Pathogenesis Of Osteonecrosis Of The Jaw Research Articles

Serum biomarkers for bisphosphonate-related osteonecrosis of the jaw: a prospective clinical study.

Bisphosphonate-related osteonecrosis of the jaw (ONJ) is an adverse effect of long-term bisphosphonate therapy. This study aimed to identify bone biomarkers for ONJ risk assessment and diagnosis. This prospective study included patients with histories of bisphosphonate therapy without current ONJ who were in need of dentoalveolar surgery of the jaw area. Serum levels of 12 possible bone markers, selected based on their involvement in ONJ pathogenesis, were compared between ONJ and control groups before dentoalveolar surgery (T0), at 8 postoperative weeks (T1), and at 4months after diagnosis(T2). Seventy-six patients who met the inclusion criteria were included in the study; 33 were assigned to the ONJ group, and 43 patients without ONJ signs or symptoms after dentoalveolar surgery were assigned to the control group. In the ONJ group, at both T0 and T1, the mean tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) levels were significantly lower and the mean Dickkopf-related protein 1 (DKK1) levels were significantly higher than the corresponding values for the control group. Linear mixed model analysis revealed significant group effects over time for serum TRACP 5b and DKK1 after adjusting for demographic, pharmacological, and diagnostic variables. Lower serum levels of TRACP 5b under a specified cut-off value (≤ 2.899 U/L) at T0 indicated a 20.40-fold increased risk of ONJ development. Patients with abnormally low serum levels of TRACP 5b and high serum levels of DKK1 should be monitored closely before and after dentoalveolar surgery for the prevention and early diagnosis of ONJ.

From Osteoclast Differentiation to Osteonecrosis of the Jaw: Molecular and Clinical Insights.

Bone physiology relies on the delicate balance between resorption and formation of its tissue. Bone resorption depends on a process called osteoclastogenesis in which bone-resorbing cells, i.e., osteoclasts, are produced by the differentiation of more undifferentiated progenitors and precursors. This process is governed by two main factors, monocyte-colony stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL). While the former exerts a proliferating effect on progenitors/precursors, the latter triggers a differentiation effect on more mature cells of the same lineage. Bone homeostasis requires a perfect space–time coordination of the involved signals. When osteoclastogenesis is poorly balanced with the differentiation of the bone forming counterparts, i.e., osteoblasts, physiological bone remodelling can turn into a pathological state, causing the systematic disruption of bone tissue which results in osteopenia or osteolysis. Examples of these conditions are represented by osteoporosis, Paget’s disease, bone metastasis, and multiple myeloma. Therefore, drugs targeting osteoclastogenesis, such as bisphosphonates and an anti-RANKL monoclonal antibody, have been developed and are currently used in the treatment of such diseases. Despite their demonstrated therapeutic efficacy, these agents are unfortunately not devoid of side effects. In this regard, a condition called osteonecrosis of the jaw (ONJ) has been recently correlated with anti-resorptive therapy. In this review we will address the involvement of osteoclasts and osteoclast-related factors in the pathogenesis of ONJ. It is to be hoped that a better understanding of the biological mechanisms underlying bone remodelling will help in the design a medical therapeutic approach for ONJ as an alternative to surgical procedures.

Current Understanding of the Pathophysiology of Osteonecrosis of the Jaw.

Osteonecrosis of the jaw (ONJ) is a rare and severe necrotic bone disease reflecting a compromise in the body's osseous healing mechanisms and unique to the craniofacial region. Antiresorptive and antiangiogenic medications have been suggested to be associated with the occurrence of ONJ; yet, the pathophysiology of this disease has not been fully elucidated. This article raises the current theories underlying the pathophysiology of ONJ. The proposed mechanisms highlight the unique localization of ONJ. The evidence-based mechanisms of ONJ pathogenesis include disturbed bone remodeling, inflammation or infection, altered immunity, soft tissue toxicity, and angiogenesis inhibition. The role of dental infections and the oral microbiome is central to ONJ, and systemic conditions such as rheumatoid arthritis and diabetes mellitus contribute through their impact on immune resiliency. Current experimental studies on mechanisms of ONJ are summarized. The definitive pathophysiology is as yet unclear. Recent studies are beginning to clarify the relative importance of the proposed mechanisms. A better understanding of osteoimmunology and the relationship of angiogenesis to the development of ONJ is needed along with detailed studies of the impact of drug holidays on the clinical condition of ONJ.

