Denosumab-related Osteonecrosis Of The Jaw Research Articles

Research progress on perioperative management of tooth extraction in denosumab-treated patients

Denosumab, a human monoclonal antibody, is used for the prevention of malignant tumor-related bone events and the treatment of osteoporosis with high fracture risk. Since its approval in China in 2019, denosumab-related osteonecrosis of the jaw (DRONJ) has attracted increasing attention. DRONJ, similar to bisphosphonate-related osteonecrosis of the jaw, often occurs after tooth extraction and manifests as exposed bone necrosis, purulent discharge, facial swelling and pain, severely impacting patients' quality of life. However, the perioperative management strategies for DRONJ differ from those for bisphosphonate-related osteonecrosis of the jaw. This article summarizes the perioperative management strategies for high-risk DRONJ patients from aspects such as oral hygiene care, antibiotic use, drug discontinuation during the perioperative period, and surgical strategy selection, aiming to provide guidance for oral surgeons in managing tooth extraction in denosumab-treated patients.

The Risk of Medication-Related Osteonecrosis of the Jaw in Children: Guidance for Antiresorptive Use in Pediatric Patients

Antiresorptive targeted cancer therapies, such as denosumab and bisphosphonates, are used in adults, but their application in pediatric cancer is more recent. Side effects such as osteonecrosis of the jaw (ONJ) observed in adults have curtailed use of these medications in the pediatric population. This study assesses the frequency of ONJ, other side effects, and the indications for use of denosumab versus bisphosphonates in pediatric subjects. A retrospective cohort study of pediatric subjects who underwent bisphosphonate or denosumab therapy at our institution from 2007-2023 was conducted. Subjects aged ≥ 18years at therapy initiation were excluded. The independent variable was antiresorptive therapy divided into 2 groups, treatment with intravenous bisphosphonates or denosumab. Primary outcomes were development of bisphosphonate-related and denosumab-related ONJ. Secondary outcomes included additional side effects. ONJ risk factors, subject demographics, indications for use, timing, duration, and cumulative dose of antiresorptive therapy were abstracted. Univariate and bivariate statistics were computed to describe the sample and measure associations between antiresorptive therapy and outcomes. P values < .05 conferred statistical significance. The sample was composed of 178 subjects with a mean age of 11.7±6.1years. There were 14 (7.9%) and 164 (92.1%) subjects treated with denosumab and bisphosphonate therapies, respectively. There were 0 cases of ONJ across all subjects. The most common indication for treatment was adjuvant targeted therapy for aggressive tumors and malignancy (39.3%) followed by osteoporosis (14.6%). Subjects treated with denosumab had higher frequencies of hypercalcemia and severe bone pain than subjects treated with bisphosphonates, 28.6% versus 1.2% (P<.001) and 14.3% versus 0.00% (P<.001), respectively. While invasive dental procedures are ideally performed before antiresorptive treatment, our data suggest that bisphosphonates may be used safely in the pediatric population with low concern for ONJ. Our data also demonstrated bisphosphonates may have a more tolerable side effect profile than denosumab. If the perceived benefits are similar, we recommend using bisphosphonates as first-line therapy in children while reserving denosumab for refractory cases. Future studies will help determine long-term side effects and differences in efficacies of these medications.

Preventive Effects of Dental Pulp Stem Cell-conditioned Media on Anti-RANKL Antibody-Related Osteonecrosis of the Jaw

Medication-related osteonecrosis of the jaw is a serious disease occurring in patients with cancer and osteoporosis, who are undergoing treatment with antiresorptive agents (ARAs) such as bisphosphonate (BP) or denosumab, an antibody targeting receptor activator of NF-κB ligand. Recently, stem cell-based therapy has been shown to be effective in preventing the development of bisphosphonate-related osteonecrosis of the jaw. However, studies on denosumab-related osteonecrosis of the jaw (DRONJ) remain limited. Here, the efficacy of treatment with dental pulp stem cell conditioned media (DPSC-CM) in preventing DRONJ in a murine model was evaluated. Local administration of DPSC-CM into the extraction socket of a mouse with DRONJ decreased the number of empty osteocyte lacunae and the prevalence of ONJ. In tissues surrounding the extraction sockets in the DPSC-CM-treated group, the expression of inflammatory cytokines was attenuated and that of osteogenesis-related molecules was enhanced compared to that in the control group. Further, the expression of Wnt signaling molecules, which had been suppressed, was improved. These findings collectively suggest that DPSC-CM prevents ONJ development in a murine DRONJ model.

