Osteonecrosis Of The Jaw Lesions Research Articles

Anti-vascular endothelial growth factor antibody monotherapy causes destructive advanced periodontitis in rice rats (Oryzomys palustris).

Angiogenesis inhibitors (AgI) are commonly used in combination chemotherapy protocols to treat cancer, and have been linked to osteonecrosis of the jaw (ONJ). However, it is unknown if AgI therapy alone is sufficient to induce ONJ. We have previously established an ONJ model in rice rats with localized periodontitis that receive zoledronic acid (ZOL). The purpose of this study was to use this model to determine the role of anti-vascular endothelial growth factor A (anti-VEGF) antibody treatment of rice rats with localized maxillary periodontitis. We hypothesized that rice rats with localized maxillary periodontitis given anti-VEGF monotherapy will develop oral lesions that resemble ONJ, defined by exposed, necrotic alveolar bone. At age 4 weeks, 45 male rice rats were randomized into three groups (n = 15): 1) VEH (saline), 2) ZOL (80 μg/kg body weight, intravenously once monthly), and 3) anti-VEGF (5 mg B20-4.1.1/kg body weight, subcutaneously twice weekly). After 24 weeks, rats were euthanized, jaws were excised and a high-resolution photograph of each quadrant was taken to assign a severity grade based on gross appearance. Jaws were then fixed, scanned by MicroCT, decalcified and sectioned for histopathologic and immunohistochemical analyses. 40-80% of the rats in the three groups developed gross oral lesions. 50% of ZOL rats developed ONJ. In contrast, 80% of the anti-VEGF rats developed destructive advanced periodontitis that was characterized by extreme alveolar bone loss and fibrosis. Anti-VEGF rats never developed exposed, necrotic bone. Furthermore, only anti-VEGF rats developed mild to severe mandibular periodontitis. Compared to VEH rats, more T-cells were found in periodontal lesions of anti-VEGF rats and more cells of the monocyte lineage were found in ONJ lesions of ZOL rats. Anti-VEGF monotherapy administered to a validated rodent model of ONJ caused a destructive advanced form of periodontitis that differed significantly from ONJ.

Surgical treatment of osteonecrosis of the jaw with the use of platelet-rich fibrin: a prospective study of 15 patients

The objective of this study was to evaluate the outcome of the surgical treatment of osteonecrosis of the jaw (ONJ) with the additional use of autologous membranes of platelet-rich fibrin (PRF). The study population consisted of 15 patients with ONJ lesions in the maxilla (n=3), mandible (n=11), or both (n=1). Eight patients had malignant disease and were treated with high-dose anti-resorptive medication; seven were treated with low-dose anti-resorptive drugs for osteoporosis. Thirteen patients had grade 2 ONJ lesions and two had grade 3 lesions. The following standardized surgical technique was applied: resection of necrotic bone, mobilization of mucoperiosteal flaps, and multiple layer coverage of bone with PRF membranes. At follow-up 7–20 months after surgery, complete mucosal healing and an absence of symptoms were found in 14 of the 15 patients (93%). The patient with persistent bone exposure had a grade 3 ONJ lesion before surgery. This study suggests that the use of PRF membranes in the surgical treatment of grade 2 ONJ may be a contributing factor to a successful outcome.

Role of microcracks in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw.

The aim of this study was to investigate the potential role of microcrack accumulation in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (ONJ) through an animal model. Twenty-four ovariectomized rats were randomly divided into a bisphosphonate group (n=19) and control group (n=5) and weekly injected with zoledronic acid and normal saline, respectively. After 6weeks, surgical intervention was performed, and the injections were continued for eight additional weeks. Then, the animals were sacrificed, and ONJ lesions were inspected for the presence of microcracks using scanning electron microscopy. Measurements included bone dimension, number of cracks, crack length, and normalized indices; crack density (Cr.Dn) and crack surface density (Cr.S.Dn) were used for group comparison. Both number of cracks and crack length in the bisphosphonate group were greater than those in the control group (P<0.05). Of the 19 rats injected with bisphosphonates, 13 rats (68.4%) were classified into the ONJ group. Cr.Dn and Cr.S.Dn were significantly greater in the ONJ group than in the non-ONJ group, indicating accumulation of unrepaired microcracks (P<0.05). Seventy-two percent of microcracks in the ONJ group conformed to the defined length that was considered significant according to a previous literature (30-80μm); whereas 12% of microcracks in the non-ONJ group were considered significant (P<0.05). Accumulation of unrepaired microcracks was significantly associated with the development of bisphosphonate-related ONJ. Further research is required to determine the role of microcracks in the pathogenesis of bisphosphonate-related ONJ. Long-term bisphosphonates use may deteriorate the biomechanical and physiological bone integrity, contributing to the pathogenesis of bisphosphonate-related ONJ.

Analysis of different therapeutic protocols for osteonecrosis of the jaw associated with oral and intravenous bisphosphonates.

