Incidence Of Osteonecrosis Of The Jaw Research Articles

Long-term use of denosumab and its association with skeletal-related events and osteonecrosis of the jaw

Denosumab, an inhibitor of receptor activator of nuclear factor kappa-B ligand, reduces skeletal-related events (SREs) and is approved for solid tumors with bone metastases. We studied long-term denosumab efficacy and safety because real-world data is scarce. This single-arm, single-center retrospective study included denosumab-treated breast cancer patients with bone metastases. Kaplan–Meier survival curves assessed exposure, SREs, osteonecrosis of the jaw (ONJ), and death. 132 patients were enrolled. The median denosumab exposure was 28.3 months (range 1.0–84.9). In the first year, 11.1% experienced SREs. This increased to 18.6% in the second, 21% in the third, and 35.1% in the fourth year and beyond. The median time to first on-study SRE has not been reached. 10 denosumab users (7.6%) developed ONJ. ONJ incidence was 0.9% in the first year, 6.2% in the second, 13.6% in the third, and 16.2% in subsequent years. The median time to first on-study ONJ has not been reached yet. Seven patients resumed denosumab after careful management of ONJ. Our data suggest that long-term treatment with denosumab may further prevent or postpone SREs at the cost of an increased risk of ONJ. The majority of patients who resumed denosumab did not experience a recurrence of ONJ.

Incidence rate of osteonecrosis of jaw after cancer treated with bisphosphonates and denosumab: A systematic review and meta-analysis.

This study aimed to assess the overall incidence of osteonecrosis of the jaw (ONJ) caused by bisphosphonates and denosumab when used for controlling bone cancer metastasis or as adjuvant therapy. A systematic search of the PubMed, Embase, and Cochrane Library databases and major meetings' proceedings as of July 30, 2022, identified randomized controlled trials (RCTs) and observational trials that evaluated ONJ caused by denosumab or bisphosphonates. The total incidence and risk ratio (RR) for ONJ were calculated using a random-effects model. A total of 42003 patients with various solid tumors reported in 23 RCTs were included. The overall ONJ incidence in cancer patients receiving denosumab or bisphosphonates was 2.08% (95% CI 1.37-2.91; p<.01; I2 =94.99%). Patients receiving denosumab had a higher ONJ incidence than those receiving bisphosphonates (RR 1.64, 95% CI 1.10-2.44; p<.05; I2 =65.4%). Subgroup analyses showed that prostate cancer patients receiving denosumab and receiving zoledronic acid had the highest ONJ incidences, 5.0% and 3.0%, respectively. The incidence of ONJ induced by different doses was also different. The incidence of ONJ caused by denosumab and bisphosphonates is low, the dose of the drug and the type of cancer have certain influence on ONJ. Therefore, clinicians should use the drug reasonably to improve the quality of life of patients.

Incidence and trend of antiresorptive agent-related osteonecrosis of the jaw from 2016 to 2020 in Kure, Japan

SummaryWe investigated the incidence/trend of osteonecrosis of the jaw by antiresorptive agent dose over a 5-year period in Kure city, Japan. The incidence was 24 times higher among osteoporosis patients with low-dose agents and 421 times higher among cancer patients with high-dose agents than in the population without agents.PurposeWe launched the registry system of osteonecrosis of the jaw (ONJ) cases in 2015 to investigate the trend in ONJ incidence. The purpose of our study was to estimate the ONJ incidence among patients with antiresorptive agent use by dosage and people without antiresorptive agent use in Kure and its trend from 2016 to 2020.MethodsFrom 2016 to 2021, 98 eligible ONJ patients were enrolled. Medication-related ONJ (MRONJ) was diagnosed based on the American Association of Oral and Maxillofacial Surgeons criteria. The annual number of those with and without antiresorptive agents was obtained from the claims database. Antiresorptive agents used for cancer and osteoporosis patients were defined as high- and low-dose medications, respectively.ResultsThe annual incidence of high-dose MRONJ was 2305.8 per 100,000 and that of low-dose MRONJ was 132.5 per 100,000, while the ONJ incidence among people without antiresorptive agents was 5.1 per 100,000. The incidence ratio was 23.6 (p < 0.001, 95% confidence interval (CI) 13.3–41.8) among osteoporosis patients who used low-dose antiresorptive agents and 420.6 (p < 0.001, 95% CI 220.8–801.4) among cancer patients who used high-dose agents compared with people who did not use these agents. MRONJ incidence increased from 2016 to 2020, but the incidence of high-dose MRONJ decreased, although this was nonsignificant.ConclusionWe demonstrated the incidence and trend of ONJ by antiresorptive agent dose over a 5-year period in Kure after launching the multiprofession study. This collaborative study for the early detection and prevention of ONJ will continue.

