Bisphosphonate-related osteonecrosis of the jaw: from the sine qua non condition of bone exposure to a non-exposed BRONJ entity.

The present work aimed to review the literature focusing on the diagnostic criteria for bisphosphonate-related osteonecrosis of the jaw (BRONJ) and its implications regarding the management of the disease. Since the report of the first cases, BRONJ concepts, diagnostic criteria and guidelines have been changed. The presence of bone exposure in the oral cavity was at first a sine qua non condition for diagnosis. However, it seems that the great concern now is the possibility of occurrence of BRONJ without this feature. Some authors warn that the bone exposure criterion leads to late diagnosis and poor response to treatment. Meanwhile, some radiographic features, such as bone sclerosis, have been postulated as early signs of the disease. Criticisms have also been raised about the clinical staging system of BRONJ. While there is no consensus on the subject, common sense recommends treating symptomatic patients taking bisphosphonate as having BRONJ despite the absence of bone exposure; and asymptomatic patients must be kept under dental follow-up, since all of them are at risk for BRONJ.

Concept, diagnosis and classification of bisphosphonate-associated osteonecrosis of the jaws. A review of the literature

BACKGROUND: Bisphosphonates (BPs) and other antiresorptive agents such as denosumab are widely prescribed for the treatment of osteoporosis and are also used in patients with multiple myeloma and metastatic breast or prostate cancer for avoiding bone reabsorption and fractures that result in increased morbidity-mortality among such individuals. MATERIAL AND METHODS: We made a bibliographic search to analyze the concept, diagnosis and the different classifications for bisphosphonate-associated osteonecrosis of the jaws. RESULTS: Osteonecrosis of the jaws (ONJ) is an important complication of exposure to BPs or other antiresorptive agents, and although its prevalence is low, it can pose management problems. The definition, diagnosis and classification of osteonecrosis have evolved since Marx reported the first cases in 2003. CONCLUSIONS: The present study offers a literature review and update on the existing diagnostic methods and classification of the disorder, with a view to facilitating earlier and more effective treatment

Disease Stage and Mode of Therapy Are Important Determinants of Treatment Outcomes for Medication-Related Osteonecrosis of the Jaw.

PURPOSE: The treatment of patients with medication-related osteonecrosis of the jaw (MRONJ) is challenging. The purpose of the present study was to estimate the frequency and identify the factors associated with clinical improvement during treatment. PATIENTS AND METHODS: We designed and implemented a retrospective cohort study and enrolled a sample of subjects diagnosed with MRONJ between 2004 and 2015. The primary predictor variables were a set of heterogeneous variables grouped into the following categories: demographic (age and gender) and clinical (location of necrosis, therapy duration, medication type, disease stage, and treatment type). The primary outcome variable was the treatment outcome, defined as stable or worse and improved or healed. The descriptive, bivariate, and multiple logistic statistics were computed, and statistical significance was defined as P < .05. RESULTS: The sample included 337 subjects with a mean age of 68.9 years. Of the 337 subjects, 256 were women (76%). A total of 143 patients (42.2%) experienced spontaneous necrosis. Twenty-four (7.1%) had had exposure to targeted antiangiogenic agents. Those with stage 1 or 2 disease were more likely to have better outcomes than those with stage 3 disease (stage 1, adjusted odds ratio [OR] 3.4, P = .005; stage 2, adjusted OR 2.2, P = .03). Treatment type was a significant variable. Subjects undergoing surgery were 28 times more likely to have a positive outcome than those receiving nonoperative therapy (adjusted OR 28.7, P < .0001). CONCLUSIONS: Subjects with MRONJ who presented with less severe disease or who underwent operative treatment were most likely to have improvement or complete healing of their MRONJ-related lesions.

Sclerosis in bisphosphonate-related osteonecrosis of the jaws and its correlation with the clinical stages: study of 43 cases.

