Cases Of Osteonecrosis Of The Jaw Research Articles

A Summary of the Rare Reports of Osteonecrosis of the Jaw Associated With Tumor Necrosis-α Inhibitors in the United States Food and Drug Administration's Adverse Event Reporting System Database

Recent case reports highlight an association between osteonecrosis of the jaw (ONJ) and antitumor necrosis factor (anti-TNF) medications. Our study reviewed and described reports of anti-TNF associated ONJ reported to the United States of America's Food and Drug Administration Adverse Event Reporting System to explore this potential adverse drug reaction further. Using the Food and Drug Administration Adverse Event Reporting System database, we identified reported cases of ONJ between 2010 and 2021. Cases were included in our study if they reported any prior or concomitant anti-TNF medication use. Additionally, only adults (age 18+) and reports from health-care professionals were included. Cases lacking subject age or gender were excluded. After duplicates were removed, a dataset was created and demographics were described including age, gender, and indication for use. Naranjo scoring was conducted to assess adverse drug reaction probability. Subject demographics were then separately described for cases without reported denosumab or bisphosphonate therapy history and compared to those with reported history or concomitant denosumab or bisphosphonate therapy. Over twenty thousand cases of ONJ were reported. Forty-four potential cases (0.22%) of anti-TNF medication-associated ONJ were identified and reviewed. Of these, female gender comprised 77.3% (35 cases) and there was an average age of 61.3years±13.7years. Twenty cases (45.5%) had no prior/concomitant bisphosphonate or denosumab therapy. Of these, 55% (11 cases) were female and the average age was 54.5±17.3years. Rheumatoid arthritis was the most frequent indication for use (5 cases, 25%) followed by inflammatory bowel disease (IBD) and psoriatic arthritis (4 cases each, 20%) in this cohort. Twenty potential cases of anti-TNF-associated ONJ without prior or concomitant medications known to be associated with ONJ were identified and described. Interestingly, male gender was more frequent and subjects were younger in these cases compared to those with prior/concomitant bisphosphonates or denosumab therapy. Naranjo scoring indicated a probable interaction for three cases. Further studies are needed to clarify the association of ONJ and anti-TNF therapy, including investigating potential mechanisms and reporting future cases with sufficient detail to assess possible confounding factors.

Denosumab-associated jaw bone necrosis in cancer patients: retrospective descriptive case series study

BackgroundDenosumab (DMB) is a bone antiresorptive agent used to treat osteoporosis or metastatic cancer of the bones. However, denosumab-associated osteonecrosis of the jaw (DRONJ) has become a common complication in cancer patients. The prevalence of osteonecrosis of the jaw (ONJ) in cancer patients is estimated to be similar for both bisphosphonate-related cases (1.1 to 1.4%) and denosumab-related cases (0.8 to 2%), with the addition of adjunctive therapy with anti-angiogenic agents reportedly increasing its prevalence to 3%. (Spec Care Dentist 36(4):231–236, 2016). The aim of this study is to report on DRONJ in cancer patients treated with DMB (Xgeva®, 120mg).Case presentationIn this study, we identified four cases of ONJ among 74 patients receiving DMB therapy for metastatic cancer. Of the four patients, three had prostate cancer and one had breast cancer. Preceding tooth extraction within 2 months of the last DMB injection was found to be a risk factor for DRONJ. Pathological examination revealed that three patients had acute and chronic inflammation, including actinomycosis colonies. Among the four patients with DRONJ referred to us, three were successfully treated without complications and had no recurrence following surgical treatment, while one did not follow up. After healing, one patient experienced a recurrence at a different site. Sequestrectomy in conjunction with antibiotic therapy and cessation of DMB use proved to be effective in managing the condition, and the ONJ site healed after an average 5-month follow-up period.ConclusionConservative surgery, along with antibiotic therapy and discontinuation of DMB, was found to be effective in managing the condition. Additional studies are needed to investigate the contribution of steroids and anticancer drugs to jaw bone necrosis, the prevalence of multicenter cases, and whether there is any drug interaction with DMB.