Osteonecrosis of the jaw among cancer patients in Denmark: risk and prognosis

Osteonecrosis of the jaw (ONJ) is a serious complication of anti-resorptive therapy used in the treatment of multiple myeloma and cancerous bone metastases. In this study, patients with either multiple myeloma or solid tumours with a simultaneous or subsequent record of anti-resorptive treatment or bone metastases were identified using population-based medical registries. These patients were followed for the outcome of ONJ. Considering death as a competing risk, the cumulative incidence of ONJ was estimated, overall and by cancer site. Patients who developed ONJ were followed for the outcome of death overall and by several risk factors for ONJ. A total of 33,975 cancer patients fulfilling the inclusion criteria were identified; 233 incidents of ONJ and a cumulative incidence of 1.9% (95% confidence interval 1.6–2.3%) over a maximum follow-up time of 7.5 years were observed. The 5-year cumulative incidence was 1.3% (95% confidence interval 1.2–1.6%) and varied by cancer site. There were 126 deaths among cancer patients with ONJ over a maximum follow-up time of 6.4 years, resulting in a 5-year mortality of 91% (95% confidence interval 81–97%). Mortality among patients with ONJ varied by cancer site, osteonecrosis stage, and by history of trauma to the mucosa.

Medication-Related Osteonecrosis of the Jaw, a Hidden Enemy. An Integrative Review

Background: Drug-induced osteonecrosis of the jaw (ONJ) ​​is a serious complication associated with prolonged use of antiresorptive (e.g., bisphosphonates and denosumab) and antiangiogenic drugs (e.g., bevacizumab and sunitinib) in patients with osteoporosis or cancer. With this situation, a progressive infection of the maxillary or mandibular bone and later an avascular necrosis of the bone occurs. The incidence of ONJ is higher in people with cancer who are frequently received high doses of antiresorptive drugs intravenously. Risk factors associated with antiresorptive or antiangiogenic therapy have been identified to possibly contributing to the onset of ONJ. Purpose: To review and analyze the current available therapeutic options to treat at-risk patients or who already have ONJ. Methods: In this integrative review of the literature, publications were searched in the ScienceDirect, PubMed, SciELO, and ResearchGate databases between 2003 and 2020. The search terms were “bisphosphonate-associated maxillary osteonecrosis,” “maxillary osteonecrosis associated with medication,” and “maxillary osteonecrosis.” Results: 64 articles were selected in which extractions are identified as the main risk factor for developing ONJ (52 % to 61 %). A second factor identified was the spontaneous appearance of bone necrosis lesions. Conclusions: It is important to implement preventive measures in medical and dental care before, during, and after antiresorptive and antiangiogenic treatments to minimize the risks of ONJ in patients.

Osteonecrosis of the jaw among patients with cancer treated with denosumab or zoledronic acid: Results of a regulator-mandated cohort postauthorization safety study in Denmark, Norway, and Sweden.