Osteonecrosis of the Jaw Developed in Mice: DISEASE VARIANTS REGULATED BY γδ T CELLS IN ORAL MUCOSAL BARRIER IMMUNITY

Osteonecrosis of the jaw (ONJ), an uncommon co-morbidity in patients treated with bisphosphonates (BP), occurs in the segment of jawbone interfacing oral mucosa. This study aimed to investigate a role of oral mucosal barrier γδ T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 μg/kg), and their maxillary left first molars were extracted 1 week later. ZOL-treated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. γδ T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL-treated γδ T cell null (Tcrd(-/-) ZOL) mice, the tooth extraction open wound progressively closed; however, histological ONJ-like lesions were identified in 75 and 60% of WT ZOL and Tcrd(-/-) ZOL mice, respectively. Although the bone exposure phenotype of ONJ was predominantly observed in WT ZOL mice, Tcrd(-/-) ZOL mice developed the pustule/fistula disease phenotype. We further addressed the role of γδ T cells from human peripheral blood (h-γδ T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h-γδ T cells exhibited rapid expansion and robust IFN-γ secretion. When h-γδ T cells were injected into ZOL-treated immunodeficient (Rag2(-/-) ZOL) mice, the oral epithelial hyperplasia developed. However, Rag2(-/-) ZOL mice did not develop osteonecrosis. The results indicate that γδ T cells are unlikely to influence the core osteonecrosis mechanism; however, they may serve as a critical modifier contributing to the different oral mucosal disease variations of ONJ.

Impaired Bone Resorption and Woven Bone Formation Are Associated with Development of Osteonecrosis of the Jaw-Like Lesions by Bisphosphonate and Anti–Receptor Activator of NF-κB Ligand Antibody in Mice

Drug-induced osteonecrosis of the jaw (ONJ) is a detrimental intraoral lesion that often occurs after dental-related interventions in patients undergoing treatment with bisphosphonates or denosumab, the neutralizing human anti-receptor activator of NF-κB ligand (RANKL) antibody (Ab). The cause of ONJ by these drugs has been speculated to their direct effects on osteoclasts. However, the extent to which osteoclasts contribute to ONJ pathogenesis remains controversial. Herein, by using a tooth-extraction mouse model with i.v. administration of mouse anti-RANKL Ab or the bisphosphonate zoledronate (ZOL), we show that unresorbed bone due to impaired formation or suppressed functions of osteoclasts, respectively, is associated with ONJ development. After tooth extraction, ONJ-like lesions developed 50% in the anti-RANKL Ab-treated mice and 30% in the ZOL-treated mice. Nonviable and unresorbed bone was found more in anti-RANKL Ab-treated mice compared with mice receiving ZOL. All mice receiving anti-RANKL Ab had an undetectable tartrate-resistant acid phosphatase (TRAP) level in the serum and no TRAP-positive osteoclasts at the extracted sockets, whereas ZOL-treated mice had a decreased TRAP level without altering the numbers of TRAP-positive osteoclasts. Interestingly, the absence of newly formed woven bone in the extracted sockets was evident in ONJ-like lesions from both anti-RANKL Ab- and ZOL-treated mice. Our study suggests that the lack of osteoclasts' bone-resorptive functions by these drugs and suppression of woven bone formation after dental trauma may be associated with ONJ development.

Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw.