On the Association between Dental Implants, Osteoporosis and Bone Modulating Therapy

Background: Osteoporosis affects bone metabolism and may result in fragility fractures. Medications include bone modulating therapy (BMT), which come with the risk of osteonecrosis of the jaws (ONJ). The literature is contradictory about the impact of osteoporosis and/or BMT on dental implant success and the incidence of ONJ. Purpose: The aim of the present study was to assess the effect of osteoporosis and BMT on early implant failure (EIF) and ONJ incidence (primary outcome parameters) following dental implant placement. Materials and Methods: Retrospective, cohort study based on dental records. Implant-supported prostheses (ISP) were delivered by experienced oral and maxillofacial surgeons and prosthodontists. Inclusion criteria: diagnosis of osteoporosis, delivery of ISP, consecutive individuals, and available data. Confounding variables included—age, gender, smoking status, BMT, bone grafting, and implant length/diameter. Results: There were a total of 72 osteoporosis patients, 46 using and 26 not using BMT. There were a total of 279 inserted implants, 154 in those using and 124 in those not using BMT. Univariate analysis of factors that may affect EIF showed no statistically significant differences between non-osteoporotic, osteoporotic using BMT, and osteoporotic patients not using BMT regarding EIF and ONJ incidence following dental implant delivery. Multivariate model using logistic regression demonstrated one factor associated with increased risk for EIF—bone augmentation. No cases of ONJ were reported up to one year post ISP delivery in any group. Conclusions: Within the limitations of the present study, it can be concluded that installing dental implants in osteoporotic patients, treated or not with BMT, is a safe procedure with EIF comparable to non-osteoporotic patients. The short-term risk for ONJ following dental implant insertion in osteoporotic (even when using BMT) patients is negligible.

Genome-wide association study of osteonecrosis of the jaw in Danish patients receiving antiresorptive therapy for osteoporosis: A case-control study

BackgroundPrior studies of the pharmacogenomics of osteonecrosis of the jaw (ONJ) have had various methodological limitations, including using candidate gene selection as their sole strategy, a small number of ONJ cases, or a study population based on an oncology setting. ObjectivesThe aim of our case-control study was to evaluate previously reported associations between genetic factors and ONJ, which were based on either genome-wide association studies (GWAS) or candidate gene approaches. Furthermore, we aimed to identify genetic risk factors for ONJ by using GWAS to determine single-nucleotide polymorphisms (SNPs) with statistically significant differences in frequency between ONJ patients and osteoporosis controls. MethodsPatients with medically confirmed ONJ and who were registered in the Scandinavian Cohort of ONJ patients were included. Controls from the general population were matched on age (±5 years), sex, and cumulative antiresorptive drug exposure. The ONJ diagnosis date for cases corresponded to the index date for matched controls. DNA isolation, genotyping, and data analyses were performed by Q2/EA Genomics using standard protocols and best practices. Blood or tissue samples for 55 ONJ cases and 125 controls were collected. Due to the low quality of the tissue samples, final analyses were based on blood samples of 40 ONJ cases and 124 controls. ResultsWe detected no significant genome-wide associations. Of the 43 SNPs with ONJ association in prior studies, none were replicated in our study. ConclusionsEven though our study sample is the largest to date, we had limited statistical power for GWAS but adequate power for replication analyses. Our study provides no evidence for any genetic predisposition to ONJ. Future studies could increase their statistical power by combining ONJ GWAS datasets and by performing a meta-analysis or pursuing a sequencing strategy in order to identify rare variants.

S166 Osteonecrosis of the Jaw Associated With Bevacizumab in Treatment: A Case Series Using the FDA Adverse Event Reporting System (FAERS) Database