Clinical Assessment of the Treatment of 18 Cases of Denosumab-related Osteonecrosis of the Jaw （DRONJ）

This study aimed to evaluate the treatment outcome of osteonecrosis of the jaw （ONJ） in 18 patients receiving only denosumab. The patients comprised 11 males and seven females, with a median age of 82.5 years and mean age of 77.9 years. Fifteen patients were cancer patients with bone metastasis and three had osteoporosis. Stage 2 was the most common stage （77.8％）. Of the 18 patients, surgical treatment was performed in five patients, while purely conservative treatment was performed in 13. Surgical treatment achieved complete mucosal healing in 100％ （5/5） and was significantly correlated with treatment outcome on univariate analysis. In purely conservative treatment, two patients achieved complete mucosal healing and two patients achieved partial ONJ resolution. The treatment efficacy rate of conservative treatment was 30.8％ （4/13）. In four patients who were effectively treated by conservative treatment, their sequestrums detached spontaneously and epithelialized after a median of 12.5 months and mean of 15 months of discontinuing denosumab. ONJ progressed or was unchanged in five patients even after discontinuation of denosumab treatment. It may take a long time even if conservative treatment is successful. We recommend surgical treatment even for denosumab related osteonecrosis of the jaw when patients can tolerate surgery.

Anti-RANKL Inhibits Thymic Function and Causes DRONJ in Mice.

Background Denosumab, a human monoclonal antibody against receptor activator of nuclear factor-kappa B ligand (RANKL), is a novel bone antiresorptive agent used in patients with osteoporosis or metastatic bone cancer. Denosumab-related osteonecrosis of the jaw (DRONJ) has been recently reported in patients using denosumab. However, the mechanisms of DRONJ are not fully understood. Appropriate pathogenic mechanisms of DRONJ have yet to be established. Therefore, we investigated the pathogenesis of DRONJ in mice. Methods Anti-mouse RANKL monoclonal antibody and melphalan were performed to create a mouse model of DRONJ-like lesions in female C57BL/6J mice. We examined the development of DRONJ-like lesions and immune function. Results We showed that administration of anti-mouse RANKL monoclonal antibody and melphalan caused DRONJ-like lesions that recapitulated major clinical manifestations of the human disease, including the characteristic features of an open alveolar socket and exposed necrotic bone. In the analysis using a mouse model of DRONJ-like lesion, it was revealed that anti-mouse RANKL monoclonal antibody and melphalan suppress autoimmune regulator (AIRE) expression in the thymus and imbalanced T cell populations. Conclusion This study suggests evidence of an immunity-based mechanism of DRONJ-like disease. This work may contribute to a better understanding of the pathogenesis of human DRONJ.

Temporary Denosumab Discontinuation Promotes Bone Healing of Osteonecrosis of the Jaw and Minimizes the Invasiveness of Surgery: A Case Presentation

Denosumab has proved effective at low doses in increasing bone mineral density in osteoporosis patients. In contrast to high-doses antiresorptive therapy, denosumab has a transient effect on the inhibition of the bone remodeling process, suggesting that denosumab-related osteonecrosis is a self-limiting disease, with a high curative potential of surgery when performed after a proper duration of receptor activator of nuclear factor-kB ligand (RANKL) inhibitor suspension. We report the long-term clinical and radiological (Computed Tomography—CT scan) data of a patient affected by secondary osteoporosis (cancer treatment-induced bone loss—CTIBL for metastatic breast cancer) who underwent surgical treatment for stage II denosumab-related osteonecrosis of the upper maxilla 7 months after denosumab suspension. A minimally invasive approach was performed with the extraction of the first right upper molar and debridement of the surrounding alveolar bone. After surgery, the patient was followed up at three-month intervals up to 1 year, and clinical and radiological data (CT scan) were recorded at each follow-up for the early detection of signs of recurrent disease. The mucosal healing remained stable in the long term, with radiological signs of bone remodeling in the post-operative site since the 6-month follow-up. The presented case strengthens the hypothesis that denosumab induces temporary alterations of bone turnover with a predictable curative effect of minimal surgical procedures in cases of denosumab-related osteonecrosis of the jaw.

