Osteonecrosis of the Jaw in Patients With Metastatic Renal Cell Cancer Treated With Bisphosphonates and Targeted Agents: Results of an Italian Multicenter Study and Review of the Literature.

Osteonecrosis of the jaw (ONJ) associated with the use of bisphosphonates has been rarely reported in metastatic renal cell cancer (RCC) patients. Since the introduction of combined therapies consisting of nitrogen-containing bisphosphonates (NBPs) and targeted agents, an increasing number of RCC patients were reported to develop ONJ, suggesting that therapeutic angiogenesis suppression might increase the risk of ONJ in NBPs users. We performed a multicenter retrospective study and reviewed literature data to assess the occurrence and to investigate the nature of ONJ in RCC patients taking NBPs and targeted agents. Nine Italian Centers contributed to the data collection. Patients with exposed and nonexposed ONJ were eligible for the study if they had been taking NBPs and were receiving targeted agents at the time of ONJ diagnosis. Forty-four RCC patients were studied. Patients were mostly male (82%), with a median age of 63 years (range, 45-85 years). Zoledronic acid (93%) and sunitinib (80%) were the most frequently used NBP and antiangiogenic agent, respectively. Other agents included Pamidronate, ibandronate, sorafenib, bevacizumab, mammalian target of rapamycin inhibitors. Forty-nine sites of ONJ were encountered, with the mandible being the preferred site of ONJ (52%); both jaws were affected in 5 cases (12%). The most common precipitating event was dental/periodontal infection (34%), followed by tooth extraction (30%). Oral triggers of ONJ were missing in 10 cases (23%). This unexpectedly high number of ONJ cases, in comparison with literature data, suggests that frequency of ONJ in RCC patients might be largely underestimated and suggests a potential role for targeted agents in the incremental risk of ONJ.

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.

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.

Effects of bisphosphonate treatment on DNA methylation in osteonecrosis of the jaw.

Bisphosphonates are used in the treatment of hypocalcaemia, mainly in cancer and osteoporosis. Some patients experience adverse events, such as BP-related osteonecrosis of the jaw (BRONJ). DNA methylation plays a key role in gene regulation in many tissues, but its involvement in bone homeostasis is not well characterized, and no information is available regarding altered methylation in BRONJ. Using the Illumina Infinium HumanMethylation27 BeadChip assay, we performed an epigenome-wide association study in peripheral blood samples from 68 patients treated with nitrogenous BP, including 35 with BRONJ. Analysis of the estimated cumulative BP exposure distribution indicated that the exposure of the case group to BP was slightly higher than that of the control group; more severely affected cases (i.e., with BRONJ in both mandible and maxilla) were significantly more exposed to BP than were those with BRONJ only in the mandible or maxilla (one-sided Wilcoxon rank sum test, p=0.002). Logistic regression analysis confirmed the positive association between cumulative bisphosphonates exposure and risk of BRONJ (OR 1.015 per mg of cumulative exposure, 95% CI 1.004-1.032, p=0.036). Although no statistically significant differences were observed between case and control groups, methylation levels of probes mapping on three genes, ERCC8, LEPREL1 and SDC2, were strongly associated with cumulative BP exposure levels (p<1.31E-007). Enrichment analysis, combining differentially methylated genes with genes involved in the mevalonate pathway, showed that BP treatment can affect the methylation pattern of genes involved in extracellular matrix organization and inflammatory responses, leading to more frequent adverse effects such as BRONJ. Differences in DNA methylation induced by BP treatment could be involved in the pathogenesis of the bone lesion.

Decreasing frequency of osteonecrosis of the jaw in cancer and myeloma patients treated with bisphosphonates: the experience of the oncology network of piedmont and aosta valley (north-Western Italy).