We analysed the degree of sclerosis in the different stages of bisphosphonate-related osteonecrosis of the jaws (BRONJ) and studied the relation between the grade of sclerosis, the clinical symptoms, and the depth of lucency. We compared 43 patients with mandibular BRONJ with a control group of 40 cases with no bony lesions. The presence of sclerotic bone, cortical irregularities, radiolucency, fragmentation or sequestration, periostitis, and narrowing of the mandibular canal were studied from computed tomographic (CT) scans using the program ImageJ 1.47v (National Institute of Health, Bethesda, USA) to measure the radiolucency, width of the cortices, and degree of sclerosis. Patients with BRONJ had more severe sclerosis than controls (p<0.01). There was also a significant difference among the different stages of BRONJ, with the highest values found in stage III (p=0.02). The degree of sclerosis differed according to sex, type of bisphosphonate, and the clinical characteristics such as pain, or suppuration, but not significantly so (p>0.05). We conclude that the degree of sclerosis increases with the clinical stage of BRONJ, and is correlated with the depth of lucency.

Up to a quarter of patients with osteonecrosis of the jaw associated with antiresorptive agents remain undiagnosed.

Recent data suggest that the traditional definition of bisphosphonate-associated osteonecrosis of the jaw (ONJ) may exclude patients who present with the non-exposed variant of the condition. To test the hypothesis that a proportion of patients with ONJ remain undiagnosed because their symptoms do not conform to the traditional case definition, we did a secondary analysis of data from MISSION (Multicentre study on phenotype, definition and classification of osteonecrosis of the jaws associated with bisphosphonates), a cross-sectional study of a large population of patients with bisphosphonate-associated ONJ who were recruited in 13 European centres. Patients with exposed and non-exposed ONJ were included. The main aim was to quantify the proportion of those who, according to the traditional case definition, would not be diagnosed with ONJ because they had no exposed necrotic bone. Data analysis included descriptive statistics, median regression, and Fisher's exact test. A total of 886 consecutive patients were recruited and 799 were studied after data cleaning (removal or correction of inaccurate data). Of these, 607 (76%) were diagnosed according to the traditional definition. Diagnosis in the remaining 192 (24%) could not be adjudicated, as they had several abnormal features relating to the jaws but no visible necrotic bone. The groups were similar for most of the phenotypic variables tested. To our knowledge this is the first study in a large population that shows that use of the traditional definition may result in one quarter of patients remaining undiagnosed. Those not considered to have ONJ had the non-exposed variant. These findings show the importance of adding this description to the traditional case definition.

Pedicled buccal fat pad flap as a reliable surgical strategy for the treatment of medication-related osteonecrosis of the jaw.

PURPOSE: The purpose of this study was to evaluate the coverage of the pedicled buccal fat pad flap (PBFP) and the long-term results of this treatment in patients with medication-related osteonecrosis of the jaw (MRONJ). PATIENTS AND METHODS: Ten patients (2 men and 8 women; average age, 72.9 yr old) diagnosed with MRONJ were selected. Patients were treated with a PBFP. Data from patients regarding MRONJ stage, defect size, bone exposure after surgery, operation time, admission period, duration of antibiotic therapy, recurrence of disease, and postoperative complications were analyzed retrospectively. RESULTS: Six patients were diagnosed with MRONJ stage 2, and 4 patients were diagnosed with MRONJ stage 3. The maximum defect in the study was 62 × 18 mm. Among the 10 patients, there was only 1 bony exposure, which occurred on postoperative day 2 after receiving the PBFP. This exposure might have been due to an incomplete resection of the affected bone. There were no severe donor site morbidities, and all patients showed satisfactory healing without incident. CONCLUSIONS: According to this evaluation, the PBFP effectively covered a relatively large surgical defect. Complications were minimal, and there was no recurrence of bony exposure during follow-up. In conclusion, using the PBFP was a reliable treatment option for the management of denuded bone in patients with MRONJ.

Bisphosphonate-related osteonecrosis of the jaw: what we have learned.

Bisphosphonate related osteonecrosis of the jaws (BRONJ) is an entity that has become prevalent upon the dental and medical community for more than 10 years. This entity is unfortunate because both oral and intravenous nitrogen containing bisphosphonates have beneficial effects for patients for certain conditions. The exact pathology of BRONJ has yet to be determined, although many hypotheses have been put forth. Since its prevalence, a clinical staging system has been developed and radiological findings have been described. BRONJ can be prevented if oral healthcare is undertaken before the start of bisphosphonate therapy or after a short time from the start of their use. However, after BRONJ has developed in patients, a myriad of treatments have been proposed that may help these patients.

Leucocyte-rich and platelet-rich fibrin for the treatment of bisphosphonate-related osteonecrosis of the jaw: a prospective feasibility study.