Denosumab-related osteonecrosis of the jaw after tooth extraction and the effects of a short drug holiday in cancer patients: a multicenter retrospective study.

This study retrospectively investigated the relationship between various risk factors, including brief discontinuation of denosumab, and development of denosumab-related osteonecrosis of the jaw (DRONJ) after tooth extraction in patients with cancer who were receiving oncologic doses of this agent. Data were collected on demographic characteristics, duration of denosumab therapy, whether or not denosumab was discontinued before tooth extraction (drug holiday), duration of discontinuation, presence of pre-existing inflammation, and whether or not additional surgical procedures were performed. Risk factors for DRONJ after tooth extraction were evaluated by univariate and multivariate analyses. A total of 136 dental extractions were performed in 72 patients (31 men, 41 women) with cancer who were receiving oncologic doses of denosumab. Post-extraction DRONJ was diagnosed in 39 teeth (28.7%) in 25 patients. Tooth extraction was significantly associated with development of DRONJ only in patients with pre-existing inflammation (odds ratio [OR] 243.77), those on corticosteroid therapy (OR 73.50), those with periapical periodontitis (OR 14.13), those who had been taking oncologic doses of denosumab for a longer period (OR 4.69), and in women (OR 1.04). There was no significant difference in the occurrence of DRONJ between patients who had a drug holiday before tooth extraction and those who did not. These findings suggest that inflamed teeth should be extracted immediately in patients with cancer who are receiving oncologic doses of denosumab. Drug holidays have no significant impact on the risk of DRONJ.

Persistent bone resorption lacunae on necrotic bone distinguish bisphosphonate-related osteonecrosis of jaw from denosumab-related osteonecrosis

Bisphosphonate and denosumab are widely used for the treatment of osteoporosis and bone metastasis of cancer to prevent excessive bone resorption. Osteonecrosis of the jaw is a serious adverse effect of bisphosphonate or denosumab referred to as bisphosphonate-related osteonecrosis of the jaw (BRONJ) or denosumab-related osteonecrosis of the jaw (DRONJ), respectively. Since bisphosphonate and denosumab inhibit bone resorption by different mechanism, we evaluated whether these drug types result in different histopathological characteristics related to bone resorption. We histopathologically investigated 10 cases of BRONJ, DRONJ, and suppurative osteomyelitis. Paraffin sections prepared from decalcified dissected jaw bones were used for histopathological observation, second harmonic generation imaging, and bone histomorphometry. The samples were also observed by a scanning electron microscope. Numerous bone resorption lacunae were observed on the necrotic bone surface in almost all cases of BRONJ; however, such resorption lacunae were limited in DRONJ and suppurative osteomyelitis. Prominent bone resorption lacunae were also confirmed by second harmonic generation imaging and scanning electron microscopy in BRONJ, but not in DRONJ or suppurative osteomyelitis. As determined by bone histomorphometry, the number of bone resorption lacunae and the length of the erosion surface of resorption lacunae were significantly higher in BRONJ group than in the DRONJ and suppurative osteomyelitis groups. These parameters were correlated between the necrotic bones and the vital bones in BRONJ. Persistent bone resorption lacunae on the necrotic bone surface are unique to BRONJ, providing a basis for distinguishing BRONJ from DRONJ and OM in histopathological diagnosis.

Differences between bisphosphonate-related and denosumab-related osteonecrosis of the jaws: a systematic review.

Bisphosphonates and denosumab are both antiresorptive medications, each with their own mechanism of action; yet both may result in the same adverse effect: medication-related osteonecrosis of the jaw (ONJ). The present systematic review aims to answer the following question: "Are bisphosphonate-related ONJ and denosumab-related ONJ any different, regarding clinical and imaging aspects?" This review followed the Joanna Briggs Review's Manual, and the searches were performed on PubMed, Cochrane, Scopus, Web of Science, and Lilacs databases and on the grey literature (ProQuest, Open Grey, and Google Scholar). The searches resulted in 7535 articles that were critically assessed. Based on the selection criteria, seven studies were included in the review: five cross-sectional studies and two randomized clinical trials. A total of 7755 patients composed the final population. An increase in bone sequestra, cortical bone lysis, and bone density was observed in bisphosphonate-related ONJ, while larger bone sequestra, more frequent periosteal reactions, and mandibular canal enhancement were noted in denosumab-related ONJ. This systematic review demonstrated that the imaging characteristics of bisphosphonate-related and denosumab-related ONJ are not similar. Although clinically similar conditions, they were found to be radiographically distinct. More studies are necessary to further elucidate these differences.