Introduction: Osteonecrosis of the jaw (ONJ) is a rare but serious adverse drug reaction (ADR) historically associated with denosumab and bisphosphonate therapy. Studies have demonstrated an association between ONJ and bevacizumab, a VEGF inhibitor now used for some gastrointestinal malignancies. This study reviewed cases of bevacizumab associated ONJ reported to the FDA Adverse Event Reporting System (FAERS) database Methods: The FAERS database was searched for all reported cases of ONJ from 2010 to 2021. Cases lacking patient age or gender were excluded from review. Only adults (age 18 and older) and reports from Healthcare Professions were included for analysis. Duplicate cases were removed. A dataset was created for bevacizumab associated ONJ and demographics were summarized. A subgroup analysis was performed for subjects receiving bevacizumab without prior or concomitant denosumab or bisphosphonate therapy. Results: 19,670 cases of ONJ were reported to the FAERS database from 2010 to 2021 with approximately half (9,556) containing complete patient demographic data. 146 cases (1.5%) of bevacizumab associated with ONJ were identified. 65.8% (96) of the patients were female and the average age was 60.9 years +/- 9.3 years. There were 34 cases without prior or concomitant bisphosphonate or denosumab therapy. Male gender was associated with 65% (22 of 34) of these cases and average age was 61 years +/- 12.0. Table/Figure depicts clinical indications for each of these 34 cases. Gastrointestinal malignancies (i.e., colon cancer and esophageal cancer) were present in 6/34 (17.6%) cases without prior denosumab/bisphosphonate therapy, 5 patients with breast cancer (14.7%) and 5 cases of prostate cancer (14.7%). Conclusion: 146 cases of bevacizumab associated with ONJ have been reported to the FAERS database and 23% of these cases did not involve medications known to cause ONJ. Clinicians should be aware that ONJ is a potential adverse effect of bevacizumab treatment.Figure 1.: This Figure represents the distribution of the clinical indications of bevacizumab-associated with ONJ as reported to the FAERS database from 2010 to 2021 Table 1. - This Table represents the distribution of the clinical indications of bevacizumab associated with ONJ as reported to the FAERS database from 2010 to 2021 along with the respective number of cases Indication for use Number of cases Colon cancer 5 Breast cancer 5 Prostate cancer 5 Unspecified 5 Renal cell cancer 4 Lung cancer 3 Other 3 Esophageal cancer 1 Brain cancer 1 Rheumatoid Arthritis 1 Plasma cell myeloma 1

Possible association of methotrexate use with osteonecrosis of the jaw: Systematic review

The aim was to search systematically, evaluate, and then summarize scientific literature about possible methotrexate-associated osteonecrosis of the jaw (ONJ), its signs and symptoms, diagnosis, treatment, and prognosis in adults. After registration at PROSPERO this systematic review was conducted and reported according to the PRISMA checklist. The following databases were systematically searched: MEDLINE, EBSCO, The Cochrane Central Register of Controlled Trials (Central), SCIndex, Scopus, Google Scholar and Registry of clinical studies with human participants. In total 9 studies with 14 patients were included in the review. All cases of ONJ associated with methotrexate were described in patients suffering from Rheumatoid arthritis (RA), and only about 40% of them were taking other concomitant medication described to be associated with ONJ (bisphosphonates). Both sexes were equally affected, and the patients were rather old (over 60 years if age), already taking methotrexate for more than 12 years on average. Antibiotics were ineffective in the treatment of ONJ; after stopping methotrexate, all lesions healed after several months on average; however, half of the cases required covering of the exposed bone with mucosal flap. Recurrence of the methotrexate-associated ONJ was not observed for at least two years after the lesions were healed. Methotrexate-associated ONJ is serious clinical condition that may occur in patients with RA, but given the small number of cases we have found in the literature, direct involvement of methotrexate in the development of ONJ remains elusive.

Long-term safety of eldecalcitol in Japanese patients with osteoporosis: a retrospective, large-scale database study

This real-world study evaluated whether long-term use of eldecalcitol (ELD) increases the risk of adverse events (AEs), namely, hypercalcemia, acute kidney injury (AKI), and urolithiasis, and analyzed the ELD-induced risk of rare AEs such as osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF). Patient records were retrieved from Medical Data Vision (MDV) and Japan Medical Data Center (JMDC) databases. The ELD-treated osteoporosis patient cohort (ELD cohort) was analyzed to determine the incidence rate of the aforementioned AEs. The patient cohort that was prescribed active vitamin D3 other than ELD (AVD cohort) was analyzed as the reference. Incidence rates of hypercalcemia, AKI, and urolithiasis in the ELD cohort were 0.942, 0.517, 2.465 events per 100 person-years, respectively, in the MDV dataset, and 0.687, 0.155, 3.785, respectively, in the JMDC dataset. The incidence rates of these AEs in the ELD cohort remained relatively constant throughout ELD treatment. A small number of patients experienced ONJ or AFF during ELD or AVD treatment. The number of ONJ and AFF cases in the both cohorts decreased over time. The two cohorts showed no difference in the concomitant use of anti-bone resorptive agents such as bisphosphonates and denosumab. The risk of hypercalcemia and AKI associated with ELD use observed in this retrospective analysis is similar to that reported previously in the Japanese post-marketing surveillance of ELD. Furthermore, ELD, similar to AVD, may not increase the risk of ONJ and AFF.