IntroductionChemotherapy-associated osteonecrosis of the jaw caused by bisphosphonates is an exposure of necrotic bone with more than eight weeks of evolution that is attributable to bisphosphonates and no prior radiation therapy. Its etiopathogenesis remains unknown, although there are two hypotheses that may explain it: the drug’s mechanism of action, and the risk factors that can lead to osteonecrosis. There is a wide range of treatment options for managing chemotherapy-associated osteonecrosis of the jaw, from conservative treatments to surgical procedures of varying levels of invasiveness, which are sometimes supplemented with adjuvant therapies.ObjectivesThe objective of this article is to group the therapeutic options for osteonecrosis of the jaw (ONJ) into seven different protocols and to evaluate their effectiveness in relation to stage of ONJ.Material and MethodsA literature review was carried out in PubMed following the PRISMA criteria. A total of 47 were collected after compiling a series of variables that define ONJ, applied treatments, and the clinical results obtained.Results and DiscussionThe 47 articles selected have a low to average estimated risk of bias and are of moderate to good quality. According to the data obtained, Protocol 3 (conservative treatment, clinical and radiological follow-up, minimally invasive surgical treatment, and adjuvant therapies) is the most favorable approach for ONJ lesions caused by oral bisphosphonates. For lesions caused by intravenous bisphosphonates, Protocol 2 (conservative treatment, clinical and radiological follow-up, minimally invasive surgical treatment, and no adjuvant therapies) is the best approach. When comparing the different stages of ONJ, Protocol 1 (conservative treatment, clinical and radiological follow-up) promotes better healing of Stage 1 ONJ lesions caused by orally administered bisphosphonates, and Protocol 3 is recommended for Stage II. For ONJ lesions attributable to intravenous bisphosphonates, Protocol 7 (conservative treatment, clinical and radiological follow-up, and adjuvant therapies) provides the best results in Stage 0; in Stages I, II, and III, Protocol 1 gives better results. Key words:Bisphosphonates, bronj, therapeutic protocol, clinical result.

Animal model for medication-related osteonecrosis of the jaw with precedent metabolic bone disease

Despite the fact that the medications used to treat abnormal bone conditions often induce osteonecrosis of the jaw (ONJ), previous attempts to establish an animal model for ONJ have shown insufficient consideration for this important prerequisite for the development of the disease. The purpose of this study was to establish an animal model with the most common metabolic bone disease, osteoporosis.Ninty-six rats were randomly divided into ovariectomy (Ov) group (n=48) and sham-operated group (n=48). Six weeks after Ov or sham surgery, rats in each group were subdivided into bisphosphonate group (n=36 each) and control group (n=12 each) and injected with zoledronic acid and normal saline, respectively, once a week. After additional 6weeks, surgical intervention was performed, and the injections were continued for 8 more weeks. The animals were then sacrificed for further macroscopic, histological, histomorphometric, radiological, and bone biomarker investigations.As histologically determined, the Ov group (77.8%) showed higher ONJ prevalence compared to the sham group (47.2%; P<0.05). Micro-structural and histomorphometric assessments revealed that rats with ONJ (ONJ group) presented with deteriorated bone architectures with higher necrotic bone fraction and lower number of osteoclasts (P<0.05). Compared to the sham-operated ONJ group, the Ov ONJ group showed significantly lower values of Tb.N, Tb.Sp, Conn.D, N.Oc/T.Ar, and TRACP 5b and CTX/TRACP (P<0.05).The ovariectomized rat model in this study successfully mimicked human ONJ lesions with an underlying bone disease and showed different bone characteristics than that of the previous ONJ model. Based on the differences, further researches for investigating pathophysiology of ONJ, including various pharmacological responses for deteriorated bone environment, are required.

Fluorodeoxyglucose Positron Emission Tomography With Computed Tomography Detects Greater Metabolic Changes That Are Not Represented by Plain Radiography for Patients With Osteonecrosis of the Jaw

