We 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.
OBJECTIVE: We 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.
METHODS: From 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.
RESULTS: The 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.
CONCLUSIONS: We 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.

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a dreaded complication in patients with compromised bone metabolism. The purpose of the present study was to examine the occurrence of ARONJ and its related factors among patients with a history of antiresorptive therapy undergoing tooth extraction using preventive protocols at a Swiss university clinic. Data were retrospectively pooled from health records of patients having received a surgical tooth extraction between January 2015 and April 2020 in the Clinic of Cranio-Maxillofacial and Oral surgery, University of Zurich. A total of 970 patients received an extraction with flap elevation or wound closure during this period. A total of 104 patients could be included in the study. Furthermore, variables including age, gender, smoking, risk profile, choice, indication and duration of antiresorptive therapy, number of extractions, extraction site, surgical technique, choice and duration of antibiotics as well as the presence of postoperative inflammatory complications were assessed. Overall, 4 patients developed ARONJ (incidence of 3.8%) after tooth extraction at the same location, without previous signs of osteonecrosis. Preventive methods included predominantly primary wound closure using a full thickness mucoperiosteal flap and prolonged perioperative antibiotic prophylaxis. In accordance with current literature, the applied protocol showed a reliable outcome in preventing ARONJ when a tooth extraction is required.

OBJECTIVE: We aimed to predict the possibility of patients with stage I and II anti-resorptive agent-related osteonecrosis of the jaw (ARONJ) developing resistance to our treatment protocol by evaluating their clinical and imaging factors.
METHODS: We enrolled 58 patients with ARONJ who underwent imaging modality. As objective variables, we considered the healing, stage-down, and stable stages as successful outcomes, and the stage-up stage as resistant-to-treatment. As explanatory variables, we investigated the clinical and imaging factors. Furthermore, we examined stage-down as an improvement outcome to compare with the stable and stage-up stages, which were considered as no-improvement outcomes. We conducted unpaired between-group comparisons on all explanatory variables using χ2 tests for independence.
RESULTS: Among 58 patients, the treatment was successful in 53 (91.4%); however, the disease was resistant in five (8.6%). Among the clinical factors, the resistant patients had a longer duration of administration of bone-modifying agents (BMAs) (cut-off: 1251 days, p = 0.032, odds ratio = 11.2, 95% confidence interval 1.115-122.518). In addition, the target disease that was being treated bone metastasis of malignant tumor was the only significant refractory factor (p = 0.024, OR: 3.667 95% CI 1.159-11.603) CONCLUSIONS: A combination of metabolic and morphological imaging modalities may be useful for oral surgeons to evaluate the disease activity and predict course of refractory ARONJ.

OBJECTIVE: The aim of our study was to describe microbial flora associated with MRONJ and characterize the susceptibility of pathogens to help guide an effective empiric antibiotic treatment in these patients.
METHODS: A retrospective, single-center analysis was performed, using 116 bone samples from 98 patients. The bone samples were homogenized and subjected to routine culture methods. Growing bacteria were differentiated to the species level using whole-cell mass spectrometry and subjected to susceptibility testing.
RESULTS: A highly diverse microbial flora was detected in necrotic bone, with a simultaneous presence of two or more bacterial species in 79% of all patients. In at least 65% of samples, gram-negative isolates were detected. Therefore, bacterial species resistant against β-lactamase inhibitors were present in at least 70% of all patients.
CONCLUSIONS: The empiric choice of antibiotics in MRONJ patients should consider the high rate of gram-negative bacteria and resistance against β-lactam antibiotics.
CONCLUSIONS: According to recent guidelines and recommendations, systemic antibiotic treatment is a key component in the treatment of all stage 2 and 3 MRONJ patients. We recommend using fluoroquinolones for empiric treatment and emphasize the use of bacterial cultivation and susceptibility testing to enable an effective antibiotic treatment.

BACKGROUND: Over the past two decades, antiresorptive agent-related osteonecrosis of the jaw (ARONJ) has become a growing concern. We examined the incidence of ARONJ and identified its risk factors in lung cancer patients in the real-world clinical setting. To our knowledge, we are the first to do so.
METHODS: We retrospectively analyzed lung cancer patients with bone metastases who had received anti-resorptive agents (zoledronate or denosumab) at the National Hospital Organization Kyoto Medical Center from October 2012 to September 2018. All ARONJ cases were diagnosed by the dentists according to the established diagnostic criteria.
RESULTS: A total of 171 patients were reviewed, 13 (7.6%) of whom experienced ARONJ. Among the 13 patients, six (46.2%), four (30.8%) and three (23.1%) had adenocarcinoma, squamous carcinoma and not otherwise specified, respectively. ARONJ was stage 2 in three (23.1%) patients and stage 3 in 10 (76.9%). More cycles of antiresorptive agents (odds ratio [OR] = 11.54; 95% confidence interval [CI], 2.47-53.99; P < 0.01), use of immune checkpoint inhibitors (ICIs; OR = 5.05; 95% CI, 1.56-16.37; P < 0.01) and longer survival duration (≥2 years; OR = 12.16; 95% CI, 3.17-46.65; P < 0.01) were independently associated with ARONJ in a multivariate analysis.
CONCLUSIONS: The incidence of ARONJ was relatively high in lung cancer patients with bone metastases. When using antiresorptive agents, oncologists should closely monitor patients for ARONJ during the course of treatment and regularly consult with dentists, especially in patients receiving ICIs.