Osteonecrosis of the jaw (ONJ) is an adverse effect of antiresorptive treatment. This study estimated incidence proportions and incidence rates of ONJ in cancer patients with bone metastases from solid tumors treated for the prevention of skeletal-related events in routine clinical practice. This cohort study in Denmark, Norway, and Sweden in 2011-2018 included 3 treatment cohorts: a denosumab inception cohort (DEIC), a zoledronic acid inception cohort (ZAIC), and a denosumab-switch cohort (DESC). The authors estimated 1- to 5-year incidence proportions and incidence rates of ONJ overall, by cancer site (breast, prostate, or other solid tumor), and by country. ONJ diagnoses were confirmed by adjudication. There were 1340 patients in the DEIC, 1352 in the ZAIC, and 408 in the DESC. The median ages of the 3 cohorts were 70, 69, and 70 years, respectively; the proportions of men were 72.6%, 53.8%, and 48.3%, respectively; and the median follow-up was 19.8, 12.9, and 13.3 months, respectively. The 5-year incidence proportions of ONJ were 5.7% (95% confidence interval [CI], 4.4%-7.3%) in the DEIC, 1.4% (95% CI, 0.8%-2.3%) in the ZAIC, and 6.6% (95% CI, 4.2%-10.0%) in the DESC. The corresponding ONJ incidence rates per 100 person-years were 3.0 (95% CI, 2.3-3.7), 1.0 (95% CI, 0.6-1.5), and 4.3 (95% CI, 2.8-6.3). Incidence proportions and incidence rates were highest in patients with prostate cancer and in Denmark. This study provides estimates of the risk of medically confirmed ONJ among patients initiating denosumab or zoledronic acid in routine clinical practice in 3 Scandinavian countries. The results varied by cancer site and by country. Denosumab and zoledronic acid reduce the risk of bone fractures, pain, and surgery in patients with advanced cancers involving bone. Osteonecrosis of the jaw (ONJ)-death of a jawbone-is a known side effect of treatment with denosumab or zoledronic acid. The authors examined almost 2900 denosumab- or zoledronic acid-treated patients with cancer in Denmark, Norway, and Sweden. Over the course of 5 years, ONJ developed in 5.7% of the patients whose initial treatment was denosumab, in 1.4% of the patients whose initial treatment was zoledronic acid, and in 6.6% of the patients who switched from zoledronic acid to denosumab.

Osteonecrosis of the jaw in metastatic renal cell carcinoma (mRCC) patients treated with zolendronic acid and denosumab: An observational retrospective multicenter trial.

299 Background: Bone is one of the most common site of metastasis occurring in 30% of metastatic renal cell carcinoma (mRCC) patients (pts)3,4. Skeletal metastases from mRCC are usually osteolytic and associated to high rate of morbidity and complication through skeletal related events (SRE). Bone-targeted therapies (BTT) such as zolendronic acid (ZOL AC) and denosumab (Dmab), shown to decrease the time-to-first and subsequent SREs12. Osteonecrosis of the jaw (ONJ) is a rare but potentially serious adverse event associated with BTT. It occurs in 1-2% of pts treated with BTT and in 10-17% of mRCC pts treated with ZOL AC or Dmab. Vascular endothelial growth factor-Tyrosine kinase inhibitors (VEGF-TKI) represent the backbone treatment for mRCC. Nevertheless, it is unclear whether the association of DMAB and ZOL AC to VEGF-TKITTagents could be associated to higher incidence of ONJ. Methods: We retrospectively collected data, from 2 Italian referring centers for mRCC, about 74 pts with bone metastases from mRCC who received, concurrently or sequentially to VEGF-TKI or immune-oncology (IO), AC ZOL and DMAB from January 2013 to January 2020. All pts provided informed consent for inclusion in the study. Results: All pts received VEGF-TKI as first line treatment. 17 pts received AC ZOL whereas 57 received DMAB. All pts received odontological consultation and orthopantomography before start BTT. The median time of Dmab and AC ZOL exposure was 11.6 months. ONJ occurred in 10/74 pts (7.4%): 6/10 pts were on first line treatment and 4/10 on second line. Treatments administered at the time of ONJ diagnosis were nivolumab (1/10), cabozantinib (2/10), sorafenib (1/10), sorafenib (1/10), sunitinib (4/10) and one pts was off therapy. Conclusions: In this real-life Italian population, treatment with BTT in mRCC pts treated with VEGF-TKI inhibitors and IO is associated to higher incidence of ONJ compared to previous report of pts treated with BTT for bone metastasis and lower compared to previous reports in mRCC. Despite the retrospective collection, we provided one of the largest sample of pts treated concurrently with VEGF-TKI or IO and BTT. Physicians should be careful in the use of BTT combined with other treatments in mRCC pts.