Imaging is important to identify subclinical changes and for treatment planning in patients with osteonecrosis of the jaw (ONJ) exposed to antiresorptive therapy. The aim of this study was to compare the findings at radiography with those at fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT) for patients with ONJ related to antiresorptive therapy. A cross-sectional retrospective analysis of patients with clinically identified ONJ lesions of the mandible was performed. Two imaging modalities were evaluated for each patient: plain radiography (ie, panoramic or periapical) and FDG PET/CT with 1-mm sections. Outcome variables for the radiographic findings were osteolytic and osteosclerotic bone changes. Outcome variables for FDG PET/CT images were localization of FDG uptake. Maximum standard uptake values (SUVmax) of abnormal FDG jaw uptake were recorded, in addition to the mean SUV of the contralateral normal mandible, and used tocalculate the target-to-background ratio. Radiographic changes and FDG uptake were classified as local (ie, corresponding to exposed cortical bone) or diffuse (ie, local changes and changes extending beyond the margins of exposed bone) for each imaging technique. Local and diffuse changes detected by each imaging modality were described and the difference in detection was compared with the McNemar test. Twenty-three patients with 25 clinically identified ONJ lesions were analyzed using radiography and FDG PET/CT. Differences were found in how radiography and FDG PET/CT detect local and diffuse changes associated with ONJ. Radiography showed local changes in 17 patients (68%), diffuse changes in 3 patients (12%), and no changes in 5 patients (20%), whereas FDG PET/CT imaging showed local changes in 17 patients (68%) and diffuse changes in 8 patients (32%). The McNemar test indicated that FDG PET/CT imaging was less likely to miss a lesion (P < .001). Mean SUVmax was 6.59, and the mean target-to-background ratio was 5.37. The results of this study show that FDG PET/CT detects local and diffuse metabolic changes that may not be represented by plain radiography for patients with ONJ related to antiresorptive therapy. The target-to-background ratio allowed the discrimination between ONJ lesions and background changes. Future studies are necessary to determine whether FDG PET/CT can determine risk and facilitate management of ONJ.

Clinical study evaluating the effect of bevacizumab on the severity of zoledronic acid-related osteonecrosis of the jaw in cancer patients

This study aimed to evaluate the effect of bevacizumab (BVZ) on the severity of osteonecrosis of the jaw (ONJ) in a cohort of cancer patients treated with intravenous zoledronic acid (ZA). We reviewed 42 oncologic patients with ONJ between 2007 and 2010. Only patients with solids tumors and who had received ZA were included. Data analyses included age, sex, underlying disease, ZA and BVZ dosages, dental history and ONJ characteristics. Of the 42 ONJ patients treated with ZA, 10 also received BVZ. In the 10 ZA/BVZ patients, the mean duration of ZA treatment at the time of ONJ diagnosis was 12.4months (±6.8), compared to 22.9months (±4.8) in the 32 patients who received ZA only (p<0.05). Cox's model analysis of the delay to ONJ diagnosis confirmed the impact of BVZ on ONJ diagnosis. In the ZA/BVZ-treated group, 7 (70%) patients developed spontaneous osteonecrosis. Multiple logistic regression analysis showed that ZA/BVZ is associated with increased risk of developing spontaneous ONJ (OR 6.07; 95% CI, [1.3–28.2], p<0.05). And finally, the number of ONJ lesions was increased in the ZA/BVZ-treated group compared to the ZA group (p<0.01). Other clinical conditions as type of tumor (prostate, breast…), cancer severity or other chemotherapy drugs also could be involved in ONJ evolution. However, this study demonstrates for the first time the potential negative influence of BVZ on the incidence and severity of ONJ in patients receiving ZA. Within the study limits, our results suggest that combination ZA/BVZ treatment may possibly predispose to the development of spontaneous and earlier ONJ.

Chemotherapeutic and antiresorptive combination therapy suppressed lymphangiogenesis and induced osteonecrosis of the jaw-like lesions in mice

Osteonecrosis of the jaw (ONJ) is a serious adverse event that occurs predominantly in patients on both antiresorptive and antineoplastic therapies. However, how these combination therapies are connected to the high frequency of ONJ in this particular patient population is unclear. This study's aim was to determine a mechanism of ONJ associated with the combination therapy of antiresorptives and chemotherapeutics. Mice received zoledronic acid (ZA) in conjunction with melphalan or dexamethasone. The maxillary first molars were extracted 3weeks after the initiation of treatment and wound healing assessed at 4weeks post-extractions using microcomputed tomography and immunohistochemistry. Mice receiving the combination treatment of ZA and melphalan developed ONJ-like lesions, while ONJ-like lesions were not found in mice on ZA or melphalan monotherapy, or the combination treatment of ZA and dexamethasone. ONJ lesions were characterized by a lack of epithelium, exposed necrotic bone, severe inflammatory cell infiltration, and minimal bone formation. Fluorescent immunohistochemistry showed that lymphatic vessel formation was significantly suppressed in ONJ-like lesions with a concomitant decrease in F4/80+ macrophages expressing vascular endothelial growth factor C (VEGFC). Interestingly, significantly suppressed lymphatics were also found in the draining lymph nodes of mice on the combination treatment of ZA and melphalan. Thus, suppressed lymphangiogenesis was strongly associated with the development of ONJ-like lesions in the current study. Since lymphangiogenesis is critical in the resolution of inflammation during wound healing, inflammation control may serve as a potential strategy to prevent ONJ.