Our aim was to assess the feasibility of using leucocyte-rich and platelet-rich fibrin (L-PRF) for the treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in a single group study. After treatment with L-PRF, the response of each patient was recorded 1 month and 4 months postoperatively. Further assessments were made of the site, stage, concentration of c-terminal crosslinked telopepide of type 1 collagen, and actinomycosis. Among the total of 34 patients, 26 (77%) showed complete resolution, 6 (18%) had delayed resolution, and 2 (6%) showed no resolution. There was a significant association between the response to treatment and the stage of BRONJ (p=0.002) but no other significant associations were detected. This study has shown that it is feasible to use L-PRF for the treatment of BRONJ, but the effectiveness cannot be judged with this study design. Randomised prospective trials are needed to confirm this.

Staging of osteonecrosis of the jaw requires computed tomography for accurate definition of the extent of bony disease.

Management of osteonecrosis of the jaw associated with antiresorptive agents is challenging, and outcomes are unpredictable. The severity of disease is the main guide to management, and can help to predict prognosis. Most available staging systems for osteonecrosis, including the widely-used American Association of Oral and Maxillofacial Surgeons (AAOMS) system, classify severity on the basis of clinical and radiographic findings. However, clinical inspection and radiography are limited in their ability to identify the extent of necrotic bone disease compared with computed tomography (CT). We have organised a large multicentre retrospective study (known as MISSION) to investigate the agreement between the AAOMS staging system and the extent of osteonecrosis of the jaw (focal compared with diffuse involvement of bone) as detected on CT. We studied 799 patients with detailed clinical phenotyping who had CT images taken. Features of diffuse bone disease were identified on CT within all AAOMS stages (20%, 8%, 48%, and 24% of patients in stages 0, 1, 2, and 3, respectively). Of the patients classified as stage 0, 110/192 (57%) had diffuse disease on CT, and about 1 in 3 with CT evidence of diffuse bone disease was misclassified by the AAOMS system as having stages 0 and 1 osteonecrosis. In addition, more than a third of patients with AAOMS stage 2 (142/405, 35%) had focal bone disease on CT. We conclude that the AAOMS staging system does not correctly identify the extent of bony disease in patients with osteonecrosis of the jaw.

Outcomes of osseous free flap reconstruction in stage III bisphosphonate-related osteonecrosis of the jaw: systematic review and a new case series.

INTRODUCTION: There is currently no gold standard for the treatment of Stage III bisphosphonate-related osteonecrosis of the jaw (BRONJ). The question remains whether osseous reconstruction can offer an additional gain in outcome given the theoretical risk of non-union at the resection margins and recurrence in the osseous free flap. The objective was to conduct a systematic review of articles describing outcomes of osseous microsurgical reconstruction in cases of BRONJ with a minimum follow-up of 12 months, and to present the long-term outcomes of a new case series of three patients. MATERIAL AND METHODS: A multi-database QUORUM-based single-reviewer systematic review identified eight papers that fulfilled the selection criteria. There are only case series and case reports available (Level 4 of the Oxford Evidence-based medicine scale). A total of 31 patients were analysed including the cases described in this article. CONCLUSION: The limited overall rate of non-union at the resection margins and the 6.5% recurrence rate of BRONJ in the transplant counters the theoretical objections and advocates for considering osseous free flap reconstruction in the treatment of refractory BRONJ Stage III lesions. However, additional data derived from larger case series or case-control studies are imperative to support this hypothesis.

A simple evaluation method for early detection of bisphosphonate-related osteonecrosis of the mandible using computed tomography.

OBJECTIVES: The aim of this study was to establish a simple method for the early detection of bisphosphonate-related osteonecrosis of the jaw (BRONJ) using computed tomography (CT). MATERIALS AND METHODS: CT images of the mandible were obtained from a total of 20 patients with BRONJ and 20 control subjects. BRONJ was classified into 2 groups, with bone exposure (Stage 1-3 BRONJ) or without (Stage 0 BRONJ). In each patient, 15 transaxial CT images were selected and 30 configured regions of interest (ROI) were identified. The ANOVA test was applied to test the relationship between the severity of systemic risk factors. RESULTS: Regarding the local status of the mandible, significant differences were observed among the Stage 0 BRONJ, Stage 1-3 BRONJ, non-BRONJ and control groups in the cancellous bone CT radiodensity values, but there were no significant differences between the Stage 0 and Stage 1-3 BRONJ groups. In the cortical bone widths, significant differences were observed only between BRONJ and the controls. CONCLUSIONS: Measuring cancellous bone CT radiodensity value has the potential to be a simple and quantitative method to detect the early stages of BRONJ.