Bacterial biofilms have emerged as potential critical triggers in the pathogenesis of bisphosphonate (BP)-related osteonecrosis of the jaw (ONJ) or BRONJ. BRONJ lesions have shown to be heavily colonized by oral bacteria, most of these difficult to cultivate and presents many clinical challenges. The purpose of this study was to characterize the bacterial diversity in BRONJ lesions and to determine host immune response. We examined tissue specimens from three cohorts (n=30); patients with periodontal disease without a history of BP therapy (Control, n=10), patients with periodontal disease having history of BP therapy but without ONJ (BP, n=5) and patients with BRONJ (BRONJ, n=15). Denaturing gradient gel electrophoresis of polymerase chain reaction (PCR)-amplified 16S rRNA gene fragments revealed less bacterial diversity in BRONJ than BP and Control cohorts. Sequence analysis detected six phyla with predominant affiliation to Firmicutes in BRONJ (71.6%), BP (70.3%) and Control (59.1%). Significant differences (P<0.05) in genera were observed, between Control/BP, Control/BRONJ and BP/BRONJ cohorts. Enzyme-linked immunosorbent assay (ELISA) results indicated that the levels of myeloperoxidase were significantly lower, whereas interleukin-6 and tumor necrosis factor-alpha levels were moderately elevated in BRONJ patients as compared to Controls. PCR array showed significant changes in BRONJ patients with downregulation of host genes, such as nucleotide-binding oligomerization domain containing protein 2, and cathepsin G, the key modulators for antibacterial response and upregulation of secretory leukocyte protease inhibitor, proteinase 3 and conserved helix–loop–helix ubiquitous kinase. The results suggest that colonization of unique bacterial communities coupled with deficient innate immune response is likely to impact the pathogenesis of ONJ.

Osteonecrosis of the jaw from bone anti‐resorptives: impact of skeletal site‐dependent mesenchymal stem cells

Recently, two Letters to the Editor addressed the use of bone mesenchymal (Gonzalvez-Garcia et al., 2012) and hematopoietic (Elad et al., 2012) stem cells in the management of osteonecrosis of the jaw (ONJ), a common complication of bone anti-resorptive therapies. Clearly, bisphosphonates and denosumab are highly efficacious in controlling dysregulated bone remodeling in osteoporosis, Paget’s disease, multiple myeloma and skeletal events of cancer metastasis, however ONJ is still an unpredictable recalcitrant oral complication (Fusco et al., 2011, Stopeck et al., 2010). The underlying pathophysiological mechanism of ONJ is still unclear, so prevention of ONJ is challenging. Also, there is paucity of randomized controlled clinical trials on ONJ therapies, so management algorithms are still empirical (Moretti et al., 2011, Stockmann et al., 2010, Montebugnoli et al., 2007). Both bisphosphonates and denosumab directly inhibit osteoclasts, but bisphosphonates also indirectly inhibit osteoclastic activity through osteoblasts and bone mesenchymal stem cells (BMSCs) both of which express the cell surface ‘receptor activator of NFκB ligand’ (RANKL) known to interact with RANK on osteoclast precursors (Nishida et al., 2005, Roelofs et al., 2006). Since BMSCs can differentiate into multiple cell types including pre-osteoblasts and osteoblasts, some investigators have successfully transplanted BMSCs to treat ONJ both clinically and in animal studies (Cella et al., 2011, Kikuiri et al., 2010, Li et al., 2013). The function of BMSCs in these studies, though attributed to immune modulation does not explain the jaw-specific character of ONJ. ONJ, induced by bone anti-resorptives specifically targets the jaw unlike other forms of osteonecrosis in response to irradiation (osteoradionecrosis), infection (osteomyelitis), corticosteroid therapy (steroid-induced osteonecrosis) and alcoholism (alcohol-induced osteonecrosis) that can develop in non-oral skeletal sites (Akintoye & Hersh, 2012). It is still unclear why ONJ targets orofacial bones, so the successful use of BMSC transplants to treat ONJ draws attention to possible roles of jaw-specific characteristics of orofacial BMSCs (OFMSCs) in ONJ pathogenesis and its preference for oral bone. It has been shown that BMSCs are phenotypically and functionally site-specific in terms of their survival, differentiation and response to growth factors when compared to MSCs from axial/appendicular bones (Akintoye et al., 2006, Aghaloo et al., 2010). Moreover, OFMSCs are more responsive to bisphosphonate and irradiation relative to non-oral BMSCs (Damek-Poprawa et al., 2010, Stefanik et al., 2008). These jaw specific characteristics of OFMSCs could shed some light into the preferential jaw localization of ONJ as well as high incidence of jaw osteoradionecrosis following head and neck cancer radiotherapy (Damek-Poprawa et al., 2010, Stefanik et al., 2008). Osteogenic differentiation and osteoclast recruiting abilities of BMSCs are necessary for bone homeostasis and repair; therefore, it is possible that anti-resorptives such as bisphosphonate and denosumab apparently uncouple osteoblast-osteoclast balance in a skeletal site-specific pattern to favor onset of ONJ. The elusiveness of mechanisms that underlie jaw-specific nature of ONJ has made prevention and complete cure of ONJ challenging without invasive surgery. Further understanding of OFMSCs functions and cellular interactions in ONJ could shed more light on its pathogenesis and promote development of potential preventive therapies.