Background. Data concerning frequency of Osteonecrosis of Jaws (ONJ) are mostly based on single center experiences. Patients and Methods. Since 2005 a multidisciplinary study group collected data of cases of ONJ in patients treated with Bisphosphonates (BP) and observed in oncology and hematology centers of a regional network. Results. By December 2008, 221 cases were registered. We report details of 200 cases, identified after cross-checking reports from centres of medical oncology, haematology, and oral care. Primary neoplasm was breast cancer (39%), myeloma (32%), prostate cancer (16%), and other types of cancer (8%). In about 50% of the cases a history of dental extraction was present. Zoledronic acid was administered (alone or with other BP) to 178 patients (89%). Median time from first infusion to ONJ diagnosis was 21.0 (zoledronic acid only) and 39.0 months (pamidronate only). The number of ONJ cases per year was 3 in 2003, 21 in 2004, 58 in 2005, 60 in 2006, 37 in 2007, and 21 in 2008. Conclusion. The number of new ONJ cases in cancer and myeloma patients increased until 2006 and then reduced. The possible reasons of this trend (introduction of zoledronic acid; increase of ONJ awareness; diffusion of preventive dental measures; late modifications of BP prescription) are herein discussed.

Tooth extractions in intravenous bisphosphonate-treated patients: a refined protocol.

PURPOSE: The aim of this prospective hospital-based study was to refine a surgical protocol for tooth extractions in patients with a history of intravenous use of a potent bisphosphonate by modifying a previously reported protocol to produce a significantly shortened operating time. PATIENTS AND METHODS: Prospective patients with a follow-up of at least 4 months were included. Tooth extractions were performed without a vestibular split-thickness flap; healing was stimulated by filling the extraction site with autologous plasma rich in growth factors (PRGF System, BTI Biotechnology Institute, Vitoria, Spain). Local and systemic infection control was obtained with dental hygiene and antibiotic therapy. RESULTS: Sixty-three patients participated in the study. Two hundred two tooth extractions were performed. Differences between the present and previous protocols (the previous protocol used a vestibular flap) were analyzed and the surgical time proved significantly shorter for the present approach (P = .00). CONCLUSIONS: The proposed surgical protocol appears to be a better choice for patients treated with intravenous bisphosphonates who need tooth extraction, because it seems to be faster and simpler than the previously reported successful protocol.

Oral mucosa produces cytokines and factors influencing osteoclast activity and endothelial cell proliferation, in patients with osteonecrosis of jaw after treatment with zoledronic acid.

OBJECTIVES: The intravenous injection of bisphosphonates, currently used as treatment for osteoporosis, bone Paget's disease, multiple myeloma, or bone metastases, can cause jaw bone necrosis especially in consequence of trauma. The present research aimed to clarify the mechanisms underlying bone necrosis, exploring involvement of the oral mucosa "in vivo." PATIENTS AND METHODS: Specimens of oral mucosa were removed from bisphosphonate-treated patients with or without jaw bone necrosis. In mucosa specimens, expression was evaluated of: cytokines involved in the inflammatory process, factors involved in osteoclast activity, i.e., receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin, a factor involved in cell proliferation, namely hydroxymethylglutaryl coenzyme A reductase, and a factor involved in angiogenesis, namely vascular endothelial growth factor (VEGF). RESULTS: Interleukin (IL)-6 and the RANK/osteoprotegerin ratio were significantly elevated in mucosa from patients with versus without jaw necrosis, whereas hydroxymethylglutaryl coenzyme A reductase and VEGF were significantly decreased. CONCLUSIONS: Our results suggest that mucosa, stimulated by bisphosphonate released from the bone, can contribute to the development of jaw necrosis, reducing VEGF, and producing IL-6 in consequence of hydroxymethylglutaryl coenzyme A reductase reduction. In turn, IL-6 stimulates osteoclast activity, as shown by the increased RANKL/osteoprotegerin ratio. CLINICAL RELEVANCE: The results of this study suggest the importance of evaluating during bisphosphonate treatment the production of IL-6, RANKL, osteoprotegerin, and VEGF, in order to monitor the jaw osteonecrosis onset. To avoid repeated mucosa excisions, the determination of these factors could be carried out in crevicular fluid.

Resective surgical approach shows a high performance in the management of advanced cases of bisphosphonate-related osteonecrosis of the jaws: a retrospective survey of 347 cases.