Gradual, but Not Sudden, Dose-Dependent Increase of ONJ Risk With Bisphosphonate Exposure: A Nationwide Cohort Study in Women With Osteoporosis.

BackgroundA causal relationship of bisphosphonate (BP) exposure with osteonecrosis of the jaw (ONJ) has been reported; however, a definite dose-dependent risk remains to be elucidated beyond current vague recommendations of 4-year oral BP for ONJ risk increase.ObjectiveTo identify the effect of bisphosphonate cumulative dose on ONJ development in women with osteoporosis.MethodsA retrospective cohort study was designed using the National Health Insurance Service—National Health Screening database of Korea. Females over the age of 50 were diagnosed with osteoporosis based on the International Classification of Diseases 10th revision (ICD-10) codes (M80, M81, and M82) with bisphosphonate prescriptions. The cumulative dose of bisphosphonate was calculated using defined daily doses (DDD) to provide an accurate BP cumulative effect on ONJ occurrence. Osteonecrosis of the jaw was identified using both ICD-10 codes and related procedure codes. The incidence rates of ONJ and hazard ratios were estimated according to the bisphosphonate cumulative dose.ResultsAmong 74,491 included subjects, 190 cases of ONJ were identified. The incidence rate substantially increased after BP cumulative dose over 1 year (25.75 for DDD < 365, which increased to 53.43 for 365 ≤ DDD < 730). Compared to subjects with a cumulative dose of DDD < 365, subjects with a cumulative dose of 365 ≤ DDD < 730 had 2.36-fold hazard for developing ONJ (p < 0.001).ConclusionA bisphosphonate cumulative dose of more than 1 year had an increased risk of ONJ development. A gradual, but not sudden, dose-dependent increase in ONJ risk with BP exposure needs to be considered in providing the optimal BP treatment duration.

Risk of Osteonecrosis of the Jaw Under Denosumab Compared to Bisphosphonates in Patients With Osteoporosis.

Osteonecrosis of the jaw (ONJ) is a rare but serious adverse event associated with antiresorptive treatment. There is little evidence regarding the incidence of ONJ among patients with osteoporosis who are treated with denosumab versus bisphosphonates (BPs). The aim of this study was to determine the risk of ONJ in a real-world population. Subjects who underwent at least one dual-energy X-ray absorptiometry (DXA) examination were included in the osteoporosis register of the Swiss Society of Rheumatology between January 1, 2015, and September 30, 2019. Statistical analyses included incidence rates, rate ratios, and hazard ratios for ONJ, considering sequential therapies and drug holidays as covariates. Among 9956 registered patients, 3068 (89% female, median age 69 years [63 to 76]) were treated with BPs or denosumab for a cumulative duration of 11,101 and 4236 patient-years, respectively. Seventeen cases of ONJ were identified: 12 in patients receiving denosumab at the time of ONJ diagnosis and 5 in patients receiving oral or intravenous BP therapy. The diagnosis of ONJ was confirmed by independent and blinded maxillofacial surgeons, using the American Association of Oral and Maxillofacial Surgeons case definition of ONJ. The incidence of ONJ per 10,000 observed patient-years was 28.3 in patients receiving denosumab and 4.5 in patients with BP-associated ONJ, yielding a rate ratio of 6.3 (95% confidence interval [CI] 2.1 to 22.8), p < 0.001. Nine of 12 patients who developed ONJ during denosumab treatment had been pretreated with BPs, but none of the 5 patients with BP-related ONJ had previously received denosumab. The risk of ONJ was higher in patients receiving denosumab therapy compared with BPs (hazard ratio 3.49, 95% CI 1.16 to 10.47, p=0.026). Previous BP therapy before switching to denosumab may be an additional risk factor for ONJ development. © 2021 American Society for Bone and Mineral Research (ASBMR).