Dynamic polarization shifting from M1 to M2 macrophages in reduced osteonecrosis of the jaw-like lesions by cessation of anti-RANKL antibody in mice.

Denosumab-related osteonecrosis of the jaw (DRONJ), which mainly occurs in cancer patients receiving anti-receptor activator NF-kappaB ligand (RANKL) antibody, reduces oral health-related quality of life. However, the exact mechanisms of and definitive treatment strategies for DRONJ remain unknown. We hypothesized that cessation of denosumab heals and/or ameliorates DRONJ, since it is a protein-based antibody agent, although stopping denosumab should be avoided in clinical situations. Therefore, the aims of this study were: 1) to create a healing and/or amelioration murine model of DRONJ-like lesions induced by chemotherapy/anti-RANKL antibody (mAb) combination therapy and tooth extraction; and 2) to investigate histopathology and immunopathology in the extraction sockets by comparing the murine model of DRONJ-like lesions with the amelioration/healing model of DRONJ-like lesions. Eight-week-old, female C57B/6J mice received chemotherapeutic drug (cyclophosphamide: CY) and mAb combination therapy (CY/mAb) with tooth extraction. Open wounds were sustained in CY/mAb-treated mice at 2 and 4 weeks post-extraction. Impaired socket healing was diagnosed as CY/mAb-related ONJ-like lesions at 3 weeks post-extraction in this study. Next, mAb was discontinued for 2 and 4 weeks after diagnosis of CY/mAb-related ONJ-like lesions. mAb cessation for 2 weeks induced partial osseous wound healing and significantly improved soft tissue wound healing of the extraction sockets. Anti-angiogenesis and normal lymphangiogenesis with CY/mAb combination therapy was not changed by mAb discontinuation. However, mAb cessation for 2 weeks significantly increased the number of CD38+F4/80+ M1 and CD163+F4/80+ M2 macrophages, which significantly increased the M2/M1 ratio in the connective tissue of extraction sockets. No direct effects of mAb on macrophages were noted both in vivo and in vitro. Therefore, the developed healing and/or amelioration murine model of CY/mAb-related ONJ-like lesions is a useful tool to investigate the histopathology and immunopathology of DRONJ in humans. Dynamic polarization shifting from M1 to M2 macrophages induced by mAb cessation may play an important role in wound healing, rather than angiogenesis and lymphangiogenesis, in DRONJ.

Distinct immunopathology in the early stages between different antiresorptives-related osteonecrosis of the jaw-like lesions in mice.

There is limited information about denosumab-related osteonecrosis of the jaw (DRONJ), unlike bisphosphonate-related ONJ (BRONJ). The mode of action is clearly different between denosumab and bisphosphonates. DRONJ occurs mainly following tooth extraction in cancer patients treated with the combination of denosumab and other drugs including chemotherapy. However, DRONJ animal models similar to these clinical situations have not been developed. The aims of this study were to 1) create a new model of high-prevalence chemotherapy/anti-RANKL antibody-related ONJ-like lesions to mimic patients receiving a denosumab/chemotherapy combination; and 2) compare the histopathological and immunopathological findings in the early stages of BRONJ-like and anti-RANKL antibody-related ONJ-like lesions. Cyclophosphamide (CY) and anti-mouse RANKL monoclonal antibody (mAb) or zoledronate combination therapy (CY/mAb and CY/ZA, respectively) was performed to create ONJ-like lesions in female C57BL/6J mice. Both maxillary first molars were extracted at 3weeks after drug administration. The animals were euthanized at either 2 or 4weeks after tooth extraction. Increased necrotic bone and empty lacunae with decreased living bone and osteocyte numbers were common histopathological findings in CY/mAb- and CY/ZA-induced impaired wound healing at 4weeks after tooth extraction, and they were diagnosed as ONJ-like lesions based on validation of BRONJ and DRONJ in humans. In areas of impaired healing at 2weeks post-extraction, decreases in angiogenesis and F4/80+LYVE-1- macrophages were noted as common immunopathological findings, although anti-angiogenesis was worse with CY/mAb than with CY/ZA. Interestingly, CY/mAb did not reduce F4/80+LYVE-1+ cells and normal lymphangiogenesis remained, whereas CY/ZA profoundly suppressed the larger size of F4/80+LYVE-1+ cells, similar to vessels with a concomitant decrease in lymphangiogenesis. Therefore, the distribution of the larger size of F4/80+LYVE-1+ cells differed in the early stages between different antiresorptive-induced ONJ-like lesions in conjunction with lymphangiogenesis, although the histopathological findings were similar. These findings suggest that the pathogenesis of BRONJ and DRONJ may differ due to the distributions of F4/80+LYVE-1+ tube-like-structured cells.