Comparison of nonexposed and exposed bisphosphonate-induced osteonecrosis of the jaws: a retrospective analysis from the Copenhagen cohort and a proposal for an updated classification system.

OBJECTIVE: Nonexposed osteonecrosis of the jaws (NE-ONJ) does not fit into the current definition of osteonecrosis, which requires exposed bone. A modification of the classification of bisphosphonate-induced osteonecrosis of the jaws (ONJ) is proposed. This study aimed to test proposed criteria for NE-ONJ and compare NE-ONJ with exposed ONJ (E-ONJ) in a retrospective analysis. STUDY DESIGN: In 102 patients with E-ONJ diagnosed according to Ruggiero et al. (2006, 2009), criteria for NE-ONJ were developed. Subgroups of NE-ONJ and E-ONJ were tested against each other using nonparametric and parametric statistics. RESULTS: Among 102 patients with ONJ, 14 had NE-ONJ and 88 had E-ONJ. NE-ONJ and E-ONJ were similar in all important data (P > .05) except bone exposure. CONCLUSIONS: NE-ONJ belongs to the same disease condition as E-ONJ. NE-ONJ may be otherwise classified as ONJ stage 1, 2, or 3 and is different from ONJ stage 0. We propose to include the criteria for NE-ONJ into the classification.

Long-term success of surgery in bisphosphonate-related osteonecrosis of the jaws (BRONJs).

OBJECTIVES: Bisphosphonates are associated with osteonecrosis of the jaw. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) may be treated conservatively or by surgery. PATIENTS AND METHODS: 108 patients underwent surgery and 88 patients were followed for a mean period of 337 days. Age, gender, dental procedures, underlying disease, and the role of bisphosphonate treatment in the success of surgery were evaluated retrospectively. RESULTS: Surgical treatment improved the stage distribution from 19% stage I, 56% stage II and 25% stage III to 59% intact mucosa, 19% stage I and 13% stage II and 8% stage III. The improvement in the stage of disease achieved by surgery was statistically significant. Further relevant parameters that favor a positive outcome of surgery were the event triggering the outbreak of BRONJ (p=0.05) and the underlying disease (p=0.05). BRONJ in the maxilla necessitated repeat surgery significantly earlier than did BRONJ in the mandible (p=0.03). CONCLUSION: Effective surgery might improve the outcome of BRONJ, although prevention still is the most important aspect of this condition.

Bisphosphonate-related osteonecrosis of the jaws: study of the staging system in a series of clinical cases.

OBJECTIVE: The aim of this study was to validate the classification of bisphosphonate-related osteonecrosis of the jaws (BRONJ) published in 2009(17) in a series of cases. MATERIAL AND METHODS: This retrospective clinical study included a series of 102 cases (81%) of intravenous BRONJ (iBRONJ, group 1) and 24 cases (19%) of oral BRONJ (oBRONJ, group 2). We recorded all patients' symptoms and clinical findings and classified each patient into a BRONJ stage (0-3; stage 0=non-exposed BRONJ). RESULTS: Most BRONJ cases (n=120, 95.2%) could be classified according to the proposed stages. Exposed necrotic areas of bone were more prevalent in group 1 than in group 2 (p<0.05). In contrast, we observed more BRONJ cases without areas of exposed bone in group 2 (n=12, 50%) than in group 1 (n=14, 13.7%; p<0.05). We could not assign six cases to any of the proposed stages. These cases had no areas of exposed necrotic bone, but had mandibular fractures, extra-oral fistula or affected maxillary sinuses. CONCLUSIONS: In our series, iBRONJ cases showed more advanced stages of BRONJ than did oBRONJ cases. We found few cases that could not be classified into any proposed stage because they had findings associated with stages 0 and 3 but lacked exposed necrotic bone.

A current update on osteonecrosis of the jaw and bisphosphonates.

Bisphosphonates are effective drugs used to treat important medical conditions affecting the skeleton, such as malignancy and osteoporosis. Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is a rare but painful condition that can affect quality of life. Healthcare professionals need to be aware of this potential side-effect of bisphosphonates, as well as ways to minimize its occurrence.