OBJECTIVE: 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.
METHODS: 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.
RESULTS: A total of 42 003 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.
CONCLUSIONS: 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.

OBJECTIVE: To determine the relation between the severity of periodontitis and osteonecrosis of the jaw (ONJ) occurrence among different cancer locations and estimate the effect of dental care on ONJ prevention in cancer patients.
METHODS: This population-based cross-sectional study was conducted through the Longitudinal Health Insurance Database, Taiwan. Patients with malignancies were collected and subdivided into groups according to their different cancer locations, the severity of periodontitis, and dental care. Multivariable logistic regression analysis was performed to assess the associations between ONJ and ONJ-related factors.
RESULTS: A total of 8,234 ONJ patients and 32,912 control patients were investigated. Lip, oral cavity, and pharynx malignancies had the highest ONJ risk among all cancer locations (OR from 3.07 to 9.56, P < 0.01). There is a linear relationship between different severities of periodontitis and ONJ. Patients with radiotherapy and severe periodontitis had the highest ONJ risk (adjusted OR, 9.56; 95% CI, 5.34-17.1). Patients with good dental care had a lower ONJ risk.
CONCLUSIONS: The periodontal condition and cancer location showed a significant impact on the risk of developing ONJ after adjusting for bisphosphonate use. Good dental care could decrease the risk of ONJ in cancer patients. The severity of periodontitis might be a target to predict the potency of ONJ.
CONCLUSIONS: Dentists must be vigilant about the increased risk of ONJ in cancer patients with periodontitis, especially in the head and neck cancer population. Good dental care is advised for cancer patients with severe periodontitis.

Gene expression alterations in periodontal ligament stem cells (PDLSCs) during bisphosphonate (BP) usage and the transcriptomic mechanism underlying BP‑related osteonecrosis of the jaw have not been fully elucidated. In the present study, human PDLSCs were isolated from adults with no history of periodontal disease, and subsequently incubated and treated with zoledronate on days 3 and 5. Subsequently, PDLSCs from all timepoints were screened using an Affymetrix Gene Expression Array. Limma differential expression analysis was performed on a normalized gene expression matrix, followed by cluster analysis, pathway and network analyses. Overall, 906 genes (352 upregulated and 554 downregulated) exhibited differential expression levels between days 0 and 5, and these were termed slow‑response genes. These slow‑response genes were enriched in cellular stress response signaling pathways (upregulated genes), as well as proliferation‑ and ossification‑associated signaling pathways (downregulated genes). Furthermore, 168 (day 3 vs. 0) and 105 (day 5 vs. 3) genes were differentially expressed between adjacent timepoints. These genes were also enriched in stress response‑ and proliferation‑associated signaling pathways, but not in ossification‑associated signaling pathways. Poly(ADP‑ribose) polymerase 1 (PARP1) and CYLD lysine 63 deubiquitinase (CYLD) had the most protein‑protein interaction partners among the slow‑response genes and were connected with both stress‑ (e.g. caspase‑1) and ossification‑associated genes [e.g. secreted phosphoprotein 1 and collagen type I α1 chain (COL1A1)]. BP treatment induced stress response‑like transcriptional alterations in PDLSCs, followed by inhibition of proliferation and ossification. These alterations may contribute to the onset of jaw osteonecrosis. PARP1 and CYLD may be two key genes involved in this pathological procedure.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication that can develop in patients treated with anti-resorptive drugs. Although the pathogenesis of MRONJ is still unclear, genetic factors have a demonstrated important role. Thus, the aim of this study was to perform a systematic review on the pharmacogenetics of MRONJ. Studies published until March 2019 were retrieved from eight databases and were selected by two independent reviewers. Evidence on several genetic polymorphisms was summarized and a meta-analysis was conducted when possible. Fourteen studies involving 1515 participants were eligible for systematic review. For CYP2C8 rs1934951, no significant difference was observed between the MRONJ and non-MRONJ groups (odds ratio (OR) 2.04, 95% confidence interval (CI) 0.88-4.73, P=0.09). However, a subgroup analysis based on only multiple myeloma status showed a positive association (OR 3.64, 95% CI 1.29-10.30, P=0.01). PPARG rs1152003 was not differently distributed between groups (OR 0.25, 95% CI 0.01-9.92, P=0.46). Also, VEGF rs3025039 was found to be correlated with the occurrence of MRONJ (OR 0.35, 95% CI 0.15-0.82, P=0.02). CYP2C8 rs1934951 (in multiple myeloma patients) and VEGF rs3025039 are associated with the development of MRONJ in patients treated with bisphosphonates. The results are promising and call for new trials with a larger sample to further explore this growing field.