OBJECTIVE: The usefulness of bone scan index (BSI), a quantitative metric of the area of uptake in computer-aided diagnosis in bone scintigraphy, has been reported for the diagnosis of anti-resorptive-agent-related osteonecrosis of the jaw (ARONJ). The aim of this study is to validate the diagnostic ability of BSI for the early detection of ARONJ. In addition, the Bone uptake value (BUV), another quantitative index obtained from bone scintigraphy that indicates the degree of radioisotope (RI) accumulation, was used to improve the diagnostic ability for early detection of ARONJ.
METHODS: A total of 34 patients (11 with ARONJ, 23 without ARONJ) who were administered anti-resorptive-agents for bone metastasis and had incidentally consulted a dental surgeon within 3 months after regular whole-body bone scintigraphy were retrospectively included in the study. The bone scintigraphy data were subjected to semiquantitative analysis of uptake in the jaw using BONENAVI (FUJIFILM Toyama Chemical, Co. Ltd., Tokyo, Japan; EXINI Diagnostics AB, Lund, Sweden) and BUV software (Technical Society for Quantitative Bone Scintigraphy and Fujifilm Toyama Chemical Co., Ltd. Tokyo, Japan). The ROI was set semi-automatically on mandibular hotspots, and the regional BSI was termed BSIJ. Planar anterior and posterior images were then sent to BUV software, with the ROI set manually as for BSI, and the regional BUV was termed BUVJ.
RESULTS: Mean BSIJ values for the ARONJ positive and ARONJ negative groups were 0.17 ± 0.83 and 0.03 ± 0.50%, respectively. Mean BUVJ values for the ARONJ positive and ARONJ negative groups were 0.47 ± 0.17 and 0.19 ± 0.11, respectively. BSIJ × BUVJ values for the ARONJ positive versus ARONJ negative groups were 0.088 ± 0.067 vs. 0.007 ± 0.010. The AUC for BSIJ, BUVJ and BSIJ × BUVJ was 0.949, 0.951 and 0.988, respectively.
CONCLUSIONS: The BSI metric of a CAD system for bone scintigraphy was useful for the early detection of ARONJ. Accuracy was improved with the additional use of BUVJ data. We recommend that SPECT imaging be performed when bone scintigraphy reveals focal or diffuse uptake in the mandible with high BSIJ and BUVJ.

MRONJ/ARONJ is a serious adverse effect of medication, although the incidence of the disease is rare, and there are still controversial issues regarding the pathogenesis of MRONJ/ARONJ. Medications that can lead to MRONJ/ARONJ are commonly used to treat osteoporosis and to prevent bone fractures caused by bone metastasis of malignancies. The long-standing disease state of ONJ deteriorates the quality of life of affected patients. Early detection and prevention of the disease are key to alleviating pain and discomfort. To date, several imaging modalities have been introduced to depict the lesions. Imaging modalities, radiography, CT, MRI and nuclear medicine provide important information for managing this challenging disease.

Antiresorptive agents are widely used in catabolic bone diseases. Not only bisphosphonates but also new drugs like Denosumab may induce osteonecrosis of the jaw as a side effect. The present review describes the current effect mechanisms of commonly used antiresorptives, pathogenetic theories for the development of antiresorptive-related osteonecrosis of the jaw (ARONJ), and potential risk factors. Furthermore, diagnostic modalities and treatment options as well as new and innovative strategies are discussed. The major key factor to avoid the occurrence of ARONJ still remains the implementation of throughout preventive measures.

Antiresorptive agent-related osteonecrosis of the jaw results in appreciable morbidity in affected patients. Nowadays many physicians prescribe an antiangiogenic agent for the management of malignant metastases. Everolimus is a serine-threonine kinase that acts as an inhibitor of mammalian target of rapamycin, which results in reduced growth of cells, angiogenesis, and survival of cells. We report the first case to our knowledge of osteonecrosis of the jaw that seemed to result from the additive effect of everolimus.