Preventing or controlling periodontitis reduces the occurrence of osteonecrosis of the jaw (ONJ) in rice rats (Oryzomys palustris).

Osteonecrosis of the jaw (ONJ) is an adverse event that requires association of both systemic risk factors, such as powerful anti-resorptives (pARs; e.g. zoledronic acid [ZOL]), and local oral risk factors (e.g. tooth extraction, periodontitis). Whereas optimal oral health prior to initiate pARs is recognized as critically important for minimizing ONJ risk, the efficacy of preventive/maintenance measures in patients who are taking pARs is understudied. Rice rats fed a standard diet (STD), rich in insoluble fiber, develop localized periodontitis. STD-rats with localized periodontitis treated with ZOL for 18-24 wk develop ONJ. Hence, we hypothesized that controlling/preventing localized periodontitis in the ZOL-treated rats, reduces ONJ occurrence. We used two approaches to attempt reducing periodontitis prevalence: 1) periodontal cleaning (PC); and 2) replacing the STD-diet with a nutritionally-equivalent diet high in soluble fiber (SF). 75 four-week-old male rats were weight-randomized into five groups (n=15) in a 24-week experiment. Three groups ate the STD-diet and two the high SF-diet. STD-diet groups received intravenous (IV) vehicle (VEH) q4wks (STD+VEH), 80μg/kg ZOL q4wks IV (STD+ZOL), or ZOL plus PC q2wks (STD+ZOL+PC). The SF-diet groups received VEH (SF+VEH) or ZOL (SF+ZOL). Jaws were processed for histopathology and evaluated for ONJ prevalence and tissue-level periodontitis. 1) 40% of STD+VEH rats developed maxillary localized periodontitis with no ONJ; 2) 50% of STD+ZOL rats developed ONJ; 3) 7% of STD+ZOL+PC rats developed ONJ (p<0.01 vs. STD+ZOL); and 4) one SF+ZOL rat developed localized periodontitis, and no SF+VEH or SF+ZOL rats developed ONJ (p<0.001 vs. STD+ZOL). 1) Periodontal cleaning in ZOL-treated rats decreases localized periodontitis severity and reduces ONJ prevalence; and 2) feeding a SF-diet to ZOL-treated rats reduces both incidence of localized periodontitis and ONJ. Our data indicates strong oral microbial community shifts according to oral health condition and trends in the shifts associated with diet.

Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer

Osteonecrosis of the jaw (ONJ) affects patients with cancer and metastatic bone disease (MBD) treated with bone-modifying agents (BMAs), yet the true incidence is unknown. To define the cumulative incidence of ONJ at 3 years in patients receiving zoledronic acid for MBD from any malignant neoplasm. This multicenter, prospective observational cohort study (SWOG Cancer Research Network S0702) included patients with MBD with either limited or no prior exposure to BMAs and a clinical care plan that included use of zoledronic acid within 30 days of registration. Medical, dental, and patient-reported outcome forms were submitted at baseline and every 6 months. Follow-up was 3 years. Osteonecrosis of the jaw was defined using established criteria. Data were collected from January 30, 2009, to December 13, 2013, and analyzed from August 24, 2018, to August 6, 2020. Cancer treatments, BMAs, and dental care were administered as clinically indicated. Cumulative incidence of confirmed ONJ, defined as an area of exposed bone in the maxillofacial region present for more than 8 weeks with no concurrent radiotherapy to the craniofacial region. Risk factors for ONJ were also examined. The SWOG S0702 trial enrolled 3491 evaluable patients (1806 women [51.7%]; median age, 63.1 [range, 2.24-93.9] years), of whom 1120 had breast cancer; 580, myeloma; 702, prostate cancer; 666, lung cancer; and 423, other neoplasm. A baseline dental examination was performed in 2263 patients (64.8%). Overall, 90 patients developed confirmed ONJ, with cumulative incidence of 0.8% (95% CI, 0.5%-1.1%) at year 1, 2.0% (95% CI, 1.5%-2.5%) at year 2, and 2.8% (95% CI, 2.3%-3.5%) at year 3; 3-year cumulative incidence was highest in patients with myeloma (4.3%; 95% CI, 2.8%-6.4%). Patients with planned zoledronic acid dosing intervals of less than 5 weeks were more likely to experience ONJ than patients with planned dosing intervals of 5 weeks or more (hazard ratio [HR], 4.65; 95% CI, 1.46-14.81; P = .009). A higher rate of ONJ was associated with fewer total number of teeth (HR, 0.51; 95% CI, 0.31-0.83; P = .006), the presence of dentures (HR, 1.83; 95% CI, 1.10-3.03; P = .02), and current smoking (HR, 2.12; 95% CI, 1.12-4.02; P = .02). As the findings show, the cumulative incidence of ONJ after 3 years was 2.8% in patients receiving zoledronic acid for MBD. Cancer type, oral health, and frequency of dosing were associated with the risk of ONJ. These data provide information to guide stratification of risk for developing ONJ in patients with MBD receiving zoledronic acid.