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384. Denosumab-Related Osteonecrosis of the Jaw: an Emergent and Potentially Complex Bone and Joint Infection

BackgroundOsteonecrosis of the jaw is a known complication of antiresorptive treatment, like bisphosphonate. More recently, denosumab was validated as a treatment in the osteoporosis and bone metastasis. Its mechanism is different from bisphosphonate but induces also a decrease of bone resorption and a risk of osteonecrosis of the jaw. In case of treatment failure by a dental surgeon or in complex cases, patients could be addressed to a bone and joint infection (BJI) reference center. The aim of this study was to analyze microbiology, as well as surgical and medical care of patients who present denosumab-related osteonecrosis of the jaw (DRONJ) and who were treated in a bone and join reference center.MethodsAll patients managed in our BJI reference center between January 2013 and December 2018 for a DRONJ were included in our retrospective observational monocentric cohort.ResultsTwelve patients (median age 71; ratio M/W 0.7) with a DRONJ (metastatic cancer, n = 10 (83%)) in grade 3 (n = 5), 2 (n = 4), 1 (n = 3) were included. Only 3 patients (25%) had a dental health control before initiating the treatment by denosumab and 7 patients (58%) had a dental surgical procedure done before the DRONJ. Eleven patients had a bone exposure, treated at least with a scaling and mucosal closure at the same time. All infections with bacterial cultures (n = 11 (91%)) were polymicrobial, including 8 (72%) with Streptococcus spp; 8 (72%) with anaerobia including 2 (18%) with Actinomyces; 5 (45%) with Staphylococcus spp; 5 (45%) with enterobacteria; 3 (27%) with Candida spp; 2 (17%) with a non-fermentative Gram-negative bacilli and 7 (64%) with others bacteria. All patients (n = 12) received a betalactam, 8 (66%) a lincosamide or a synergistin, 5 (41%) an antifungal, 5 (41%) metronidazole, 4 (33%) a fluoroquinolone, 3 (25%) a glycopeptide and 2 (17%) other antibiotics. The median follow-up was 6 months. Eight patients were cured after a medico-surgical care and a median duration of antibiotics of 97 days (including 28.5 days in intravenous). 2 patients required a suppressive antibiotic treatment, 1 relapsed at a distance of the treatment and 1 died from some other causes.ConclusionDRONJ is a potential complex BJI, for which some patients could benefit from medical care in a BJI reference center.Disclosures All authors: No reported disclosures.

Histologic analysis of medication-related osteonecrosis of the jaw compared with antiresorptive-exposed bone and other infectious, inflammatory, and necrotic jaw diseases.

This study characterized histologic features of medication-related osteonecrosis of the jaw (MRONJ) through analysis of tissues from patients and healthy individuals. Bone biopsies were collected from various infectious, inflammatory, and necrotic jaw diseases. Samples were divided into bone exposed to bisphosphonates or denosumab, as well as bisphosphonate-related osteonecrosis of the jaw (BRONJ), denosumab-related osteonecrosis of the jaw (DRONJ), and mixed necrosis, enabling us to identify features of single agent necrosis without influence from previous therapies. Hematoxylin and eosin (H&E), receptor activator of nuclear factor κ-Β ligand (RANKL), tartrate-resistant acid phosphatase (TRAP), osteoprotegerin, toluidine blue, CD14, and CD68 staining and micro-computed tomography (micro-CT) analysis were performed. Groups were compared by using analysis of variance (ANOVA). In total, 156 bone samples were collected from 105 patients. MRONJ variants exhibited more infectious infiltration. Bisphosphonate (P < .001) and mixed necrosis (P = .002) demonstrated more RANKL- and TRAP-positive osteoclasts. Denosumab necrosis (P = .007), and bone exposed to bisphosphonates (P = .028) in combination with denosumab (P = .022) demonstrated significantly lower numbers of osteocytes per area. CD14 and CD68 positivity was increased for BRONJ (P = .008; P < .001, respectively). MRONJ variants exhibited the widest trabecular width and decreased medullary space to bone. No diminished vascular network in MRONJ samples was observed. Histologic features differ among MRONJ variants, with oversuppressed bone turnover, dysfunctional bone resorption, and a disturbed osteocyte network as potential mechanisms of pathogenesis.