Prospective Observational Study of 110 Multiple Myeloma (MM) Patients On Monthly Versus 3 Monthly Infusion of Zoledronic Acid

AbstractAbstract 4245 Introduction:Osteonecrosis of the jaw (ONJ) is a recognized risk of bisphosphonate infusion; the incidence, etiology, risk factors and pathophysiology remains largely undefined. In this prospective study we evaluated patients on long-term zoledronic acid infusions; the aims of the study were to provide a comprehensive clinical, oral/dental assessment of patients prospectively and sequentially measure changes in zoledronic acid PKs, cytokines, microbial signatures and bone turnover markers in saliva and serum in correlation with 2 major clinical end points development of ONJ and myeloma relapse. Methods and patients:Over 6 months 110 patients were enrolled and followed for 18 months. Patients were on zoledronic acid infusions: monthly (n=75) for patients with significant bone disease (relapsed or newly diagnosed) or every 3 months (n=35) for those in stable remission > 3years. During the study follow up therapy was changed to pamidronate (n=4) due to renal insufficiency or denosumab (n=1). Patients had clinical and oral evaluations and saliva and blood samples collected at baseline and every 3 months up to 18 months; saliva samples were obtained before and after (5 and 15 minutes) zoledronic acid infusions. Results:Median time from MM diagnosis was 3.7 years (range: 1.5–13) for 100 patients; 10 newly diagnosed patients were enrolled as control with a median of 7 months (range: 1–9). Median age was 60 yrs (range: 32–82); 60 were Caucasians, 49 African American, one Asian; 68 were males. At study entry 79% of the patients were in remission: CR (n=35, 32%) of them 15 were in CR for > 7 years, PR (n=52, 47%) and PD (n=23, 21%). Twenty-four patients were not receiving any MM therapy; most were on maintenance with lenalidomide (n=52) or thalidomide (n=11) and the rest on other regimens (n=23). Fifty patients progressed during the 18 month study period; they continued the study with various salvage therapies that included: bortezomib (n=14), carfilzomib (n=14), lenalidomide (n=6) and clinical trails (n=16). Thirteen patients had died: 9 from complications of relapsed MM and 4 from other causes. Eighteen patients withdrew consent for sample collection and dental evaluations but were followed clinically. Most patients had prior-to-study entry dental procedures (extractions, n=80). The prevalent oral pathology detected on dental evaluations included: gingivitis (n=41), moderate/severe periodontal disease (n=35) and gross dental caries (n=15). During the 18 months of observation; 13 patients developed ONJ. Median time from MM diagnosis to ONJ was 5.7 years (range: 1.9–12 years). Risk factors for ONJ were relapsed disease (n=11), monthly zoledronic acid (n=8), dental extractions (n=8), severe periodontal disease (n=9), older age [median age was 62 yrs] and prior ONJ (n=3). ONJ treatment was conservative with antibiotics and holding BP therapy: 9 patients had complete healing of the site of ONJ and 4 had persistent non-healing ONJ lesions. Sequential saliva and serum samples were assessed for various cytokines involved in immune/inflammatory process (IL-1β, IL-6, IL-17, TNF-α, IFN-α, TGF-β, MIP-1 α β, MMP-9); bone turnover (Osteopontin, ostiocalcin, RANKL, Osteoprotregerin) and angiogenesis factors (VEGF and EGF) in 42 patients with ONJ (n=13), severe periodontal disease (n=10) and normal control (n=19), the later included 10 patients in remission and 9 with relapsed MM. In conclusion:In this longitudinal observational study, the ONJ incidence was 11%, 70% eventually healed. Our cytokine analysis suggest that saliva may accurately detect changes reflective of mucosal inflammation as well as bone turnover markers; data correlating these changes with ONJ and MM status will be presented. Disclosures:No relevant conflicts of interest to declare.

Efficacy and tolerability of medical ozone gas insufflations in patients with osteonecrosis of the jaw treated with bisphosphonates—Preliminary data: Medical ozone gas insufflation in treating ONJ lesions