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).

Impact of Extended-Interval Versus Standard Dosing of Zoledronic Acid on Skeletal Events in Non-Small-Cell Lung Cancer and Small-Cell Lung Cancer Patients With Bone Metastases.

Zoledronic acid every 4 weeks (Q4wk) reduces the incidence of skeletal-related events (SREs) in patients with metastatic lung cancer. Lung cancer patients were excluded from extended-interval dosing trials (every 12 weeks [Q12wk]) that demonstrated noninferiority of the 2 dosing schemes. To date, the optimal dosing of zoledronic acid in metastatic lung cancer remains unknown. To determine whether zoledronic acid dosed Q12wk is similar to Q4wk dosing for prevention of SRE in patients with metastatic lung cancer. A retrospective analysis was performed in patients with non-small-cell lung cancer and small-cell lung cancer with bone metastases who received Q12wk and Q4wk zoledronic acid. The primary outcome was incidence of SRE at 1 year. Secondary analyses included time to first SRE, overall survival (OS), incidence of osteonecrosis of the jaw (ONJ), kidney dysfunction, and hypocalcemia. A total of 34 patients received Q12wk and 46 patients received Q4wk zoledronic acid. Incidence of SRE at 1 year (Q12wk, 23.5%, vs Q4wk, 23.9%; 95% CI = -0.184 to 0.192; P = 0.968) and median time to SRE (not reached for either cohort; P = 0.530) did not differ. The Q12wk cohort had longer median OS (24.00 vs 8.97 months; P = 0.022). There were no differences in incidence of ONJ, kidney dysfunction, and hypocalcemia. This is the first report examining extended-interval dosing of zoledronic acid in metastatic lung cancer. Incidence and time to SRE at 1 year were similar. This extended-interval dosing may be safe and reasonable for patients with lung cancer with bone metastases.

Meta-analysis of clinical trials to assess denosumab over zoledronic acid in bone metastasis.

Background Bone metastases-induced skeletal complications result in reduced patient survival, lower quality of life, and an increase in healthcare costs. Previously, zoledronic acid (ZA) was the standard choice of treatment for bone metastases, but another drug, denosumab, has also shown promise. However, the clinical utility of these two drugs requires further exploration. Aim of the review Due to the lack of direct comparisons regarding the efficacy of these drugs in both solid tumors and multiple myeloma (MM), we herein tried to conduct a meta-analysis to compare their efficacy in parallel for bone metastases treatment in both solid tumor and MM patients. Methods Multiple databases including Cochrane Library, MEDLINE, EMBASE, and Web of Science were searched to identify randomized controlled trials (RCTs) reported up to March 2019 directly comparing denosumab with ZA in solid tumors and MM. Information about the following events was primarily searched: time to first on-study skeletal-related event (SRE), time to first and subsequent SREs, and overall survival. Information about secondary outcomes including disease progression, pain, health-related quality of life, and adverse events was also recorded. Results Overall, we analyzed data from four distinct RCTs including 7441 patients, and our analysis revealed that patients in the denosumab group had a significantly delayed incidence to the first and subsequent SREs. In addition, denosumab resulted in a higher incidence of hypocalcemia and osteonecrosis of the jaw (ONJ), and a lower incidence of renal toxicity and acute phase reactions, in comparison to ZA. Conclusion Overall, denosumab showed superiority in delaying the first and subsequent SREs, and hence seems to be a promising choice for managing bone metastases in both solid tumors and MM. However, it can induce a higher incidence of ONJ and hypocalcaemia, but these are preventable and manageable effects.