Safety of Intravenous Bisphosphonates for the Treatment of Hypercalcemia in Patients With Preexisting Renal Dysfunction.

Although intravenous (IV) bisphosphonates are first-line medications for the management of hypercalcemia, studies examining their use in patients with preexisting renal dysfunction are limited. The objective of this study is to describe the safety and efficacy of pamidronate and zoledronic acid in the treatment of hypercalcemia in patients with baseline renal dysfunction. A retrospective analysis was conducted of IV pamidronate and zoledronic acid in adult patients with hypercalcemia and creatinine clearance (CrCl) <60 mL/min. The primary endpoint was incidence of all-grade serum creatinine (SCr) elevations. Secondary endpoints included refractory hypercalcemia, hypocalcemia, osteonecrosis of the jaw (ONJ), corrected serum calcium (CSC) decrease ≥1.0 mg/dL by day 7 of bisphosphonate administration, and normalization of CSC ≤10.5 mg/dL by days 10 and 30. A total of 113 patients were included (n = 55 pamidronate, n = 58 zoledronic acid). The primary endpoint of all-grade SCr elevation occurred in 28 (24.8%) patients. Grades 3/4 SCr elevations occurred in 10.9% of patients treated with pamidronate and 1.7% of patients receiving zoledronic acid. Approximately 16% and 14% of patients developed grades 1 and 2 hypocalcemia, respectively, and there were no cases of ONJ. Overall, 64.6% of patients achieved normalization of CSC by day 10, and there were no statistical differences between bisphosphonate type and renal function. The analysis suggests an association between IV bisphosphonates and increased rates of SCr elevations among patients with preexisting renal dysfunction. Future prospective studies are necessary to elucidate these findings.

Efficacy and toxicity of extending bone modifying agents beyond two years for bone metastases in breast or castrate-resistant prostate cancer patients: A systematic review.

e24083 Background: Randomized clinical trials evaluated bone modifying agents (BMAs) such as bisphosphonates and denosumab for bone metastases for 1-2 years in duration even though BMA therapy is commonly administered for much longer. A systematic review on the risk-benefit of continuing BMAs for longer than 2 years in breast cancer or castrate-resistant prostate cancer was conducted. Methods: Medline, Embase and Cochrane Register of Controlled Trials were searched (1970 - February 2019) for randomized studies, observational studies, and case series reporting on BMA efficacy and toxicity beyond 2 years. Efficacy was assessed by skeletal-related event (SRE) rates and quality of life metrics. Toxicity was assessed by rates of osteonecrosis of the jaw (ONJ), renal impairment, hypocalcemia, and atypical femoral fractures (AFF). Results: Of 2107 citations, 64 studies were identified. A total of 3 prospective and 9 retrospective studies were eligible. Data beyond 2 years was limited to subgroup analyses in all studies. Three studies [zoledronate (ZOL) (n = 481), pamidronate (PAM) (n = 87), PAM-ZOL (n = 43) ibandronate (n = 30)] reported on SRE-related endpoints. Only one study reported SRE rates based on duration of BMA exposure and showed reduced SRE rates from 27.6% (0-24 months) to 15.5% ( &gt; 24 months) over time. None reported on quality of life. All 12 studies [denosumab (n = 948), ZOL (n = 1036), PAM (n = 163), PAM-ZOL (n = 522), ibandronate (n = 118)] reported on at least one toxicity outcome. Data from 7 bisphosphonate studies (n = 1077) and 1 denosumab study (n = 948) reported on ONJ incidence. In 3 studies (n = 67, n = 221, n = 948), ONJ incidence ranged from 1-4% in the first 2 years and from 3.8-18% beyond 2 years. In another study (n = 252), the cumulative hazard of ONJ was 0% (1% ZOL), 3% (7% ZOL), 7% (21% ZOL) and 11% (21% ZOL) at 12, 24, 36, and 48 months, respectively (p = 0.005); 4 remaining studies reported 1 (n = 181), 3 (n = 57), 7 (n = 99) and 2 (n = 200) cases of ONJ, all after 24 months. Incidence of clinically significant hypocalcemia ranged from 1-2%. Incidence of severe renal function decline was ≤ 3%. AFF occurred in two subjects in one of two studies after 37 and 79 months of BMA exposure. Conclusions: Although the evidence informing the use of BMA is heterogeneous and based on retrospective analysis, BMA exposure beyond 2 years is associated with reduced SRE risk and increased ONJ incidence. Prospective randomized studies addressing the use of BMA for more than 2 years is needed with greater emphasis on quality of life.

