Michael Ehrenfeld

Bisphosphonate-related osteonecrosis of the jaws - Characteristics, risk factors, clinical features, localization and impact on oncological treatment

INTRODUCTIONnOsteonecrosis of the jaw (ONJ) is a serious side-effect of intravenous nitrogen-containing bisphosphonate therapy frequently used in the treatment of malignant diseases. Despite numerous case series published so far studies with detailed investigations into risk factors, the precise localization of ONJ and impact of ONJ on the oncological treatment remain sparse.nnnPATIENTS AND METHODSnThis single-centre study collated medical records (2003-2009) of all patients that suffered from ONJ within the Department of Oral and Maxillofacial Surgery, Ludwig-Maximilians-University of Munich, Germany. In total, 126 patients fulfilled the case criteria of ONJ and were examined clinically. The complete medical history including detailed questionnaires was collected of 66 patients, focussing in particular on the identification of underlying risk factors, clinical features, ONJ localization as well as the impact on the oncological treatment.nnnRESULTSnThe majority of ONJ cases occurred in patients suffering from malignant diseases (n=117; 92.8%), in particular breast cancer (n=57; 45.2%), multiple myeloma (n=37; 29.4%) and prostate cancer (n=13; 10.3%), all received nitrogen-containing bisphosphonates intravenously. ONJ was also diagnosed in 9 patients (7.1%) suffering from osteoporosis or rheumatoid arthritis. The most prevalent clinical feature was exposed necrotic bone (93.9%) in the oral cavity which was accompanied in 78.8% of cases by pain. A predilection for the mandible and in particular for molar and premolar regions in both jaws was shown. Although no recommendation concerning the oncologic treatment was made, the manifestation of ONJ resulted (in a significant proportion of the patients) in a change of medication and schedule. The most frequent co-medications were steroids and anti-angiogenetic drugs, such as thalidomide.nnnDISCUSSIONnThe predilection for mandibular molar and premolar regions, and the infectious conditions that often precede the onset of ONJ support recent pathogenesis theories stating that local inflammation and associated pH-changes may trigger the release and activation of nitrogen-containing bisphosphonates ultimately resulting in necrosis.nnnCONCLUSIONnThe development of ONJ has a multi-factorial aetiology and the clinical presentation can vary markedly. ONJ cannot only impair the quality of life but also the treatment of the underlying disease.

Osteoporosis and bisphosphonates-related osteonecrosis of the jaw: Not just a sporadic coincidence – a multi-centre study

INTRODUCTIONnBisphosphonates (BPs) are powerful drugs that inhibit bone metabolism. Adverse side effects are rare but potentially severe such as bisphosphonate-related osteonecrosis of the jaw (BRONJ). To date, research has primarily focused on the development and progression of BRONJ in cancer patients with bone metastasis, who have received high dosages of BPs intravenously. However, a potential dilemma may arise from a far larger cohort, namely the millions of osteoporosis patients on long-term oral BP therapy.nnnPATIENTS AND METHODSnThis current study assessed 470 cases of BRONJ diagnosed between 2004 and 2008 at eleven different European clinical centres and has resulted in the identification of a considerable cohort of osteoporosis patients suffering from BRONJ. Each patient was clinically examined and a detailed medical history was raised.nnnRESULTSnIn total, 37/470 cases (7.8%) were associated with oral BP therapy due to osteoporosis. The majority (57%) of affected individuals did not have any risk factors for BRONJ as defined by the American Association of Oral and Maxillofacial Surgery. The average duration of BP intake of patients without risk factors was longer and the respective patients were older compared to patients with risk factors, but no statistical significant difference was found. In 78% of patients the duration of oral BP therapy exceeded 3 years prior to BRONJ diagnosis.nnnDISCUSSIONnThe results from this study suggest that the relative frequency of osteoporosis patients on oral BPs suffering from BRONJ is higher than previously reported. There is an urgent need to substantiate epidemiological characteristics of BRONJ in large cohorts of individuals.

Bisphosphonate-Related Osteonecrosis of the Jaw: Is pH the Missing Part in the Pathogenesis Puzzle?

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a side effect of bisphosphonate therapy, primarily diagnosed in patients with cancer and metastatic bone disease and receiving intravenous administrations of nitrogen-containing bisphosphonates. If diagnosis or treatment is delayed, BRONJ can develop to a severe and devastating disease. Numerous studies have focused on BRONJ, with possible pathomechanisms identified to be oversuppression of bone turnover, ischemia due to antiangiogenetic effects, local infections, or soft tissue toxicity. However, the precise pathogenesis largely remains elusive and questions of paramount importance await to be answered, namely 1) Why is only the jaw bone affected? 2) Why and how do the derivatives differ in their potency to induce a BRONJ? and 3) Why and when is BRONJ manifested? The present perspective reflects on existing theories and introduces the hypothesis that local tissue acidosis in the jaw bone offers a conclusive pathogenesis model and may prove to be the missing link in BRONJ.

Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism.