Incidence of and risk for osteonecrosis of the jaw in Korean osteoporosis patients treated with bisphosphonates: A nationwide cohort-study.

To estimate the incidence of osteonecrosis of the jaw (ONJ) in patients treated with bisphosphonates (BPs) and to identify clinical risk factors that increase the risk for ONJ in Korean osteoporosis patients. We used data acquired from the Korean National Health Insurance Service. Among 2,140,149 participants with osteoporosis in 2012, we selected 164,926 new BP users and 164,926 age- and sex-matched control subjects. The control group included only patients with no prescriptions for BPs between January 1, 2011, and December 31, 2016. Participants were followed for 4years. Over the 4-year follow-up period, the cumulative incidence rates of ONJ were 20.9 and 6.9 per 100,000 person-years in the BP and control groups, respectively. The BP group had an increased risk for ONJ compared to the control group after adjusting for multiple variables (hazard ratio [HR] 3.72, 95% CI 2.70-5.11). Advanced age (≥70years), comorbid diseases such as diabetes, hypertension, and rheumatoid arthritis (RA) were independent risk factors for the development of ONJ. In addition, tooth extraction (HR 9.85), gingivitis, and periodontal disease (HR 4.78) were strongly associated with ONJ. ONJ incidence was 21 per 100,000 person-years in osteoporosis patients receiving bisphosphonates. Clinical factors including advanced age, diabetes, RA, dental disease, as well as BP use were significantly associated with ONJ.

Dental consideration and management of cancer patients before initiation of IV bisphosphonates

Purpose Osteonecrosis of the jaw (ONJ) related to intravenous bisphosphonates (IVBP) is characterized by exposed necrotic bone in the maxillofacial region in patients who have received or are receiving treatment with IVBP and have no history of radiation therapy of the jaws.1 The risk of complication of using IVBP for oncologic purposes can be reduced with effective management of cancer patients. Therefore, it is imperative for practitioners to follow patient-specific guidelines for the dental management of patients who will be treated with IVBP. The purpose of this article was to provide a patient-specific, individualized approach for the dental management of patients before initiation of IVBP to prevent ONJ. This guideline will focus on 3 separate factors: the cancer, the patient, and the dentition. Methods A systematic literature review was conducted via PubMed using the following medical subject headings and terms: “bisphosphonates,” “avascular necrosis,” “bisphosphonate-related osteonecrosis of the jaw,” and “medication-related osteonecrosis of the jaw.” We then cross-referenced the same terms with the terms “multiple myeloma (MM),” “breast cancer,” “prostate cancer,” “jaw disease,” and “metastatic cancer” to identify publications that can provide evidence to develop pretreatment dental guidelines in cancer patients treated with IVBP. Articles were reviewed as a result of the PubMed literature search. The cancer types evaluated included breast cancer, prostate cancer, and MM. Relevant studies regarding patient- and dentition-related factors and their relation to IVBP treatment of the said cancers, survival, or comorbidities were evaluated. Results Upon review of articles, 137 articles met our inclusion criteria. No association was found between development of ONJ and the primary tumor site. The hazard of developing ONJ was significantly higher in patients who received zoledronic acid alone compared to those who received pamidronate alone or in combination with zoledronic acid. Our review also concluded that time of exposure to IVBP is strongly associated with development of ONJ, with exposure beyond 4 years of IVBP treatment increasing the incidence of ONJ significantly.2 Our literature search indicated that the risk of development of ONJ after IVBP treatment in cancer patient is also dose dependent, with higher doses being associated with higher risk of ONJ. This suggests that not only does the type of IVBP treatment positively correlate with the likelihood of developing ONJ, the dose and duration of IVBP therapy is also a significant factor. Our analysis identified several unique patient characteristics, including motivation, presence of a support system, socioeconomic status, nutrition, and race, which have all been found to affect the outcomes of IVBP therapy. Dental disease and available supportive dental management was found to significantly impact treatment and quality of life in this patient population. Conclusion Complications from IVBP treatment in cancer patients can have a lifelong impact on quality of life. Dentists and oral and maxillofacial surgeons can play a major role in preventing and minimizing these complications. The cancer, the patient, and the dentition should be analyzed thoroughly to assemble an effective pre-IVBP dental treatment plan. A pre-IVBP extraction-based dental treatment plan is warranted for patients with history of noncompliance, limited financial means, lack of motivation, and presence of tooth factors that decrease the prognosis of dentition. Use of zoledronic acid, IVBP for extended period of 4+ years, and dosage of 22.6 doses or higher are associated with significantly higher chance of developing ONJ and a more aggressive dental treatment (e.g., extraction vs restoration) should be utilized in treatment of these patients.