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Osteonecrosis of the jaws associated with denosumab: Study of clinical and radiographic characteristics in a series of clinical cases.

BackgroundThe objective of this study was to describe the clinical and radiographic characteristics of our series of medication-related osteonecrosis of the jaws (ONJ) associated with denosumab. Material and MethodsWe presented 15 cases of ONJ associated with denosumab; 11 received treatment for their osteoporosis and four for cancer treatments. We recorded the most frequent clinical findings, symptoms and radiographic characteristics in our patient group, as well as local and systemic contributing factors. ResultsThe mean time of treatment with denosumab was 23.83 ± 12.84 months. 40% of the patients had a previous history of treatment with bisphosphonates. The most common local factor was tooth extraction (11 cases; 73.3%), and in most cases there was necrotic bone exposure (13/15, 86.67%). Osteolysis, bone sclerosis and cortical erosion were the most common radiographic findings. Stage 1 was the most frequent, present in 60% of the cases. ConclusionsIn our patient group, most were in the early stages of ONJ. Key words:Denosumab, osteonecrosis, jaws, radiology.

Incidence of osteonecrosis of the jaw in Japanese osteoporosis patients taking minodronic acid.

Osteonecrosis of the jaw (ONJ) associated with bisphosphonate therapy is a rare but severe side effect in osteoporosis patients. Recently, the number of osteoporosis patients with ONJ has dramatically increased in Japan. This has contributed to an increase in the number of patients avoiding extractions. However, there has been no prospective study providing definitive incidence data for ONJ in Japanese patients. The purpose of this study was to elucidate the true as well as suspected incidence of ONJ. A total of 3229 subjects (1612 subjects in the minodronic acid group and 1617 subjects in the raloxifene group) in the Japanese Osteoporosis Intervention Trial protocol number 4 participated in this study. ONJ was diagnosed by experienced dentists. Suspected Stage 0 and 1 (bone exposure of the jaw) ONJ was assessed by a structured questionnaire at baseline and at 6, 12, 18, and 24months. No established ONJ cases were diagnosed during the study. The incidence of suspected Stage 0 and/or Stage 1 ONJ was 6.14 per 1000 patient-years in the minodronic acid group and 3.38 per 1000 patient-years in the raloxifene group [hazard ratio (95% confidence interval) = 1.82 (0.84-3.93), P = 0.13]. Approximately 50-60% of bone exposures that appeared during the study had disappeared at the next observation. Although the subjects in this study may have developed a greater interest in the health of the oral cavity, the incidence of ONJ after minodronic acid treatment would be lower than the expected incident rate.

Osteonecrosis of the jaw in the era of targeted therapy and immunotherapy in oncology.

Osteonecrosis of the jaw (ONJ) is a well-known pathological condition in oncology derived from the use of bisphosphonates (BPs) and denosumab. Many molecular and immunological targets have been introduced for daily use in cancer treatment in recent years; consequently, new cases of ONJ have been reported in association with these drugs, especially if administered with BPs and denosumab. When the drugs are administered alone, ONJ is rarely seen. The objective of our study was to analyze the recent literature relative to the association of ONJ with these new drugs highlighting the pathogenic, clinical and therapeutic aspects. The close collaboration between maxillofacial surgeon, oncologist, dentist, and dental hygienist remains the most important aspect for the prevention, prompt recognition, and treatment of this pathology.

Osteonecrosis of the jaws caused by myelodysplasia: a case report

Osteonecrosis of the jaws caused by myelodysplasia: a case report

Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review.

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. To review characteristics of ONJ in cancer patients receiving non-antiresorptives. A systematic review of the literature between 2009 and 2017 was conducted by the Bone Study Group of MASCC/ISOO. 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 60years 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 8weeks) was noted. Important differences included earlier time to ONJ onset (median 20weeks), absence of trigger event (40%), and greater likelihood of healing and shorter healing time (median 8weeks) 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. 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.