UNASSIGNED: Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival. However, the risk of adverse events associated with bisphosphonate therapy for breast cancer remains poorly defined.
UNASSIGNED: A literature search was conducted using the PubMed, EMBASE, Cochrane and Web of Science libraries. Risk ratio (RR) was calculated to evaluate the adverse events of the meta-analytic results. Osteonecrosis of the jaw (ONJ) incidence was calculated using the random effect model (D+L pooled) for meta-analysis.
UNASSIGNED: A total of 47 studies comprising 20,607 patients were included; 23 randomized controlled studies (RCTs) provided data of adverse events for bisphosphonate therapy versus without bisphosphonates. Bisphosphonates were significantly associated with influenza-like illness (RR = 4.52), fatigue (RR = 1.08), fever (RR = 1.82), dyspepsia (RR = 1.25), anorexia (RR = 1.29), and urinary tract infection (RR = 1.32). No differences were observed in other adverse events. We combined the incidence of ONJ in 24 retrospective studies to analyze the incidence of ONJ using bisphosphonates. The pooled probability of ONJ toxicity in the bisphosphonates group was 2%.
UNASSIGNED: Bisphosphonates were significantly associated with influenza-like illness, fatigue, fever, dyspepsia, anorexia, and urinary tract infection. Furthermore, bisphosphonates increase the risk of ONJ toxicity.

Bisphosphonates can directly inhibit osteoclasts, which may lead to increased bone density, reduced blood flow, and osteonecrosis of the jaw. Bisphosphonate-related osteonecrosis is usually observed in the jaw bone. In this article, we report a patient with bisphosphonate-related osteonecrosis of the jaw (BRONJ) complicated with wrist scaphoid osteomyelitis. Furthermore, we introduce the pathogenesis, treatment, and prevention of BRONJ.
双膦酸盐类药物可以抑制破骨细胞功能，使颌骨骨密度升高，血流减少，发生骨坏死。双膦酸盐类药物相关性骨坏死多发于颌骨。本文报道1例双膦酸盐相关性颌骨坏死并发腕部舟状骨骨髓炎，并结合文献讨论双膦酸盐药物性颌骨坏死的发病机制、治疗与预防等。.

Bisphosphonate (BP)-related osteonecrosis of the jaw, previously known as BRONJ, now referred to more broadly as medication-related osteonecrosis of the jaw (MRONJ), is a morbid condition that represents a significant risk for oncology patients who have received high dose intravenous (IV) infusion of a potent nitrogen containing BP (N-BP) drug. At present, no clinical procedure is available to prevent or effectively treat MRONJ. Although the pathophysiological basis is not yet fully understood, legacy adsorbed N-BP in jawbone has been proposed to be associated with BRONJ by one or more mechanisms. We hypothesized that removal of the pre-adsorbed N-BP drug common to these pathological mechanisms from alveolar bone could be an effective preventative/therapeutic strategy. This study demonstrates that fluorescently labeled BP pre-adsorbed on the surface of murine maxillo-cranial bone in vivo can be displaced by subsequent application of other BPs. We previously described rodent BRONJ models involving the combination of N-BP treatment such as zoledronate (ZOL) and dental initiating factors such as tooth extraction. We further refined our mouse model by using gel food during the first 7 days of the tooth extraction wound healing period, which decreased confounding food pellet impaction problems in the open boney socket. This refined mouse model does not manifest BRONJ-like severe jawbone exposure, but development of osteonecrosis around the extraction socket and chronic gingival inflammation are clearly exhibited. In this study, we examined the effect of benign BP displacement of legacy N-BP on tooth extraction wound healing in the in vivo model. Systemic IV administration of a low potency BP (lpBP: defined as inactive at 100 μM in a standard protein anti-prenylation assay) did not significantly attenuate jawbone osteonecrosis. We then developed an intra-oral formulation of lpBP, which when injected into the gingiva adjacent to the tooth prior to extraction, dramatically reduced the osteocyte necrosis area. Furthermore, the tooth extraction wound healing pattern was normalized, as evidenced by timely closure of oral soft tissue without epithelial hyperplasia, significantly reduced gingival inflammation and increased new bone filling in the extraction socket. Our results are consistent with the hypothesis that local application of a rescue BP prior to dental surgery can decrease the amount of a legacy N-BP drug in proximate jawbone surfaces below the threshold that promotes osteocyte necrosis. This observation should provide a conceptual basis for a novel strategy to improve socket healing in patients treated with BPs while preserving therapeutic benefit from anti-resorptive N-BP drug in vertebral and appendicular bones.

