Kenneth E. Fleisher

Predicting risk for bisphosphonate-related osteonecrosis of the jaws: CTX versus radiographic markers

BACKGROUND AND OBJECTIVE The most common risk factor for bisphosphonate-related osteonecrosis of the jaws (BRONJ) is dentoalveolar surgery. It has been suggested that reduced serum C-terminal telopeptide (CTX) can determine the degree of osteoclast suppression and may predict the development of BRONJ after dentoalveolar surgery. Although there are many radiographic appearances associated with BRONJ, there are little data that describes changes preceding dentoalveolar surgery. The objective of this retrospective study was: 1) to investigate if reduced serum CTX values (i.e., <150 pg/mL) were associated with BRONJ after dentoalveolar surgery; and 2) to determine if specific radiographic changes are associated with teeth that develop BRONJ after extraction. STUDY DESIGN A retrospective review of radiographic and/or serum CTX data was performed for 68 patients with a history of bisphosphonate therapy who either underwent dental extraction or were diagnosed with BRONJ in the Department of Oral and Maxillofacial Surgery during the period 2007-2009. Postoperative healing was assessed for 26 patients with reduced serum CTX levels (<150 pg/mL) who either underwent dental extraction or treatment for BRONJ. Preoperative radiographs were evaluated for 55 patients who either healed normally or developed BRONJ after dental extraction. RESULTS All 26 patients (100%) who had serum CTX levels <150 pg/mL healed successfully after dentoalveolar surgery (20 patients) or after treatment for BRONJ (6 patients). Among the 55 patients who underwent radiographic evaluation, 24 patients (83%) with BRONJ exhibited periodontal ligament (PDL) widening associated with extracted teeth, whereas only 3 patients (11%) who healed normally demonstrated PDL widening. CONCLUSION These data suggest that radiographic PDL widening may be a more sensitive indicator than CTX testing in predicting risk of BRONJ. Current guidelines that recommend minimal surgical intervention may need to be revised to include alternative strategies for the elimination or management of this pathology.

Antibiotic effects on bacterial profile in osteonecrosis of the jaw

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.

Dynamic Sagittal Half-Fourier Acquired Single-Shot Turbo Spin-Echo MR Imaging of the Temporomandibular Joint: Initial Experience and Comparison with Sagittal Oblique Proton-Attenuation Images

BACKGROUND AND PURPOSE: Our aim was to assess dynamic half-Fourier acquired single-shot turbo spin-echo (HASTE) MR imaging of the temporomandibular joint (TMJ) using parallel imaging, in comparison with static proton density (Pd) imaging. MATERIALS AND METHODS: Thirty-four TMJs from 17 subjects (7 volunteers, 10 patients) were imaged in a multichannel head coil on a 1.5T magnet by using a 35-second dynamic sagittal HASTE acquisition (TR/TE, 1180/65 msec; matrix, 128 × 128; section thickness, 7 mm; 30 images) and sagittal oblique Pd in closed- and open-mouthed positions (TR/TE, 1800/12 msec; matrix, 256 × 256; section thickness, 2 mm; 15 sections). Images were reviewed by 3 readers and rated for confidence of disk position, presence of motion artifact, range of motion, and presence of disk displacement on a 5-point scale. Consensus review of cases was also performed to assess disk dislocation and limited range of motion. RESULTS: More static examinations were rated as having motion artifact (19.6% versus 6.9%, P = .016), limited range of motion (30.4% versus 17.7%, P = .016), and disk dislocations (31.4% versus 22.6%, P = .071). Confidence ratings were higher on dynamic examinations (4.11 versus 3.74, P = .018). Chi-squared tests demonstrated no significant difference in consensus reviews of the 2 examination types. CONCLUSION: Dynamic HASTE TMJ MR imaging is a time-efficient adjunct to standard MR imaging protocols, producing fewer motion artifacts, additional range of motion information, and a dynamic assessment of disk position, when compared with static imaging. Further study is needed to evaluate the role of this sequence in diagnosing disk displacement.

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 Onset Times Are Based on the Route of Bisphosphonate Therapy

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.