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.

Osteonecrosis of the jaw (ONJ) in radium 223 (Ra223)-treated metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with exposure to zoledronic acid and/or denosumab.

5575 Background: Bone health agents (BHA) including denosumab, a monoclonal antibody, and Zoledronic acid (ZA), a bisphosphonate, are recommended for men with CRPC and bone metastases to prevent skeletal-related complications. ONJ occurs in about 5% of patients (pts) on BHA. The incidence of ONJ in pts treated with Ra223 and BHA remains unknown, particularly in those who receive sequential treatment of BHAs. Here we describe the rate of ONJ in a real-world setting in mCRPC pts treated with Ra223 in 3 groups: 1) denosumab alone, 2) ZA alone, and 3) sequential ZA /denosumab or vice versa. Methods: A retrospective analysis of a cohort of mCRPC pts with bone metastases who received Ra223. Follow-up was until date of death or last data entry. Chart inclusion criteria included patients who received Ra223 between November 2010 to August 2018 with documentations of data points. Results: A total of 177 pts received Ra223 between 11/2010 and 8/2018. Median age 73 at 1st Ra223 (range 40-93); Median PSA 15.8- at 1st Ra223 (range 0.1-1952); Demographics-AA-10, C-130, Asian-9, unspecified-28; Median Alk Phos 95 at 1st Ra233 (range 25-1515). 93 % (164/177) received BHA. Of the 164 who received BHA, 45% (73/164) received denosumab only, 37% (61/164) received ZA only, and 18% (30/164) received sequential treatment. ONJ developed in 9.7% (16/164) of all patients on BHA. Denosumab alone caused ONJ in 7 of 73 pts (9.6%). ZA alone caused ONJ in 6 of 61 pts (9.8%). ONJ occurred in 3 of 30 pts (10%) in the sequential group. The median number of doses of BHA before development of ONJ was 10 with denosumab, 20 with ZA, and 19.5 (denosumab) and 22 (ZA) in the sequential group. Conclusions: In patients treated with Ra223 and a BHA, the rate of ONJ is 9.7%. The rate of ONJ was similar in groups treated with denosumab alone, ZA alone, and sequential treatment of ZA and denosumab However, ONJ developed more quickly in patients on denosumab. We conclude that the risk of ONJ is increased in patients treated with Ra223 and BHA. ZA or sequential therapy appears to delay time to onset of ONJ compared to denosumab. Clinicians should be mindful of the toxic synergy between Ra223 and BHA. ZA may be the preferred BHA partner with Ra223.

Osteonecrosis of the jaw in patients with cancer receiving zoledronic acid for bone metastases: SWOG S0702, NCT00874211.