Osteonecrosis of the Jaw (ONJ) is an adverse event reported especially in patients receiving cancer treatments regimen, bisphosphonates (BPs), and denosumab. We performed an open-label, prospective study in patients treated with zoledronic acid who developed ONJ lesions >2.5cm, and had no benefit after the treatment with the standard therapy, to evaluate the efficacy and tolerability of medical ozone (O3) treatment delivered as gas insufflations on each ONJ lesions.Twenty-four patients (mean age 62.5, range 41–80; 12 female) with bone metastases due to breast (11), prostate (4)and lung (4)cancers, myeloma (2), or osteoporosis (3), previously treated with zoledronic acid and not underwent dental preventive measures and with ONJ lesions >2.5cm, were observed and treated with topical O3 gas insufflation every third day for a minimum of 10 for each pathological area or till necrotic bone sequestrum or surgery. We used a special insufflation bell-shaped device adjusted to the specific characteristics of the patient, capable of eliminating any residue of O3 diffusion by degrading it and releasing O2 into the air. Azithromicin 500mg/day was administered for 10 days in all patients before the first three gas insufflation although they had previously received various cycles of antibiotics. Ten patients required more than 10 O3 gas insufflations due to multiple lesions and/or purulent sovrainfections; one patient received two further O3 insufflations while waiting the day of surgery. Six of 24 patients interrupted the O3 gas therapy for oncological disease progression (five patients) and for fear of an experimental therapy (one patient). Six patients had the sequestrum and complete or partial (one patient) spontaneous expulsion of the necrotic bone followed by oral mucosa re-epithelization after a range of 4–27 of O3 gas insufflations. No patient reported adverse events. In 12 patients with the largest and deeper ONJ lesions, O3 gas therapy produced the sequestrum of the necrotic bone after 10 to 38 insufflations; surgery was necessary to remove it (11 patients). Of interest, removal was possible without the resection of healthy mandible edge because of the presence of bone sequestrum.All together the response rate was 75.0% (95% CI, 53.3–90.2%) in ITT analysis and 100% (95% CI, 81.5–100%) in the PP analysis.In all patients treated with O3 gas ± surgery, no ONJ relapse appeared (follow-up mean 18 months, range 1–3 years). Medical O3 gas insufflations is an effective and safe treatment for patients treated with BPs who developed ONJ lesions >2.5cm.Short abstract: ONJ is an adverse event reported in patients receiving cancer treatments regimen, bisphosphonates and denosumab. We performed an open-label, prospective study in 24 patients with solid tumours, myeloma or osteoporosis due to hormonal therapy, treated with zoledronic acid without previuos preventive dental screening, who developed ONJ lesions >2.5cm, and had no benefit after standard therapy, to evaluate the efficacy and tolerability of medical ozone (O3) treatment delivered as gas insufflations on each ONJ lesions.The patients were treated with O3 every third day for a minimum of 10 for each pathological area or till necrotic bone sequestrum or surgery. Eleven patients required more than ten O3 gas insufflations. Six of 24 patients interrupted the therapy for oncological disease progression. Six patients had the sequestrum and complete or partial (one patient) spontaneous expulsion of the necrotic bone followed by oral mucosa re-epithelization after a range of 4 to 27 of O3 gas insufflations. No patient reported adverse events. In 12 patients with the largest and deeper ONJ lesions, O3 gas therapy produced the sequestrum of the necrotic bone after 10 to 38 insufflations; surgery was necessary to remove it (11 patients). Of interest, removal was possible without the resection of healthy mandible edge because of the presence of bone sequestrum.All together the response rate was 75.0% (95% CI, 53.3–90.2%) in ITT analysis and 100% (95% CI, 81.5–100%) in the PP analysis.In all patients treated with O3 gas ± surgery, no ONJ relapse appeared (follow-up mean 18 months, range 1–3 years).

Bisphosphonate-Associated Osteonecrosis of the Jaw: Are We Dealing with a Localized Non-Traditional Calciphylaxis?

The bisphosphonate (BP) family of drugs has been used as a vital component in cancer therapy and many other diseases. One of the main adverse effects related to (BP) is BP-associated osteonecrosis of the jaw (ONJ). Although this condition was first recognized in 2003, the pathophysiologic mechanism remains undefined. Our hypothesis is that ONJs clinical course and delayed wound healing is in part correlated to a localized non-traditional calciphylaxis. This effect is identified by the evidence of calcium deposition in the connective tissue and around small blood vessels in the soft tissues immediately adjacent to ONJ lesions. This phenomenon helps to fill gaps in the cascade of events which leads to soft tissue ischemia, necrosis, and non-healing ONJ lesions. Our finding adds to the current knowledge of the potential pathophysiologic mechanisms related to ONJ.

Epidemiology and pathogenesis of osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) is defined as exposed bone in the oral cavity that persists despite appropriate therapy. Over the past decade, ONJ has been reported in about 5% of patients with cancer receiving high-dose intravenous bisphosphonates, and more recently in similar patients treated with denosumab, another potent inhibitor of osteoclastic bone resorption. The condition has also been described in patients treated with bisphosphonates for benign diseases, such as osteoporosis, but whether bisphosphonates or denosumab increase the incidence above that seen in untreated patients of comparable age and frailty is yet to be established. The pathogenesis of ONJ is uncertain: the toxic effects of bisphosphonates in a wide variety of cells could increase susceptibility to infections in the oral cavity or impair mucosal healing, and denosumab might interfere with monocyte and macrophage function. Local osteolysis is an important defense against infection on bone surfaces that is blocked by both bisphosphonates and denosumab. Preventive dentistry prior to high-dose antiresorptive therapy is a critical measure in cancer patients, but is not usually justified in patients with osteoporosis. The management of established ONJ lesions is problematic: the greatest success seems to come from vigorous antimicrobial therapy with judicious use of surgical debridement.