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.

Zoledronic acid inhibits macrophage SOCS3 expression and enhances cytokine production.

Suppressor of cytokine signaling-3 (SOCS3) has multiple functions including inhibition of Janus kinase (Jak) activity, regulation of protein degradation, and suppression of cytokine signaling. SOCS3 modulates macrophage response to cytokines such as IL-6 and leptin that are systemically induced in obesity. Obesity is a suspected risk factor for SOCS3-related pathology such as rheumatoid arthritis and Crohn's disease as well as zoledronic acid (ZA)-induced osteonecrosis of the jaw (ONJ). Thus, understanding the ability of bisphosphonates to modulate SOCS3 is necessary to qualify their contribution to these disorders. ONJ occurs in up to 10% of patients using intravenous bisphosphonates and has an unknown pathogenesis that may be linked to decreased bone turnover, altered vascularity, bacterial invasion, and compromised wound healing. Given the increased risk of ONJ with obesity and importance of macrophages in wound healing, we hypothesized that amino-bisphosphonates could contribute to the pathogenesis of ONJ by regulating macrophage responses to cytokines such as leptin and IL-6. We report that ZA is a novel inhibitor of SOCS3 in primary macrophages and human ONJ biopsy specimens. Inhibition of SOCS3 by ZA resulted in significant increases in IL-6 production. SOCS3 transcription is regulated by nuclear accumulation of phosphorylated-Stat3 (P-Stat3). We found that ZA decreased phosphorylation of Stat3 in a mevalonate-pathway dependent manner. However, restoration of P-Stat3 was not sufficient to correct SOCS3 inhibition. We propose that disruption of macrophage SOCS3 expression by amino-bisphosphonates such as ZA may be a novel contributor to inflammatory phenotypes in obesity and the pathogenesis of ONJ.

A peroxisome proliferator‐activated receptor gamma (PPARG) polymorphism is associated with zoledronic acid‐related osteonecrosis of the jaw in multiple myeloma patients: analysis by DMET microarray profiling

A peroxisome proliferator‐activated receptor gamma (<i>PPARG</i>) polymorphism is associated with zoledronic acid‐related osteonecrosis of the jaw in multiple myeloma patients: analysis by DMET microarray profiling

Effect of bisphosphonates on human gingival fibroblast production of mediators of osteoclastogenesis: RANKL, osteoprotegerin and interleukin-6

Osteonecrosis of the jaw (ONJ) is associated with bisphosphonate (BP) therapy. BPs alter osteoblast production of mediators of osteoclastogenesis, including interleukin (IL)-6, RANKL and osteoprotegerin (OPG), a RANKL antagonist. This can inhibit bone turnover and lead to necrosis. There is little information on the contribution of gingival fibroblasts, near bone-resorption sites, to the IL-6/RANKL/OPG network, the effects of BPs, or fibroblast involvement in ONJ pathogenesis. Therefore, the objective of this study was to determine the effects of alendronate and pamidronate on the constitutive production, or the lipopolysaccharide (LPS)- or IL-1β-stimulated production, of IL-6, RANKL and OPG by human gingival fibroblasts. Human gingival fibroblasts were derived from explants obtained from healthy individuals with noninflamed gingiva. Cytotoxicity was determined by measuring the activity of a mitochondrial enzyme. Fibroblasts were pre-incubated or not with BPs (0.01 nm-1 μm), then incubated or not with LPS or IL-1β. The concentrations of IL-6, OPG and RANKL were measured using ELISA. Data were analyzed using analysis of variance (ANOVA) and Scheffé's F procedure. LPS and BPs were not cytotoxic. The cells produced IL-6, OPG and RANKL, all of which were stimulated by IL-1β or LPS (p ≤ 0.04). BPs generally increased the production of IL-6 and OPG (p ≤ 0.04) and decreased the production of RANKL (p ≤ 0.02). BPs generally further increased the production of LPS- or IL-1β-stimulated IL-6 (p ≤ 0.04) and had no effect on, or further increased, the production of LPS- or IL-1β-stimulated OPG (p ≤ 0.04). BPs decreased the production of LPS- or IL-1β-stimulated RANKL (p ≤ 0.04) and decreased constitutive, LPS-stimulated and IL-1β-stimulated RANKL/OPG ratios (p ≤ 0.02). The action of alendronate and pamidronate on human gingival fibroblasts, through altering the production of RANKL and OPG, appears to contribute to a microenvironment favoring the inhibition of bone resorption and ONJ.