11502 Background: Osteonecrosis of the jaw (ONJ) may occur in cancer patients (pts) with metastatic bone disease (MBD) treated with bone modifying agents. No large prospective studies have precisely determined the incidence of ONJ. A better understanding of the true incidence and predictors of ONJ is needed. Methods: SWOG S0702 was a prospective observational study that assessed the cumulative incidence (CI) of ONJ at 3 years in pts with MBD from any malignancy receiving zoledronic acid (Zol). Participants must have had either limited or no prior exposure to bone modifying agents and a clinical care plan that included use of Zol within 30 days of registration. Cancer treatments, bone modifying agents (including Zol), and dental care were administered as clinically indicated and were not directed by S0702. Baseline and every 6 m followup dental exams were recommended. Report forms (medical, dental and pt reported outcomes) were submitted every 6 m but if ONJ was diagnosed, follow up interval became every 3 m. Protocol defined ONJ required exposed bone in the maxillofacial region present 8 weeks or more in a pt who was receiving or had been exposed to a bisphosphonate, and had not had radiation therapy to the craniofacial region. Results: The study enrolled 3,491 evaluable pts (breast 1,120; myeloma 580; prostate 702, lung 666, other 423) between 2009-2013. About 2/3 of pts had a baseline dental exam. Overall, 87 pts had confirmed ONJ. The cumulative incidence of ONJ was 0.8% at year 1 (95% CI: 0.5%-1.1%), 2.0% at year 2 (95% CI: 1.5%-2.5%), and 2.8% at year 3 (95% CI: 2.3-3.5%). Rates of 3-year confirmed ONJ were highest in myeloma pts (4.3%; 95% CI, 2.8%-6.4%). Pts with planned Zol dosing intervals of every 3-4 weeks (n = 3,032, 87.2%) were much more likely to experience ONJ than pts with planned dosing intervals of 5 weeks or greater (n = 447, 12.8%; 3.2% vs 0.7%; HR = 4.80, 95% CI, 1.52-15.18, p = .008). Fewer total number of teeth, the presence of dentures and any oral surgery at baseline were all associated with a higher rate of ONJ. Conclusions: About 1 in 40 patients receiving Zol for MBD developed ONJ. S0702 provides information to guide stratification of risk for developing ONJ in pts with MBD receiving Zol. Cancer type, oral health and frequency of Zol dosing affect risk of ONJ. Clinical trial information: NCT00874211.

Invasive Oral Procedures and Events in Postmenopausal Women With Osteoporosis Treated With Denosumab for Up to 10 Years.

Antiresorptive therapy has been associated with osteonecrosis of the jaw (ONJ), an infrequent but potentially serious adverse event. To assess information on invasive oral procedures and events (OPEs)-dental implants, tooth extraction, natural tooth loss, scaling/root planing, and jaw surgery-during the 7-year Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Extension study and to present details of positively adjudicated ONJ cases. Randomized, double-blind, placebo-controlled, 3-year trial (FREEDOM) followed by 7 years of open-label denosumab (FREEDOM Extension). At Extension Year 3, women were asked to record their history of invasive OPEs since the start of the Extension to Year 2.5 and oral events in the prior 6 months. The questionnaire was then administered every 6 months until the end of the Extension. Multicenter, multinational clinical trial. Postmenopausal women with osteoporosis. Subcutaneous denosumab 60 mg or placebo every 6 months for 3 years, then 7 years of open-label denosumab. Self-reports of OPEs and adjudicated cases of ONJ. Of respondents, 45.1% reported at least one invasive OPE. The exposure-adjusted ONJ rate in FREEDOM Extension was 5.2 per 10,000 person-years. ONJ incidence was higher in those reporting an OPE (0.68%) than not (0.05%). Although invasive OPEs were common in these denosumab-treated women and were associated with an increased ONJ incidence, the overall rate of ONJ was low, and all cases with complete follow-up resolved with treatment.

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.

Increased risk of bisphosphonate-related osteonecrosis of the jaw in patients with Sjögren’s syndrome: nationwide population-based cohort study

ObjectiveThe aim of this study was to explore whether patients with Sjögren’s syndrome (SS) were susceptible to bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) after tooth extraction in the entire...