Faculty Bibliography

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.International Journal of Oral Science advance online publication, 8 August 2014; doi:10.1038/ijos.2014.46.

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

PURPOSE: Osteonecrosis of the jaw (ONJ) has been reported to be associated with patients receiving bisphosphonate (BP) therapy. There are many reports that suggest that the time of exposure to BPs is a significant risk factor for ONJ and that the greatest risk occurs after dentoalveolar surgery. The aim of this study was to retrospectively investigate the duration of BP therapy and related events before the onset of ONJ based on an intravenous (IV) or oral route of administration. MATERIALS AND METHODS: We conducted a retrospective cohort study of patients referred to our institution to identify the onset of ONJ based on the exposure to BP therapy and associated triggers (ie, dentoalveolar surgery or spontaneous occurrence) based on the route of BP administration. Demographic data (ie, age, gender, and race), medical diagnosis related to BP therapy, and information as to whether the BP therapy was continued at the time of ONJ diagnosis were also collected. RESULTS: We reviewed the records for 114 patients with a history of ONJ. We divided patient cohorts by route of BP administration, with 76 patients having a history of IV BP therapy and 38 patients having a history of oral BP therapy. The overall onset of ONJ was earlier in the IV BP group (median, 3 years) compared with the oral BP group (median, 5 years). There was no statistical difference in the duration to occurrence of ONJ associated with dental extraction compared with spontaneous occurrence for both the IV and oral BP groups. CONCLUSIONS: The median onset of ONJ for patients undergoing IV BP therapy occurs earlier than the median onset for patients undergoing oral BP therapy, and there was no difference in onset occurring spontaneously and after dental extraction. The significance of these findings suggests that patients who receive IV BP therapy should be closely evaluated after the initiation of BP therapy. The lack of evidence suggesting greater onset after dental extraction may provide clinical support for dentoalveolar surgery that is indicated for patients with a history of BP therapy. Research focusing on the clinical circumstances and physiologic events during early antiresorptive therapy may provide insight as to the critical risk factors.

Oral Diseases (2011) doi: 10.1111/j.1601-0825.2011.01848.x Objective: Oral infection is considered to play a critical role in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ), and antibiotic therapy has become a mainstay of BRONJ therapy. This study was aimed to investigate the effect of antibiotics on bacterial diversity in BRONJ tissues. Materials and methods: The bacterial profile from soft tissues associated with the BRONJ lesion was determined using 16S rRNA-based denaturing gradient gel electrophoresis (DGGE) and sequencing. Twenty BRONJ subjects classified as stage 0-2 were enrolled in this study, and patient groups were divided into an antibiotic cohort (n = 10) treated with systemic antibiotic and a non-antibiotic cohort (n = 10) with no prior antibiotic therapy. Results: The DGGE fingerprints indicated no significant differences in bacterial diversity of BRONJ tissue samples. Patients on antibiotics had higher relative abundance of phylum Firmicutes with bacterial species, Streptococcus intermedius, Lactobacillus gasseri, Mogibacterium timidum, and Solobacterium moorei, whereas patients without antibiotics had greater amounts of Parvimonas micra and Streptococcus anginosus. Thirty percent of bacterial populations were uncultured (yet-to be cultured) phylotypes. Conclusion: This study using limited sample size indicated that oral antibiotic therapy may have a limited efficacy on the bacterial population associated with BRONJ lesions