Prognostic Value of Bone Scintigraphy in Cancer Patients With Osteonecrosis of the Jaw

identifying imaging predictors of healing of osteonecrosis of the jaw (ONJ) in cancer patients may assist in better stratification of treatment strategies. patients with ONJ were followed prospectively and underwent bone scintigraphy, both planar and single-photon emission computed tomography (SPECT) imaging. End points were time to healing and the number of recurrences. Studied parameters included lesion visibility, pattern of uptake, and quantification of uptake relative to the unaffected side. a total of 22 patients were recruited (3 men; 19 women) with a stage 1 ONJ lesion in 8, stage 2 in 9, and stage 3 ONJ in 5 patients. Median duration of follow-up was 12 months (range, 6-37). SPECT acquisitions proved superior over planar images in detecting ONJ lesions (P = 0.03). Quantification of tracer uptake in the ONJ lesion relative to the unaffected side showed increasing uptake with higher stages of ONJ: mean, 1.67 (95% confidence interval [CI], 1.17-2.18) in stage 1, 2.72 (95% CI, 2.24-3.20) in stage 2, and 4.62 (95% CI, 3.98-5.26) in stage 3. In addition, this relative ratio of uptake was found to be an independent predictor of ONJ healing (hazard ratio, 0.24; 95% CI, 0.07-0.82; P = 0.02). Neither ONJ stage nor relative ratio of uptake were predictors of the occurrence of ONJ relapses. bone scintigraphy in patients with ONJ is feasible and SPECT acquisitions are preferred over planar images. Relative quantification of tracer uptake provides prognostic information independent of clinical stage that may assist in identifying patients with a poor prognosis.

Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats

Necrotic bone exposure in the oral cavity has recently been reported in patients treated with nitrogen-containing bisphosphonates as part of their therapeutic regimen for multiple myeloma or metastatic cancers to bone. It has been postulated that systemic conditions associated with cancer patients combined with tooth extraction may increase the risk of osteonecrosis of the jaw (ONJ). The objective of this study was to establish an animal model of bisphosphonate-related ONJ by testing the combination of these risk factors. The generation of ONJ lesions in rats resembling human disease was achieved under the confluence of intravenous injection of zoledronate (ZOL; 35 µg/kg every 2 weeks), maxillary molar extraction, and vitamin D deficiency [VitD(−)]. The prevalence of ONJ in the VitD(−)/ZOL group was 66.7%, which was significantly higher (p < .05, Fisher exact test) than the control (0%), VitD(−) (0%), and ZOL alone (14.3%) groups. Similar to human patients, rat ONJ lesions prolonged the oral exposure of necrotic bone sequestra and were uniquely associated with pseudoepitheliomatous hyperplasia. The number of terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–biotin nick-end label–positive (TUNEL+) osteoclasts significantly increased on the surface of post–tooth extraction alveolar bone of the VitD(−)/ZOL group, where sustained inflammation was depicted by [18F]fluorodeoxyglucose micro-positron emission tomography (µPET). ONJ lesions were found to be associated with dense accumulation of mixed inflammatory/immune cells. These cells, composed of neutrophils and lymphocytes, appeared to juxtapose apoptotic osteoclasts. It is suggested that the pathophysiologic mechanism(s) underpinning ONJ may involve the interaction between bisphosphonates and compromised vitamin D functions in the realm of skeletal homeostasis and innate immunity. © 2010 American Society for Bone and Mineral Research.

Medical Ozone (O3) Oil or Gas Applications Heal Osteonecrosis of the Jaw (ONJ) in Patients Treated with Bisphosphonates (BPs). Preliminary Results of a Single Arm Study.

Abstract Treatment of bone metastasis with BP is aimed at preventing skeletal related events (SREs) and rarely leads to ONJ (&amp;lt;1%) (Hoff, JBMR. 2008). Preventive dental care is a simple and effective way to reduce the risk reduction of ONJ in 75% of the cases (Ripamonti, Ann Oncol. 2009). To date, there are still no standardized therapy for the treatment of ONJ. We report the effect of localized of O3 oil or gas application in cancer patients (12 breast cancer, 4 prostate cancer, 2 lung cancer, 1 NHL, 3 multiple myeloma) with ONJ observed in our institution. Patients had previously received nitrogene-BPs treatment in the absence of odontoiatric preventive measures. All the patients were in had stable disease without progression; 10 of them had ONJ lesions ≤ to 2.5 cm.O3 oil suspension applications on ONJ lesions ≤ 2.5 cm was carried out with localized applications directly on the lesions; patients with larger lesions (≥ 2.5 cm) were treated with the ozone gas locally applied. All the patients received treatment of O3 oil every third day and all of them were treated with antibiotic therapy (azithromycin, 500 mg/day) 10 days prior the initiation of the treatment with O3 oil. The statistical analysis is based on a Simon two-stage design, the second stage is on-going. In this preliminary analysis we focus on 10 patients treated with O3 oil with a medium follow up of 8 months, and 12 patients on medical gas ozone.73% of the patients (n=16) showed complete response in terms of radiological lesion disappearance with complete reconstruction of oral tissue. Among them, fourteen patients developed spontaneous sequestrum with expulsion of the necrotic bone whereas in 2 patients with large extension of bone involvement surgical intervention was necessary.Seventy percent of the patients treated with O3 oil experienced a complete response after 4 applications whereas patients treated with gas needed 4 to 16 applications (depending on the severity of the lesion). No patients presented adverse events related to the use of ozone treatments. Six patients are still on treatment and are improving as well.According to these results few application of O3 oil suspension in patients with smaller lesions and gas medical ozone for wider lesions following antibiotic therapy can rapidly lead to complete healing of ONJ. Further cases and complete follow-up data are required. These data indicate that ONJ is a manageable condition which can be not only prevented by means previously dental examination but also healed with medical ozone applications. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5046.