OBJECTIVE: Determine the association between sialadenitis and osteonecrosis of the jaw (ONJ) in head and neck cancer (HNC) patients with varying severity of sialadenitis, treatment modalities, and cancer locations.
METHODS: A total of 40,168 HNC patients, including 1907 ONJ subjects and 7559 matched comparisons, were enrolled from a Longitudinal Health Insurance Database for Catastrophic Illness Patients of Taiwan between 2000 and 2006. The association with sialadenitis and ONJ was estimated by logic regression and presented as the odds ratio (OR) and 95% confidence intervals (CIs).
RESULTS: The occurrence of sialadenitis increased the risk of ONJ by 2.55-fold in HNC patients (95% CI = 2.20-2.95). The ONJ incidence was proportion to sialadenitis severity (OR = 2.53 to 4.43). Irradiated HNC patients had a higher tendency to develop jaw necrosis (osteoradionecrosis, ORN) (OR = 5.05, 95% CI = 4.39-5.80). When combined with irradiation exposure, sialadenitis significantly induced the occurrence of ORN (OR = 8.94, 95% CI = 7.40-10.8), especially in oral cancer patients (OR = 15.9 95% CI = 12.5-20.3). The risk of ONJ increased with radiotherapy dosage and duration, except for nasopharyngeal cancer (NPC) patients.
CONCLUSIONS: There was a close association between sialadenitis and ONJ in the HNC population. The severity of sialadenitis was positive correlated to ONJ risk. Radiotherapy combined with sialadenitis significantly raised ORN incidence in HNC patients except for NPC patients.
CONCLUSIONS: HNC patients complained that xerostomia from sialadenitis might increase the risk to develop ONJ, especially among those who received radiotherapy.

Medication-related osteonecrosis of the jaw (MRONJ) was first reported more than a decade ago. Since then, numerous cases have been diagnosed. Currently, there are three groups of drugs related to MRONJ: bisphosphonates, denosumab and anti-angiogenic drugs. As MRONJ can lead to debilitating clinical sequels and limited effective treatment options are available, much research has been done in understanding its pathophysiology. Until now, the exact pathogenesis of MRONJ has not been fully elucidated. While history of invasive dental procedures or local trauma may be present, some cases occur spontaneously without any preceding factors. This review aims to examine and discuss the three main hypotheses for the pathogenesis of MRONJ, namely suppressed bone turnover, cellular toxicity and infection.

To identify the risk factors for osteonecrosis of the jaw (ONJ) in oral cancer patients after surgery with and without adjuvant therapy in a nationwide, population-based study.
Using the Taiwan National Health Insurance Research Dataset, we recruited patients with newly diagnosed oral cancer between 1997 and 2011. All of them underwent primary surgery. Data regarding demographic characteristics; tooth extractions; medications; and cancer treatments, including types of mandibular surgery, radiotherapy and platinum-based chemotherapy, were collected for analysis.
We identified 25,858 patients who suffered 2802 ONJ events. The ONJ incidence rate was 3.45 per 100 person-years. Lip cancer was associated with the highest risk of ONJ, followed by buccal mucosa, gum, mouth floor and tongue cancer. Using a time-dependent Cox regression model, multivariable analysis demonstrated that mandibulotomy (hazard ratio (HR), 1.25; 95% confidence interval (CI), 1.01-1.55; p<0.001), radiotherapy (HR, 1.39; 95% CI, 1.26-1.54; p<0.001) and platinum-based chemotherapy (HR, 1.94; 95% CI, 1.56-2.41; p<0.001) were significant risk factors for ONJ. In the subgroup analysis of patients receiving radiotherapy and patients not receiving radiotherapy, platinum-based chemotherapy remained a risk factor for ONJ.
Mandibulotomy, radiotherapy and platinum-based chemotherapy were associated with an increased ONJ risk. Chemotherapy was a risk factor regardless of whether radiotherapy was administered.