PURPOSE: The aim of this study was to evaluate the results of the surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in a large cohort. MATERIALS AND METHODS: A retrospective cohort multicenter study was designed. Patients were enrolled if they were diagnosed with BRONJ and received operative treatment. Data on demographic, health status, perioperative, and surgical factors were collected retrospectively. The primary outcome variable was a change in BRONJ staging (improvement, worsening, or no change). Interventions were grouped by local debridement and resective surgery. Data were collected for other variables as cofactors. Univariate analysis and logistic regressions were then performed. RESULTS: Of the 347 BRONJ-affected subjects, 59% showed improvement, 30% showed no change, and 11% showed worsening. Improvement was observed in 49% of cases treated with local debridement and 68% of cases treated with resective surgery. Multivariate analysis indicated that maxillary location, resective surgery, and no additional corticosteroid treatment were associated with a positive outcome. CONCLUSIONS: Surgical treatment of BRONJ appeared to be more effective when resective procedures were performed. Nonetheless, other factors, such as the absence of symptoms and the types of drug administration, should be taken into account before clinical decisions are made.

Platelet-rich therapies in the treatment of intravenous bisphosphonate-related osteonecrosis of the jaw: a report of 32 cases.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an important complication in cancer patients taking intravenous BPs (BPs). In most cases, BRONJ is associated with an oral surgery procedure involving jaw bone. Currently, BRONJ management remains controversial, and there is no definitive standard of care for this disease. In fact, several articles in the recent literature discuss treatments that range from topical to surgical treatment, without definitive conclusion about treatment. A clinical study was conducted on 32 patients treated with i.v BPs for oncologic pathologies affected by BRONJ. The patients were treated by resection of the necrotic bone with primary closure of the mucosa over the bony defect using plasma rich in growth factors (PRGF). Orthopanoramic and computed tomography were performed before and after surgery. No intraoperative complications were observed, and all 32 cases were treated successfully. Our data on the use of PRGF demonstrate positive results for this surgical treatment. PRGF may enhance vascularization and regeneration of osseous and epithelial tissues.

Initial experience on the outcome of teeth extractions in intravenous bisphosphonate-treated patients: a cautionary report.

PURPOSE: More cases of osteonecrosis of the jaws in patients treated with intravenous bisphosphonates have been reported. The aim of this prospective hospital-based study was to detail a surgical protocol for teeth extraction in such patients. PATIENTS AND METHODS: Prospective patients with a follow-up of at least 4 months were included. A surgical procedure using an ultrasonic surgical apparatus (Mectron Piezosurgery Device, Mectron Medical Technology, Carasco, Italy) was undertaken. Healing was stimulated by filling the extraction site with autologous plasma rich in growth factors (PRGF System, BTI Biotechnology Institute, Vitoria, Spain). Local and systemic infection controls were also obtained with antibiotic therapy. RESULTS: Sixty-four patients took part in the study. Two hundred twenty teeth extractions were performed in a surgical setting. Bisphosphonate-related osteonecrosis of the jaw occurred in 5 postextraction sites (2.27%); no statistical differences could be reported regarding age, gender, duration of bisphosphonate treatment, concomitant corticosteroid therapy, mean surgical time, and patients' underlying diseases. In contrast, the mandible appeared to be at greater risk than the maxilla to develop bisphosphonate-related osteonecrosis of the jaw (P = .0342). CONCLUSIONS: Even with many limitations, the proposed surgical protocol appears to be a possible choice for patients treated with intravenous bisphosphonates who need teeth extraction. Further prospective, possibly randomized studies are necessary to determine if this statement would be the same with larger patient samples in different clinical settings.

Treatment outcomes in patients with bisphosphonate-related osteonecrosis of the jaws: a prospective study.

OBJECTIVES: The aim of this study was to evaluate the 2-year success rate of management of patients with bisphosphonate-related osteonecrosis of the jaws (BRONJ). STUDY DESIGN: A prospective study was performed. Positive outcome variables were the resolution of symptoms and the status of the mucosa. RESULTS: A total of 37 patients are described. The precipitating event was a dental extraction in 22 cases (59.5%). Thirteen patients (35.1%) underwent surgery, and 24 (64.9%) underwent antimicrobial therapy alone. After 2 years, 20 patients (54.1%) presented with soft tissue closure over previously exposed bone, and there were no statistical differences in gender, age, bisphosphonate treatment, or treatment modalities. Spontaneous lesions seemed to have a worse prognosis (P = .001). CONCLUSIONS: Initial antimicrobial treatment, and later surgery for unresponsive patients, might be a feasible treatment modality for BRONJ. Because these results are not conclusive, it would be very interesting to know if this statement would be the same with a greater number of patients.