Denosumab-related osteonecrosis of the jaw in a patient with osteoporosis: case report

Denosumab-related osteonecrosis of the jaw in a patient with osteoporosis: case report

Osteonecrosis of the jaw in patients treated with denosumab: A multicenter case series

PurposeOsteonecrosis of the jaw has been recently reported in patients receiving denosumab for the treatment of metastatic bone disease and osteoporosis. It is essential to investigate this disease as a new osteonecrosis entity in order to recognize its optimal management strategies. Materials and MethodsA total of 63 cases of denosumab-related osteonecrosis of the jaw (DRONJ) diagnosed at two clinical centres were retrospectively reviewed. Demographics, comorbidities, antiresorptive medication use, local preceding event, location, DRONJ stage, treatment and treatment outcomes were analyzed. ResultsIn all, 69 MRONJ lesions in 63 patients were diagnosed. The mean patient age was 70 ± 9 years. Denosumab was the only received antiresorptive medication in 50.8% of the patients. Discontinuation of denosumab prior to treatment was recorded for 66.7% of the patients, with a mean period of 6 ± 3.4 months. Stage 2 was the most common stage of the disease (71%). The lesions were predominantly located in the mandible (63.5%). The most common preceding local event was extraction (55.6%). Surgical treatment was performed in 95.7% of the cases, while purely conservative treatment was performed in 4.3%. DRONJ healed after surgical treatment in 71.7% of the treated lesions. Complete mucosal healing was achieved in 77.2% of the lesions treated with fluorescence-guided surgery (17/22). Clinical characteristics and treatment outcomes were not significantly different between patients with and without previous intake of bisphosphonates. ConclusionDRONJ is more prevalent at extraction and local infection sites in cancer patients. Within the limitation of this study, surgical treatment, particularly fluorescence-guided surgery, appears to be effective for the management of DRONJ. The prior use of bisphosphonates does not seem to affect severity nor the treatment success rate of DRONJ.

Osteonecrosis of the jaw in patients transitioning from bisphosphonates to denosumab treatment for osteoporosis

Antiresorptive-related osteonecrosis of the jaw (ARONJ) is a rare but severe side effect of antiresorptive treatment with bisphosphonates or RANKL-antibody denosumab in patients with malignant diseases or osteoporosis. Whilst osteonecrosis of the jaw (ONJ) related to the administration of bisphosphonates (BPs) has been investigated for more than 1 decade now, only few data are available on denosumab-related ONJ, especially in patients with osteoporosis. From 2008 to 2016, 52 osteoporosis patients were treated with ARONJ in the Department of Oral and Maxillofacial Surgery, University Medical Center Freiburg, Germany. In all patients, a surgical regimen consisting of complete removal of necrotic bone, primary wound closure and perioperative i.v. antibiotic therapy was applied. Of the 52 patients, 38 developed ARONJ after BP monotherapy; in 11 patients, antiresorptive therapy had been transitioned from BPs to denosumab and 3 patients had received denosumab monotherapy. From July 2013, when the first patient with ONJ and transitioning therapy from BPs to denosumab presented to our department, to October 2016, we found recurrences in 17.6% of the patients with BP monotherapy and in 45.5% of the patients with transitioning therapy from BPs to denosumab. Transitioning antiresorptive therapy from BPs to denosumab may be an additional risk factor for developing ARONJ. In these patients, treatment of ARONJ-lesions seems to provoke more complications. An additional dental screening before transitioning should be initiated. Further studies are needed to evaluate if a first-line treatment with denosumab decreases the incidence of ARONJ in patients with osteoporosis and simplifies its treatment.