Microbial Biofilms in Osteomyelitis of the Jaw and Osteonecrosis of the Jaw Secondary to Bisphosphonate Therapy

The authors report their observations with respect to microbial biofilms in osteomyelitis of the jaw (OMJ), compare these findings with those for osteonecrosis of the jaw (ONJ) secondary to bisphosphonate therapy and discuss recent findings that the pathogenesis of ONJ may represent a biofilm-mediated infectious disease in the context of bisphosphonate therapy. In 2004, a program was established at the University of Southern California, Los Angeles, to evaluate, treat and monitor patients who have OMJ and ONJ. Twenty people from this cohort of study patients who were scheduled to undergo surgical debridement or sequestrectomy and who met the authors' inclusion criteria gave informed consent for the study. The authors examined bone samples histopathologically and via scanning electron microscopy, a technique applicable to biofilm characterization. Specimens from all patients with OMJ and ONJ exhibited large surface areas of bone occluded with well-developed biofilms comprising microbial organisms embedded in an extracellular polymeric substance. Actinomyces predominated in OMJ cases, whereas ONJ cases represented more diverse bacterial organisms in addition to fungal organisms not seen in OMJ. The authors observed resorption pits, septic clots, putative nanowires and host inflammatory cells in all specimens. The findings of this study support a role for microbial biofilms in both disease processes. Microbial biofilms are a potential target for therapy that includes antibiofilm modalities in the treatment and prevention of OMJ and ONJ.

Bisphosphonat-assoziierte Osteonekrosen des Kieferknochens

Intravenous application of bisphosphonates (BP) represents an established therapeutic strategy of tumor-associated bone metastasis and severe hypercalcemia. Patients can develop osteonecrosis of the jaw (ONJ) as a side effect of this therapy. The diagnosis of ONJ is based on three criteria: a) patients have been or are currently treated with BP; b) a deficiency in wound healing, which is in 70-80% associated with necrotic alveolar bone, characteristically exposed, is present for at least 8 weeks and c) no radiotherapy of the head and neck was performed. The suppression of bone turnover, concomitant with high functional load of the alveolar bone, and the subsequent accumulation of microfractures are considered the main pathologic factors of this disease. The cumulative incidence of ONJ lies approximately between 1 and 10% in oncologic patients, being associated with the antiresorptive potency and the respective molecular structure of the BPs. Patients with multiple myeloma develop ONJ more frequently than patients with other oncological diseases such as metastasizing breast- and prostate cancer, a fact that may also be due to the higher transfusion/injection frequency of BP in these patients. Dental treatment strategies are responsible for the occurrence of ONJ in approximately 80% of cases. Based on a clinical staging, patients can be grouped into three categories and should receive the corresponding treatment regime. Prospective clinical studies are required for a better understanding of etiology and pathogenesis of ONJ to make treatment, risk estimation and prognosis of ONJ more accurate.