Drug holiday patterns and bisphosphonate-related osteonecrosis of the jaw.

There is limited evidence regarding the appropriate length of a bisphosphonate (BP) holiday to reduce the risk of osteonecrosis of the jaw (ONJ). In this cross-sectional study, we investigated the population-based patterns of the gaps between BP discontinuation and ONJ diagnosis. We used the claims database of the National Health Insurance Service in Korea. Among BP users between 2006 and 2015, incident ONJ cases during 2010-2015 with no history of ONJ in the last 4years were identified. We assessed the time gap from the last BP administration to ONJ diagnosis. Among 1,569 incident ONJ cases, 836 (53.3%) occurred after BP discontinuation. The cumulative proportions of ONJ occurrence within 1month, 3months, 1year, 2years, and 3years after discontinuation were 58.9%, 70.8%, 87.0%, 93.2%, and 96.1%, respectively. The length of drug holidays showed no significant difference between patients with or without comorbid cancer and diabetes mellitus (p-value, 0.12 and 0.52, respectively). However, the use of injectable BP formulations significantly affected ONJ incidence (p<0.01). Most ONJ cases occurred within 3years from BP suspension, with a higher prevalence among BP injection users with 1year or lesser BP holiday.

Osteonecrosis of the Jaw in Myeloma Patients Receiving Denosumab or Zoledronic Acid. A Commentary of the Pivotal Trial by Raje et al. Published on Lancet Oncology.

The recent randomized trial, published by Raje et al., on Lancet Oncology is potentially practice changing. It proposes that denosumab is a valid alternative to zoledronic acid in the treatment of myeloma patients. However, several points need further data and more details, such as information on incidence, diagnosis, and follow-up of osteonecrosis of the jaw (ONJ) cases, observed among treated patients. Adopted definition to adjudicate ONJ cases, type of registration of potential ONJ cases, length of observation are possible causes of potential underestimation of ONJ incidence in their study. Future updated evaluations with longer follow-up, and including actuarial estimation, are required for final judgment on ONJ risk in myeloma patients receiving denosumab, and comparison with ONJ risk by zoledronic acid.

SIRT1/HERC4 Locus Associated With Bisphosphonate-Induced Osteonecrosis of the Jaw: An Exome-Wide Association Analysis.

Osteonecrosis of the jaw (ONJ) is a rare, but serious drug side effect, mainly associated with the use of intravenous (iv) bisphosphonates (BPs). The purpose of this study was to identify genetic variants associated with ONJ in patients of European ancestry treated with iv BPs using whole-exome sequencing (WES). The WES phase 1 included 44 multiple myeloma patients (22 ONJ cases and 22 controls) and WES phase 2 included 17 ONJ patients with solid tumors. Multivariable logistic regression analysis was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age, sex, and principal components for ancestry. Meta-analysis of WES phase 1 and 2 was performed to estimate the combined ORs. In silico analyses were then performed to identify expression quantitative loci (eQTL) single-nucleotide polymorphisms (SNPs) that are in high linkage disequilibrium (LD) with the top SNPs. The associations of the potentially functional SNPs were replicated and validated in an independent case-control study of 48 patients of European ancestry treated with iv BPs (19 ONJ cases and 29 controls). The top SNPs in the exome-wide association meta-analysis were two SNPs on chromosome 10: SIRT1 SNP rs7896005 and HERC4 SNP rs3758392 with identical OR of 0.07 (0.01-0.46; p = 3.83 × 10-5 ). In the in silico functional analyses, two promoter region SNPs (rs7894483 and rs3758391) were identified to be in high LD with the index SNPs and are eQTLs for SIRT1 gene in whole blood in the GTEx database. The ORs were 0.30 (0.10-0.88), 0.26 (0.12-0.55), and 0.26 (0.12-0.55) for the WES top SNP rs7896005 and two promoter SNPs rs7894483 and rs3758391, respectively, in the replication sample. In summary, we identified the SIRT1/HERC4 locus on chromosome 10 to be associated with iv BP-induced ONJ and two promoter SNPs that might be the potential genetic markers for this association. © 2017 The Authors.Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.