PURPOSEnOsteonecrosis of the jaw has been reported in patients receiving high doses of intravenous nitrogen-containing bisphosphonates (N-BPs) because of malignant disease. The exact pathomechanisms have been elusive and questions of paramount importance remain unanswered. Recent studies have indicated toxic effects of bisphosphonates on different cell types, apart from osteoclast inhibition. Multipotent stem cells play an important role in the processes of wound healing and bone regeneration, which seem to be especially impaired in the jaws of patients receiving high doses of N-BPs. Therefore, the aim of the present study was to investigate the effects of different bisphosphonate derivatives and dose levels combined with varying pH levels on the mesenchymal stem cells in vitro.nnnMATERIALS AND METHODSnThe effect of 2 N-BPs (zoledronate and ibandronate) and 1 non-N-BP (clodronate) on immortalized mesenchymal stem cells was tested at different concentrations, reflecting 1, 3, and 6 months and 1, 3, 5, and 10 years of exposure to standard oncology doses of the 2 N-BPs and equimolar concentrations of clodronate at different pH values (7.4, 7.0, 6.7, and 6.3). Cell viability and activity were analyzed using a WST assay. Cell motility was investigated using scratch wound assays and visualized using time-lapse microscopy.nnnRESULTSnBoth types of bisphosphonates revealed remarkable differences. Zoledronate and ibandronate showed a dose- and pH-dependent cellular toxicity. Increasing concentrations of both N-BPs and an acidic milieu led to a significant decrease in cell viability and activity (P < .01), with more pronounced effects for zoledronate. Equimolar concentrations of clodronate did not affect the cell survival or activity significantly, apart from the effect of pH reduction itself, which was also detectable in the patients in the control group who did not receive bisphosphonates.nnnCONCLUSIONSnOur results have shown that high concentrations of N-BPs and a local acidic milieu, which is commonly present in infections of the jaw, might play a key role in the pathogenesis of osteonecrosis of the jaw in patients receiving high doses of N-BPs for malignant diseases. Also the potency of N-BPs might be different, suggesting a greater risk of osteonecrosis of the jaw with zoledronate.

Fluorescence-Guided Bone Resection in Bisphosphonate-Related Osteonecrosis of the Jaws: First Clinical Results of a Prospective Pilot Study

PURPOSEnSurgical debridement is the therapy of choice in advanced stages of bisphosphonate-related osteonecrosis of the jaws (BRONJ). However, the therapy is currently only loosely standardized because no suitable imaging modalities exist. This study aims to redress this by exploring the suitability and reproducibility of applying a fluorescence-guided bone resection to patients with BRONJ.nnnPATIENTS AND METHODSnThis prospective pilot study comprised 15 patients with 20 BRONJ lesions (only stages II and III) with a history of intravenous bisphosphonate treatment for metastatic bone diseases. Before surgical treatment, each patient received a 10-day administration of doxycycline. Fluorescence-guided resection of necrotic bone was performed by means of a certified fluorescence lamp. Success of the procedure was proclaimed if mucosal closure was observed and symptoms were absent 4 weeks postoperatively.nnnRESULTSnThe 4-week postoperative follow-up identified a mucosal closure in 17 of 20 BRONJ lesions (85%). These patients were free of any symptoms. Failure as defined by mucosal dehiscence and exposed bone was observed in 3 of 20 BRONJ lesions (15%).nnnCONCLUSIONnThe success rate of this surgical regimen of BRONJ was respectable, and thus fluorescence-guided bone resection can be considered an effective treatment for stage II and stage III BRONJ. Furthermore, the reproducibility of the technique offers an opportunity to standardize the surgical therapy. Further studies are called for that compare the fluorescence-guided bone resection with conventional surgical approaches, as well as surgical versus conservative treatment in the early stages (stages 0 and I) of BRONJ.

Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review

The aim of this systematic review was to answer the question: What are the treatments available for bisphosphonate-related osteonecrosis of the jaws (BRONJ) and their outcomes? A literature search of PubMed, Cochrane Library, and Web of Science databases was conducted in accordance with the PRISMA statement, search phrases were (jaw osteonecrosis OR bisphosphonate-related osteonecrosis OR bisphosphonate osteonecrosis) AND (treatment OR outcomes). Ninety-seven articles published between 2003 and February 2014 were reviewed. The studies reported 4879 cases of BRONJ. The mean age of the patients was 66.5 ± 4.7 years. The male to female ratio was 1:2. The mean duration of bisphosphonate (BP) administration was 38.2 ± 15.7 months. The quality of the publications was good, with some moderate and poor. Minimally invasive surgical treatment was the treatment most used. Medical treatment was also used. Adjunctive treatments included laser, growth factors, hyperbaric oxygen and ozone. The articles provided a broad range of outcome variables to assess the treatment of BRONJ and the outcomes of each treatment. Considerable heterogeneity was found regarding study design, sample size, and treatment modalities. Clinical trials with larger samples are required to provide sufficient information for each treatment modality to predict the outcomes of each treatment.