Ibandronate uptake in the jaw is similar to long bones and vertebrae in the rat

Intravenous bisphosphonates may be involved in the development of osteonecrosis of the jaw (ONJ). However, a mechanistic causality has not been demonstrated. To evaluate whether there is higher drug uptake by the jaw versus other bones that might be involved in ONJ pathogenesis, we performed a pilot experiment comparing ibandronate uptake in rat mandible, femur, and lumbar vertebrae after repeated administration. Rats (n = 1/group) received daily subcutaneous injections of ibandronate in doses ranging from 0.003 to 0.3 mg/kg/day for 9 days. Five days after the last injection, the animals were killed and the right femur, lumbar vertebrae L3-L5, and the right mandible were removed. After cleaning and drying, bone dry weight was recorded, and ibandronate concentration was determined in whole-bone hydrolyzates by gas chromatography mass spectrometry. Concentrations of ibandronate increased dose-dependently in all bones with similar concentrations per bone at each dose level ranging from values below quantification limit (low dose) up to approximately 10 ng ibandronate/mg bone dry weight (high dose). In this rat study, there was a relatively similar bisphosphonate uptake between the femur and lumbar vertebrae bones whereas the uptake in the jaw was statistically smaller with regard to the absolute values (P < 0.05). Thus, there is no suggestion of preferential bisphosphonate uptake in the jaw.

Antibiotic Prophylaxis Before Dental Procedures Can Reduce ONJ Incidence.

Osteonecrosis of the jaw (ONJ) is a frequent complication in bisphosphonate-treated multiple myeloma (MM) patients. The pathogenesis is unclear, and major risk factors are duration of bisphosphonate treatment and dental procedures. The histology of osteonecrotic bone shows osteomyelitis and inflammatory infiltrates, and, in most cases, presence of Actynomycetes. Since dental procedures are a major risk factor for ONJ development and oral microflora can be involved in the pathogenesis of the disease, we conducted a retrospective observational trial comparing ONJ occurrence and related risk factors in two groups of MM patients, who received zoledronic acid treatment at two Italian hematological centres. In one centre all patients systematically received as antibiotic prophylaxis amoxicillin-clavulanate 1 gm bid or levofloxacin 500 mg once a day starting from one day before to 3 days after any dental procedure (group A, 52 patients), while in the other centre patients did not receive any prophylaxis (group B, 61 patients). Dental procedures were categorized according to their invasivity and their supposed probability to cause ONJ. Extractions, implants, and professional cleanings were considered at high risk, while fillings were considered low risk procedures. Thirty-three group A patients (63%) and 32 group B patients (52%) received high risk procedures; 4 group A patients (8%) and 5 group B patients (8%) received low risk procedures, while 15 (29%) and 24 (39%) patients, respectively, had a denture. The duration of zoledronic acid exposure differed significantly between the two groups, with a median of 26 months for A patients and 12 months for B patients (p<0.0001). In group A no cases of ONJ were observed, while in group B 8 cases (13%) of ONJ were diagnosed, with a significant difference between the two groups (p=0.007). There was a temporal correlation between dental procedure and ONJ, with a median time of 60 days (range 37–990). The relative risk of ONJ after a dental procedure was 4.8 (p=0.01). The pooled analysis of the two groups showed that age, sex, transplant procedure, and thalidomide therapy did not correlate with ONJ. In both groups the presence of dentures was not associated with ONJ. While in group B incidence of ONJ is consistent with data reported in the literature, which range between 7% and 11%, group A patients had an unexpected low occurrence of this complication, despite a significantly longer exposure to zoledronic acid. This finding suggests a possible role of antibiotic prophylaxis in protecting from ONJ after dental procedures. Further, our observation, along with the correlation between dental procedures and ONJ development, can contribute to the proposal of a comprehensive model of ONJ pathogenesis: trauma of the alveolar bone modified by bisphosphonates induces a bacterial translocation with a subsequent induction of infection, inflammation and necrosis. In this perspective, since antibiotic prophylaxis is a simple and low cost precaution, it's reasonable to propose it as part of standard care to zoledronic acid treated MM patients before any dental procedure.

Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome

Osteonecrosis of the jaw (ONJ) is a well-known devastating side effect of bisphosphonate therapy for cancer. Several ONJ cases of patients using oral bisphosphonates have been reported in the literature. The present study analyzed the clinical features, predisposing factors, and treatment outcome of 11 patients with oral bisphosphonates-related ONJ. Osteonecrosis of the jaw (ONJ) is a well-known side effect of parenteral bisphosphonates therapy. Although ONJ has been reported in patients using oral bisphosphonates, documentation of this entity is sparse. It was hypothesized that the clinical features, predisposing factors, and treatment outcome of this population are different from those of oncologic patients. This retrospective bi-central study involved 98 ONJ patients, 13 of whom were treated with oral bisphosphonates. Two patients were excluded because of previous use of intravenous bisphosphonates. The profiles of 11 patients were analyzed. The mean duration of alendronate use before developing ONJ was 4.1 years. ONJ was triggered by dental surgery in 9 patients and by ill-fitted dentures in 2. Heavy smokers were the most recalcitrant subjects. Among the nine patients with at least 6 months of follow-up, ONJ healed completely in three, partially in four, and not at all in two. ONJ is a rare devastating side effect of oral bisphosphonates associated with patient morbidity and high financial burden. Clinicians must be aware of this entity and inform patients of the risks of dental surgery. The synergistic effect of smoking in the pathogenesis of ONJ should be further investigated.