“Osteonecrosis of the Jaw: Experience of a Single center”.

Abstract 4935 BackgroundBisphosphonates have been proven to be effective in preventing or delaying skeletal complications in multiple myeloma with a significant improvement of the quality of life. Although these agents are usually well tolerated, osteonecrosis of the jaw (ONJ) has been recently associated with the use of bisphophonates. Nevertheless, the true incidence of this complication is not clearly defined. Therefore, we studied the incidence, characteristics and risk factors for the development of ONJ among patients with multiple myeloma treated with biphosphonates in our institution. Patients and methodsFive-hundred and sixteen patients who received biphosphonates (zoledronic acid, pamidronate, bondronate) and had a minimum exposure of 6 months to the drug were included in this analysis. These patients were asked reterospectivly to fill out a form containing several queries, including sex and age, type and time of neoplasia diagnosis, treatment and neoplasia status, odonthoiatric anamnesis, type and duration of therapy with BP, microbial isolation in site of lesion, specific treatment for osteonecrosis, number of patients (pts) affected by MM treated with BP from 2007 to 2009. From this retrospective review thirty-five patients were identified with pain of the jaw. ResultsTwo-hundred of five-hundred and sixteen patients received bondronate, seventy-four patients pamidronate, one-hundred and seventy-four patients zoledronic acid, twenty-three patients oral bisphosphonate and two patients are unable to name the bisphosphonate. Thirty-five patients were identified with pain of the jaw. A total of twenty-five ONJ cases were identified either by histology or estimation of the surgeon among all patients treated and referred to our institute. Five patients had no ONJ, only non-specific pain of the jaw. Five patients have other disease of the jaw (1 patient osteoymelitis; 1 patient cyst of the jaw; 1 patient epulis gigantocellularis, 1 patient granuloma, 1 patient plasmozytoma of the jaw). Ten patients who were diagnosed with ONJ received bondonate, eleven patients pamidonate and thirteen patients zoledronic acid. The majority of the ONJ lesions completely healed in 24 patients. Overall, most of the ONJ lesions were associated with dental procedures and pain was the symptom most frequently reported. ConclusionONJ is a serious complication of bisphosphonate therapy. But with active monitoring for ONJ and early input from dental experts, ONJ has been mild to moderate in severity, had minimal impact on overall quality of life and improved or healed in the majority of patients. These results suggest that with proper management, ONJ is a manageable, infrequent complication that may be associated with a reduced SRE (skeletal-related events) risk and improved overall survival. Length of exposure and the probably the type of biphosphonate used appear to be the most important risk factor for this complication. DisclosuresGoldschmidt:Johnson and Johnson: Research Funding, Speakers Bureau.

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) was first reported in the dental literature in 2003. The term was coined to describe a spectrum of dental problems seen in cancer patients treated with high doses of intravenous bisphosphonates for the prevention of skeletal-related events. By consensus, the syndrome is now defined by the presence of exposed bone in the mouth which fails to heal after appropriate intervention over a period of 6 or 8 weeks. It is most common in patients with breast or prostate cancers, or multiple myeloma treated with bisphosphonates, of whom about 5% develop the condition. In patients receiving the much lower drug doses used in osteoporosis, the incidence appears to be approximately 1/100,000 patient-years, probably comparable to that in the general population. It is likely that ONJ results from direct drug toxicity to cells of bone and soft tissue. The bone in ONJ lesions does not appear to be 'frozen' but rather there is very active bone resorption taking place, which is likely to be responsible for the local release at high concentrations of bisphosphonates. Infection probably plays a pivotal role in driving this resorption, so its active management is critical. Obvious abnormalities are apparent with a variety of radiologic modalities, and it is not clear that radiographs are inferior to other approaches. Most authors favor a conservative approach to surgical debridement of the lesions.

Long-Term Follow-Up of Multiple Myeloma (MM) Patients (pts) with Osteonecrosis of the Jaw (ONJ).

