the jaw; Prevalence; Osteoporosis; Comorbidity; Corticosteroid

Oral Toxicities in Cancer Patients, Who Receive Immunotherapy: A Case Series of 24 Patients

The oral problems of 24 cancer patients on immunotherapy between 2017–2022 and referred by their oncologists, were reported. The age range was 49–80 years, and the median was 64 years. Lung cancer was the most common disease. Three patients a had history of autoimmune disease prior to cancer diagnosis. Patients received immunotherapy for two to 48 months. Prior to immunotherapy, 17 patients received cytotoxic chemotherapy, five angiogenesis inhibitors and one1 radiotherapy to head/neck. During immunotherapy, four patients received chemotherapy, one received bevacizumab, and eight received bone targeting agents, either alone or in combination. Presenting symptoms were oral pain (18 patients, 75%), dental pain (five patients), xerostomia (five patients), burning/itching (seven patients), bleeding (three patients), swelling (three patients), and taste problems (dysgeusia) (three patients). One patient was asymptomatic. Immune-related lesions were observed in 15 patients (62.50%), of which three were exacerbations of prior autoimmune disease. Three patients reported severe deterioration and itching after using a mouthwash. We also observed six (25%) infections (four candidiasis and two herpes simplex), and six (25.00%) cases of medication-related osteonecrosis of the jaw (MRONJ). Five of those MRONJ cases developed among the eight patients with the administration of bone targeting agents and one in a patient with bevacizumab. Two patients presented with more than one lesion. In conclusion, immune-related lesions were most common; oral infections and MRONJ were also observed. Various oral complications might be related to the interplay between immunotherapy and other therapies prior or concurrent to immunotherapy.

Novel modified quantitative index for cone-beam CT assessment of medication-related osteonecrosis of the jaw - comparative analysis with original index

PurposeThe main research goal was to address the critical need for an objective and quantitative index to describe the nature and extent of radiographic features of medication-related osteonecrosis of the jaw (MRONJ) lesions and complement the descriptive radiographic interpretation of the lesion and its clinical assessment. Method and MaterialsA retrospective review of MRONJ patients assessed at our institution was performed to compare the Composite Radiographic Index (CRI), identified from a prior scoping review, with a proposed modification, the Modified CRI index (‘Mod-CRI’). The Mod-CRI index was weighted to assign a higher score for diffuse radiographic involvement of a given lesion, and delineated MRONJ lesions into those with ‘high’ and ‘low’ severity. Twenty-two MRONJ cases imaged with CBCT were retrospectively assessed with both CRI and Mod-CRI indices and the two indices were compared for their ability to quantitatively describe cone-beam computerized tomography (CBCT) radiographic features and complement the clinical staging of the MRONJ lesion. ResultsThere was a statistically significant association between increased clinical stage and higher mod-CRI score (p = 0.040).The Mod-CRI index sorted the patients who scored intermediate scores with the CRI (n = 15) into either the low (n = 8) or high categories (n = 7). ConclusionThe Mod-CRI index eliminated the ambiguous intermediate-category-scores in the previously published CRI index and provided greater clarity to the interpretation of a given index score. Adopting the Mod-CRI could improve MRONJ assessment and enhance communication between the radiologist and the clinician.

Medication-induced osteonecrosis of the jaw: a review of cases from the Food and Drug Administration Adverse Event Reporting System (FAERS)

BackgroundOsteonecrosis of the jaw (ONJ) is a rare but serious adverse drug reaction (ADR) commonly associated with bisphosphonate and denosumab therapy. Prior research utilized an online, public FDA Adverse Event Reporting System (FAERS) Database to explore this ADR. This data identified and described several novel medications associated with ONJ. Our study aims to build upon the prior findings, reporting trends of medication induced ONJ over time and identifying newly described medications.MethodsWe searched the FAERS database for all reported cases of medication related osteonecrosis of the jaw (MRONJ) from 2010 to 2021. Cases lacking patient age or gender were excluded. Only adults (18 +) and reports from Healthcare Professions were included. Duplicate cases were removed. The top 20 medications were identified and described for April 2010-December 2014 and April 2015-January 2021.ResultsNineteen thousand six hundred sixty-eight cases of ONJ were reported to the FAERS database from 2010–2021. 8,908 cases met inclusion criteria. 3,132 cases were from 2010–2014 and 5,776 cases from 2015–2021. Within the cases from 2010–2014, 64.7% were female and 35.3% were male, and the average age was 66.1 ± 11.1 years. Between 2015–2021, 64.3% were female and 35.7% were male, and the average age was 69.2 ± 11.5 years. Review of the 2010–2014 data identified several medications and drug classes associated with ONJ not previously described. They include lenalidomide, corticosteroids (prednisolone and dexamethasone), docetaxel and paclitaxel, letrozole, methotrexate, imatinib, and teriparatide. Novel drugs and classes described between 2015–2021 include palbociclib, pomalidomide, radium 223, nivolumab, and cabozantinib.DiscussionWhile stricter inclusion criteria and removal of duplicate cases led to fewer overall identified cases of MRONJ when compared to prior research, our data represents a more reliable analysis of MRONJ reports to the FAERS database. Denosumab was the most frequently reported medication associated with ONJ. While unable to imply incidence rates from our data due to the nature of the FAERS database, our findings provide further description of the various medications associated with ONJ and elucidate patient demographics associated with the ADR. Additionally, our study identifies cases of several newly described drugs and drug classes that have not been previously described in literature.