Bisphosphonatassoziierte Osteonekrose des Kiefers

Bisphosphonates (BP) are widely used in patients with osteoporosis or malignant tumors with bony metastases such as breast cancer and plasmocytoma because of their potency to affect osteoclasts and bone resorption. Osteonecrosis of the jaw (ONJ) has been described as a potential side effect since 2003. After a review of the literature we present results of a questionnaire, which was sent to departments of oral and maxillofacial surgery (OMFS) in German-speaking countries. We present 349 patients from the literature, 54 patients from the departments of OMFS and 19 cases from our own department. These patients ware analyzed depending on their disease, their medication, localization of the affected area, histological signs and therapeutic outcome. Of 73 patients, 68 (93%) were treated with pamidronate or zoledronate; 69 (94%) patients suffered from malignant diseases, 3 (5%) had osteoporosis, and 1 (1%) had Paget's disease. In 57 (78%) patients the ONJ affected the mandible, in 12 (16%) the maxilla and in 4 (5%) both jaws. A previous tooth extraction was reported in 38 (52%) patients, and in 35 (48%) ONJ occurred spontaneously. Histological findings were similar to osteomyelitis with a high number of actinomyces colonies. Nine (12%) patients received non-surgical treatment only, 52 (71%) patients underwent minor surgical procedures (e. g. decortication) and 19 (26%) patients underwent marginal or segmental resection of the jaw. Considering all treatment modalities, healing was achieved in 55; the most effective was marginal and segmental resection (88%). Though millions of patients receive BP treatment only a few suffer from ONJ. The incidence in cancer patients with pamidronate and zoledronate therapy is 4%-10%. Because of the similarity to "phossy jaw", seen in patients dealing with white phosphorus in the nineteenth century, some authors call the new entity "bis-phossy jaw". As the pathogenesis of ONJ is not clear we recommend that the descriptive term bisphosphonate-associated osteonecrosis should be used. Bone resection and safe soft tissue closure is the treatment of choice. We recommend systematic dental care for patients receiving BP medication. Information exchange between oncologists, oral and maxillofacial surgeons and dentists is important.

1291 POSTER Capecitabine (XEL)+Oxaliplatin (OX) in elderly people (EP) with Colorectal Cancer (CRC): Comparison of safety (S) and feasibility (F) of two different schedules. preliminary findings

The authors report their observations with respect to microbial biofilms in osteomyelitis of the jaw (OMJ), compare these findings with those for osteonecrosis of the jaw (ONJ) secondary to bisphosphonate therapy and discuss recent findings that the pathogenesis of ONJ may represent a biofilm-mediated infectious disease in the context of bisphosphonate therapy.In 2004, a program was established at the University of Southern California, Los Angeles, to evaluate, treat and monitor patients who have OMJ and ONJ. Twenty people from this cohort of study patients who were scheduled to undergo surgical debridement or sequestrectomy and who met the authors' inclusion criteria gave informed consent for the study. The authors examined bone samples histopathologically and via scanning electron microscopy, a technique applicable to biofilm characterization.Specimens from all patients with OMJ and ONJ exhibited large surface areas of bone occluded with well-developed biofilms comprising microbial organisms embedded in an extracellular polymeric substance. Actinomyces predominated in OMJ cases, whereas ONJ cases represented more diverse bacterial organisms in addition to fungal organisms not seen in OMJ. The authors observed resorption pits, septic clots, putative nanowires and host inflammatory cells in all specimens.The findings of this study support a role for microbial biofilms in both disease processes.Microbial biofilms are a potential target for therapy that includes antibiofilm modalities in the treatment and prevention of OMJ and ONJ.