Effect of low-level laser irradiation on bisphosphonate-induced osteonecrosis of the jaws: preliminary results of a prospective study.

OBJECTIVE: The aim of this study was to detail the clinical efficacy of low-level laser therapy (LLLT) for the management of bisphosphonate-induced osteonecrosis of the jaws (ONJ-BP). BACKGROUND: ONJ-BP is the correct term, recently emerged, to describe a significant complication in a subset of patients receiving drugs such as zoledronic acid, pamidronate, and alendronate. No definitive standard of care has been set for ONJ-BP and no definitively agreed guidelines have been provided. There is currently no consensus on the correct approach to the issue. MATERIALS AND METHODS: The investigators studied a prospective cohort of 20 patients affected by ONJ-BP, who received biostimulation with a pulsed diode laser (GaAs). Patients were exposed to a 904-nm infrared laser (50 kHz, 28.4 J/cm(2) energy density, 40% duty cycle, spot size 0.8 cm). Outcome variables were the size of lesions, edema, visual analogue score of pain, presence of pus, fistulas, and halitosis. Preoperative results were compared with the postoperative outcome and statistically evaluated. RESULTS: Four weeks after LLLT, a statistically significant difference was observed for reported pain (p = 0.0001), clinical size (p = 0.0034), edema (p = 0.0005), and presence of pus and fistulas (p = 0.0078 and p = 0.03, respectively). CONCLUSION: This study suggests that LLLT would appear to be a promising modality of treatment for patients with ONJ-BP, providing that clinical efficacy is safe and well tolerated, especially by those patients who require conservative treatment. Of course, this needs to be addressed further in larger and randomly controlled studies in different clinical settings.

Computerized tomographic findings in bisphosphonate-associated osteonecrosis of the jaw in patients with cancer.

OBJECTIVES: To study bisphosphonate-associated osteonecrosis of the jaw with respect to radiographic, demographic, and clinical features. STUDY DESIGN: Thirty-two patients with painful exposed bone in the jaws subsequent to treatment with bisphosphonates for various neoplastic diseases were examined with both dental panoramic radiograph and multislice spiral computerized tomography (CT). Each case was assessed for the following radiologic signs: structural alteration of trabecular bone, cortical bone erosion, osteosclerosis, small sequestrum, extensive sequestrum, and presence of periosteal new bone. The McNemar, chi2, and Kruskall-Wallis tests were performed to analyze the association between radiologic signs, demographic data, clinical aspects of the lesion, and type and duration of bisphosphonate therapy. Hierarchical cluster analysis was used to group patients into categories on the basis of CT signs and dental panoramic radiograph signs. The agreement between CT and dental panoramic radiograph clusters was analyzed by kappa index. RESULTS: Dental panoramic radiograph proved positive for features of osteonecrosis in 18 cases and CT in 30. Computerized tomography was far superior to dental panoramic radiograph in detecting all the radiologic signs. The cluster analysis applied to CT signs showed a classification of the 32 patients in 4 categories characterized by an increasing number of signs coherent with the clinical extension of the lesions. Structural alteration of trabecular bone and cortical bone erosion, a constant finding in the 30 positive CTs, could be sometimes differentiated only with difficulty from those due to recent extraction. Dental panoramic radiograph missed the correct diagnosis of sequestration in 15 cases. Intense periosteal reaction was often found. The most extensive maxillary lesions were associated with new bone formation in Schneider mucous membrane, never described previously, and oroantral communications. CONCLUSIONS: Dental panoramic radiograph were found to be of limited use in assessing bisphosphonate-associated osteonecrosis of the jaw in patients for whom CT imaging was subsequently ordered.