Case series of medication-related osteonecrosis of the jaw (MRONJ) patients prescribed a drug holiday

The role of a drug holiday in the management of medication-related osteonecrosis of the jaw (MRONJ) remains controversial. Current UK guidance does not recommend this practice given the lack of conclusive evidence, and potential risk of skeletal-related events or cancer metastasis. This paper aims to describe a series of fifty patients with confirmed MRONJ who were prescribed a drug holiday as part of their management. Data were collected on exposures including: anti-resorptive and/or anti-angiogenic drug history, duration of drug, method of administration, concurrent therapy, MRONJ stage, management of MRONJ and duration of drug holiday. The primary outcome was complete healing as documented in the clinical notes. Multivariate Cox regression analysis was performed to evaluate the association between exposures and primary MRONJ outcome. Models were adjusted for age, sex, and index of multiple deprivation. Survival analysis was performed using a log-rank test, censoring any patients with no primary outcome recorded (p < 0.05). A total of 44% of patients stopped their medication for >36 months. Over half of all MRONJ cases presented in the posterior mandible and dental extraction was the most common precipitating factor (76%). Almost three-quarters (72%) of patients achieved complete healing. MRONJ recurrence (new site) was reported at 30%, mainly in those with incomplete healing of the initial area. There was a lack of evidence for an association between all recorded exposures and the primary MRONJ outcome using multivariate Cox regression. Similarly, we did not demonstrate evidence for an association between the duration of the drug holiday and MRONJ outcome. Our results support published guidelines, which do not recommend the discontinuation of bone modifying drugs for the prevention of MRONJ, or as part of treatment for established MRONJ.

Usefulness of quantitative bone SPECT/CT for evaluating medication-related osteonecrosis of the jaw treatment response.

For assessment of therapeutic response in medication-related osteonecrosis of the jaw (MRONJ) cases, the clinical usefulness of quantitative bone single-photon computed tomography-computed tomography (SPECT/CT) results was investigated. Sixteen patients (18 lesions) with a clinical diagnosis of MRONJ underwent bone SPECT/CT scanning before and during/after anti-inflammatory therapy given for 3 or more months. The GI-BONE software package was used to determine standard uptake values (SUVs), including maximum (SUVmax), peak (SUVpeak), and mean (SUVmean), and metabolic bone volume (MBV) and also total bone uptake (TBU). In both responders (downstage) and non-responders (upstage or no change), differences in quantitative values between the first and second SPECT/CT examinations were analyzed using a Wilcoxon test. Following therapy, significant reductions in SUVmax, SUVpeak, SUVmean, MBV and TBU values for 11 lesions were noted in the responders after therapy (p = 0.003, p = 0.006, p = 0.004, p = 0.003, and p = 0.002, respectively). On the other hand, those for the seven lesions in the non-responder group were not significantly different (p = 0.17, p = 0.16, p = 0.26, p = 0.96, and p = 0.12, respectively). Results for SUVmax change showed sensitivity and specificity values of 45.5% and 85.7%, respectively, for differentiating responders from non-responders, with -37.3% the optimal cutoff value. Those for MBV change were 72.7 and 85.7%, respectively, with -29.4% the optimal cutoff value. Those for TBU change were 81.8% and 85.7%, respectively, with -36.3% the optimal cutoff value. The present findings showed that therapeutic response in MRONJ cases could be determined by use of quantitative SUV, MBV, and TBU values based on bone SPECT/CT findings.

Medication-Related Osteonecrosis of the Jaw: A Cross-Sectional Survey among Urologists in Switzerland, Germany, and Austria.

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially preventable adverse side effect of mainly antiresorptive drugs. MRONJ is expected to become a growing clinical problem due to the aging population and the increasing number of patients requiring antiresorptive agents. Knowledge and awareness about MRONJ and elimination of the oral and dental risk factors before starting antiresorptive therapy (AR) are fundamental to reducing the incidence of MRONJ. In urology, ARs are used primarily in patients suffering from bone metastases due to prostate cancer and to prevent cancer-treatment-induced bone loss (CTIBL) in prostate cancer patients receiving endocrine therapy. This postal survey aimed to evaluate disease-related knowledge and awareness about implementing oral examinations for patients starting AR among Swiss, German, and Austrian urologists. A total of 176 urologists returned the completed questionnaire, yielding a response rate of 11.7%. Of the respondents, 44.9% (n = 79) and 24.4% (n = 43) stated that they give more than five first-time prescriptions of denosumab and of intravenous or oral bisphosphonates per year, respectively. Only 14.8% (n = 26) of the participating urologists had never encountered MRONJ cases related to BPs. Of the participants, 89.8% (n = 158) had implemented referrals to dentists for oral examination before initiating AR. The mean percentage of correct answers regarding the knowledge about MRONJ was 70.9% ± 11.2%. In contrast to previous surveys on MRONJ among physicians, this study showed that the participating urologists were sufficiently informed about MRONJ, as reflected by the high number of participants implementing preventive dental screenings.

MEDICATION-RELATED OSTEONECROSIS OF THE JAW ASSOCIATED WITH PAZOPANIB AND ORAL BISPHOSPHONATES

The drugs most commonly associated with medication-related osteonecrosis of the jaw (MRONJ) are bisphosphonates (BPs), denosumab, as well as bevacizumab and sunitinib, among others. MRONJ prevalence among oral BP (OBP) users varies from 0.004% to 0.1%, reaching 0.21% after 4 years of use. Pazopanib is a multi-tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). To date, about 12 cases of MRONJ associated with pazopanib have been reported. A 64-year-old woman was referred presenting bone exposure in the mandible 60 days ago. There was no history of local surgery or trauma. Her medications included pazopanib for RCC treatment 7 months ago and OBPs for osteoporosis treatment 8 years ago. Clinical, radiographic, and histopathologic findings were consistent with MRONJ. The potential risk due to the simultaneous use of 2 drugs known to be associated with MRONJ should be better clarified with the report of further cases.