Risk factors for ONJ in MM pts include dental extraction, bisphosphonates (BP) use, older age and longer survival. There is also an increased risk of skeletal related events (SRE) in ONJ pts (Badros, JCO 2006). The current study provides long term follow-up data for ONJ pts with regard to ONJ recurrence, SRE and MM status. The study included 97 pts: 60 from Greece and 37 from the US. Pts' characteristics are summarized in the table below. Median follow-up time has not been reached; lower limit of the 95%CI was 3.2 yrs. ONJ resolved in 60 of 97 pts (62%), resolved and recurred in 12 pts (12%), and did not heal over a 9 months period in 25 pts (26%). Dental extraction preceded ONJ in 46 of 97 pts (47%) and was more common in pts with a single episode of ONJ (35 of 60, 58%) than in the recurrent and non-healing pts (11 of 37, 30%) (p-value=0.007). The median number of ONJ episodes in the recurrent group was 3 (range, 2–6); recurrence of ONJ was precipitated by re-initiation of BP and by dental procedures in 5 and 4 pts of 12, respectively. There was a trend toward higher ONJ recurrence rate in the US (8 of 37, 22%) versus the Greek (4 out of 60, 7%) pts (p-value=0.053). Surgery was performed more often in the US than in Greece 17 of 37 (45%) versus 19 of 60 pts (32%). BP reinitiation was more frequent in US 16 of 37 (43%) than in Greece 3 of 60 (5%). Non-healing ONJ lesions were managed with antibiotics; 10 of 25 pts developed fistulas and needed surgery; in 9 pts the lesions remained asymptomatic. Twenty-one ONJ pts had SRE including fractures (ribs, vertebrae and long bones, n=13) and avascular necrosis of the femur (n=8). The rate of MM relapse was higher in pts with recurrent and non-healing ONJ (84%) compared to pts with a single episode (62%) (p-value=0.02). The median OS from diagnosis of MM was 10.8 yrs (95% CI; 9.3 yrs- not reached) and did not differ between pts with single, recurrent/non-healing ONJ (p= 0.2). In summary, pts in whom ONJ followed dental procedures were less likely to have recurrence or non-healing, both, although infrequent, were linked to BP re-challenge, mostly in the setting of relapsed MM. Non-healing ONJ lesions remained stable/asymptomatic without extensive intervention. BP should be discontinuation until ONJ lesions heal. The decision to restart BP should be individualized based on MM-SRE risk.ONJ Pts characteristics and outcomeONJ, n= 97one episode, n=60recurrent, n=12non-healing, n=25age at MM; median (range)60 (26–77)61 (26–77)55 (43–76)61 (36–73)Sex; male/female59/3838/228/413/12Caucasian/AA87/1054/610/223/2Isotype; IgG, A, D, LCH60/20/1/1636/11/1/127/2/0/317/7/0/1MM ttt at ONJ (n=93); none/dex/thal/len/bort22/31/26/6/811/25/16/4/25/1/3/1/16/5/7/1/4MM status at ONJ diagnosis; CR/PR/PD7/54/334/37/173/8/10/9/15BP use; AZ/Z59/3534/2310/215/10Dental extraction463555Restarted BP191162bone complciations211434MM course after ONJ; continous remission/Relapse29/6823/372/104/21MM status at last follow up; CR/PR/PD (died)3/59/35(28)3/35/22(20)0/10/2(2)0/14/11(6)AA, African American; ttt, treatment; CR, complete remission; PR, partial remission; PD, progressive disease; Dex, dexamethasone, thal, thalidomide; Len, lenalidomide; Bort, bortezomib; A, pamidronate; Z zoledronic acid. The Fisher's Exact test was used, all p-values reported are two-sided.

Hyperbaric Oxygen Treatment and Bisphosphonate-Induced Osteonecrosis of the Jaw: A Case Series

Bisphosphonate (BP)-associated osteonecrosis of the jaw (ONJ) is an emerging problem with few therapeutic options. Our pilot study of BP-ONJ investigated a possible role for hyperbaric oxygen (HBO(2)) therapy. A total of 16 patients, ranging in age from 43 to 78 years, with BP-ONJ were treated with adjunctive HBO(2) between July 2003 and April 2006. Staging was based on the size and number of oral lesions. Clinical response after treatment and at distant follow-up; the odds of remission, stabilization, or relapse; and time to failure analysis were calculated. The median time on BP therapy before appearance of ONJ symptoms was 18 months, and that from symptom onset to HBO(2) therapy was 12 months. Fourteen of 16 patients (87.5%) improved in stage. The size and number of ONJ lesions were decreased after HBO(2) therapy (P < .001 and P = .008, respectively; Wilcoxon signed-rank test). Immediately after HBO(2) therapy, 7 of 16 patients (44%) were in remission and 8 (50%) had stabilized; however, stabilization without remission was sustained in only 2 patients. At follow-up, 10 of the patients (62.5%) were still in remission or had stabilized. The 7 patients who continued on BP treatment during HBO(2) therapy had a shorter time to failure (8.5 months; 95% confidence interval [CI] = 7.1 to 9.8) than those who discontinued the drug (20.1 months; 95% CI = 17.5 to 23.9; P = .006 by the log-rank test). Clinical response was not associated with cancer type or malignancy remission status. Adjunctive HBO(2) therapy may benefit patients with BP-ONJ; however, the outcome is improved with cessation of BP administration.