Denosumab‐related osteonecrosis of the jaw: A retrospective study

Osteonecrosis of the jaw is a very delicate side effect of Denosumab. The aim of this retrospective study was to assess the occurrence rate of Denosumab-related osteonecrosis of the jaw (DRONJ) at the Cancer Institute of Lorraine (ICL) and to highlight necrosis risk factors. To that purpose, we analyzed the medical records of 249 consecutive patients treated with Denosumab at the ICL during the past 5 years. Patients who received orofacial radiotherapy or a previous treatment with a bisphosphonate were excluded. The P-value was set at .005. A total of 141 patients treated at the ICL between January 2010 and December 2015 were included. All patients were treated with XGEVA® . Of the 141 patients included in the study, 10 developed DRONJ. The incidence of DRONJ increases with the duration of follow-up as follows: 3% at 1 year, 7% at 2 years, and 8% from 30 months on. No risk factor for necrosis could be identified except the realization of prior dental extraction (P = .025). Our results raise important questions about the dental management of these patients, in particular, concerning the healing period between dental extractions and the initiation of Denosumab.

Denosumab-related osteonecrosis of the jaw in a patient with bone metastases of prostate cancer: A case report and literature review.

Denosumab, a human monoclonal antibody directed against the receptor activator of nuclear factor-κβ ligand (RANKL), is used for the treatment of patients with metastatic cancer of the bone or osteoporosis. Recent reports have demonstrated that denosumab can induce osteonecrosis of the jaw (ONJ), but reported cases of this are uncommon. The present study reports the case of an 86-year-old male with prostate cancer patient exhibiting bone metastases who developed ONJ whilst receiving denosumab. To elucidate the influence of denosumab on the development of ONJ, the present study also reviewed the literature, including clinical trials and case reports. In the clinical trials, the prevalence of denosumab-related ONJ was higher in patients with cancer compared with those with osteoporosis. The high risk of ONJ in patients with cancer was thought to be associated with the differing dose and frequency of denosumab administration. The prevalence of ONJ was not significantly different between patients receiving denosumab and bisphoshonate (BP). In the reported cases, denosumab-related ONJ had a similar clinical presentation to BP-related ONJ. There was also a tendency for denosumab-related ONJ to develop in the mandible of elderly patients. Previous invasive dental treatment was a commonly shared characteristic of patients with denosumab-related ONJ. A complex medical history was also suspected to affect the prevalence. No clear association between the dose or duration of denosumab treatment and the development of ONJ was observed. Although conservative treatments are given for denosumab-related ONJ, non-improving cases were managed surgically with primarily positive results. Because denosumab may offer superior results compared with BP for the treatment of metastatic cancer of the bone or osteoporosis, the use of denosumab is expected to increase in the near future. Clinicians should also be aware of the risk factors for denosumab-related ONJ, in order to aid in its diagnosis. In addition, patients treated with denosumab should receive prophylactic treatment to maintain their oral health prior to, during and after denosumab treatment.

Clinical course and therapeutic outcomes of operatively and non-operatively managed patients with denosumab-related osteonecrosis of the jaw (DRONJ)

PurposeDetails regarding risk factors, onset, and outcomes for denosumab-related osteonecrosis (DRONJ) are sparse. This study examines the clinical characteristics and operative and non-operative therapeutic outcomes in patients with DRONJ not previously exposed to other antiresorptives. MethodsA retrospective medical record review was conducted, and data were collected, including clinical findings, management, healing outcomes, and radiologic, histologic, and micro-computed tomography (CT) analyses. ResultsSeventeen patients were treated with denosumab, with 14.1 ± 8.3 doses before DRONJ onset. The majority of lesions were observed at sites of dental prostheses (41%) and dental extractions (35%). Sixteen patients were managed non-operatively (10/16) or operatively (6/16) with either major (5/6) or minor surgery (1/6) and included in the follow-up analysis. Complete healing was significant in patients treated with major surgery (80%) compared to the non-operative group (20%; p < 0.035). Denosumab was discontinued in 60% of non-operative patients and major surgery patients with no effect on healing. Histologic findings of 4 patients analyzed exhibited a decreased number of osteocyte lacunae, and micro-CT of 3 patients scanned revealed trabecular thickening. ConclusionDRONJ lesions occurred mostly at sites of prostheses sores after a mean of 14 doses of denosumab. Major surgery demonstrated more complete healing than non-operative management, and denosumab cessation did not improve healing outcomes.