Successful surgical management of osteonecrosis of the jaw due to RANK-ligand inhibitor treatment using fluorescence guided bone resection

Osteonecrosis of the jaw has recently been described in patients receiving subcutaneous administration of RANKL-inhibitors (denosumab). However, due to promising study results, more patients will receive denosumab in order to avoid skeletal complications due to metastatic bone disease and osteoporosis. Therefore, this has the potential to become a comparable challenge to the bisphosphonate induced jaw necrosis in the area of Oral and Maxillofacial Surgery. Indeed, so far no convincing surgical technique has been described to overcome the non-healing mucosal lesions with exposed bone due to RANKL-inhibitor therapy. In this technical note, we report two successful cases of surgical treatment of jaw-bone necrosis under RANKL-inhibitor treatment using fluorescence guided bone resection. In conclusion, the technique is suggested as treatment option for this entity of osteonecrosis of thexa0jaw.

Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: A trigger for BRONJ development?

INTRODUCTIONnScientific debate outlines tooth extraction as a potential trigger for the onset of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Therefore, the aim of this study was to investigate the outcome of tooth extractions in patients receiving bisphosphonate therapy.nnnPATIENTS AND METHODSnA retrospective cohort study was performed on patients with a history of oral or intravenous bisphosphonate administration and tooth extraction between 2007 and 2013 in a single university hospital oral and maxillofacial surgical unit. In all patients, extractions were performed according to the guidelines of the German Society of Oral and Maxillofacial Surgery. The outcome variable was the onset of typical BRONJ signs during postoperative follow-up.nnnRESULTSnIn 72 subjects (53 female, 19 male; mean age 67.5 years) receiving oral (n = 27) and/or intravenous (n = 45) bisphosphonates due to malignant tumor (n = 43) or osteoporosis (n = 29), 216 tooth extractions were performed. The mean duration of intake was 36.2 months. In 67 out of 72 patients (93.1%) and 209 out of the 216 extraction sites the postoperative course was uneventful and the wounds healed without complications. Three of the 72 patients (4.2%) developed osteonecrosis of the jaw in four of the 216 extraction sites (1.9%). Duration and route of administration, oral hygiene and steroid intake were identified as potential risk factors for the development of BRONJ.nnnCONCLUSIONnTooth extraction in patients receiving bisphosphonates can be performed in a safe and predictable way, even in high-risk patients, when performed according to established guidelines. It is not tooth extractions themselves, but rather prevailing infectious conditions that may be a key risk factor for the development of BRONJ.

Incidence of maxillary sinusitis and oro-antral fistulae in bisphosphonate-related osteonecrosis of the jaw.

OBJECTIVEnBisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side-effect of bisphosphonate therapy. In the majority of cases BRONJ occurs in the mandible. As a consequence a detailed investigation of BRONJ of the maxilla and in particular of involvement of the maxillary sinus has largely so far been neglected. The aim of this study was to analyse the frequency of maxillary sinusitis and oro-antral fistulae in BRONJ of the maxilla.nnnSUBJECTS AND METHODSnA retrospective multicentre analysis was carried out in three Departments of Oral and Maxillofacial Surgery focussing on patients suffering from BRONJ in the maxilla. The role of involvement of the maxillary sinus, in particular sinusitis and oro-antral fistula, was analysed.nnnRESULTSnOut of a total of 170 patients suffering from BRONJ 53 cases (31.2%) with involvement of the maxilla were identified. At least one sign of maxillary sinusitis was present in 43.6% (23/53) and an oro-antral fistula in the course of the disease was detected in 35.8% (19/53) of those patients. The mean length of time of bisphosphonate intake was 36.16±16.32 months. Zoledronate was most frequently associated (60.4%) with symptoms, followed by the combination of Zoledronate/Ibandronate (13.2%), and Zoledronate/Pamidronate or Pamidronate alone (both 7.5%).nnnCONCLUSIONnMaxillary sinusitis and oro-antral fistulae are associated with a BRONJ manifestation in the upper jaw in approximately 44%. The involvement of the maxillary sinus should be given special attention and three-dimensional imaging modalities might be necessary, not only to evaluate the extent of necrosis, but also to exclude involvement of the maxillary sinus.

The Use of MMF Screws: Surgical Technique, Indications, Contraindications, and Common Problems in Review of the Literature

Mandibulo-maxillary fixation (MMF) screws are inserted into the bony base of both jaws in the process of fracture realignment and immobilisation. The screw heads act as anchor points to fasten wire loops or rubber bands connecting the mandible to the maxilla. Traditional interdental chain-linked wiring or arch bar techniques provide the anchorage by attached cleats, hooks, or eyelets. In comparison to these tooth-borne appliances MMF screws facilitate and shorten the way to achieve intermaxillary fixation considerably. In addition, MMF screws help to reduce the hazards of glove perforation and wire stick injuries. On the downside, MMF screws are attributed with the risk of tooth root damage and a lack of versatility beyond the pure maintenance of occlusion such as stabilizing loose teeth or splinting fragments of the alveolar process. The surgical technique of MMF screws as well as the pros and cons of the clinical application are reviewed. The adequate screw placement to prevent serious tooth root injuries is still an issue to rethink and modify conceptual guidelines.