Metastatic cancer identified in osteonecrosis specimens of the jaws in patients receiving intravenous bisphosphonate medications.

PURPOSE The aim of the present study was to investigate the microscopic presence of metastatic cancer in jaw specimens clinically and histologically diagnosed as having osteonecrosis in patients receiving intravenous bisphosphonate medications. PATIENTS AND METHODS A retrospective cohort multicenter study was designed. Patients from the University of Tennessee Medical Center, New York University Medical Center, and New York Center for Orthognathic and Maxillofacial Surgery were enrolled who had been treated with intravenous bisphosphonate medications for an underlying diagnosis of cancer and who had been clinically diagnosed with bisphosphonate-related osteonecrosis of the jaws (BRONJ). The institutional review boards approved the present study. The primary predictor variable was the clinical presence of BRONJ. The primary outcome variable was the microscopic presence of metastatic cancer in the osteonecrotic jaw specimens. RESULTS A total of 744 sites of BRONJ were clinically diagnosed. Of these sites, 552 (74%) were diagnosed in patients who had received intravenous bisphosphonate medications. Of these 552 sites, 357 (65%) underwent microscopic evaluation through biopsy, sequestrectomy, or resection with curative intent. Of the 357 sites of BRONJ subjected to microscopic analysis, 19 (5.3%) sites were diagnosed with 20 cancers in 16 patients. CONCLUSIONS Albeit rare, the presence of cancer in a BRONJ specimen represents 1 explanation for the development of osteonecrosis in patients exposed to intravenous bisphosphonate medications in whom a clinical diagnosis of BRONJ has been applied. Additional molecular information is needed to provide an explanation for this observation.

Concentration dependent effects of tobacco particulates from different types of cigarettes on expression of drug metabolizing proteins, and benzo(a)pyrene metabolism in primary normal human oral epithelial cells

The ability of tobacco smoke (TS) to modulate phase I and II enzymes and affect metabolism of tobacco carcinogens is likely an important factor in its carcinogenicity. For the first time several types of TS particulates (TSP) were compared in different primary cultured human oral epithelial cells (NOE) for their abilities to affect metabolism of the tobacco carcinogen, (BaP) to genotoxic products, and expression of drug metabolizing enzymes. TSP from, reference filtered (2RF4), mentholated (MS), reference unfiltered, (IR3), ultra low tar (UL), and cigarettes that primarily heat tobacco (ECL) were tested. Cells pretreated with TSP concentrations of 0.2-10 μg/ml generally showed increased rates of BaP metabolism; those treated with TSP concentrations above 10 μg/ml showed decreased rates. Effects of TSPs were similar when expressed on a weight basis. Weights of TSP/cigarette varied in the order: MS≈IR3>2RF4>ECL>UL. All TSPs induced the phase I proteins, cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1), phase II proteins, NAD(P)H dehydrogenase quinone 1 (NQO1), and microsomal glutathione S-transferase 1 (MGST1), and additionally, hydroxysteroid (17-beta) dehydrogenase 2 (HSD17B2), as assessed by qRT-PCR. The pattern of gene induction at probable physiological levels favored activation over detoxification.

Does Fluorodeoxyglucose Positron Emission Tomography With Computed Tomography Facilitate Treatment of Medication-Related Osteonecrosis of the Jaw?

PURPOSE There is considerable controversy over the treatment of medication-related osteonecrosis of the jaw (MRONJ) and growing interest and debate related to the timing, type, technique, and goals of surgical intervention. The specific aim was to evaluate the predictive value of fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT) on healing outcomes in patients undergoing surgery for MRONJ of the mandible. MATERIALS AND METHODS A retrospective cohort study of 31 patients with 33 MRONJ lesions of the mandible who had undergone surgery using FDG PET-CT was conducted. Data were collected on FDG uptake patterns, healing, follow-up, demographics, lesion characteristics, antiresorptive therapy, and adjunctive therapy. Panoramic and/or periapical radiographs were used to identify non-restorable teeth and PET-CT images were used to identify sequestra and FDG uptake. Above the mandibular canal, surgery consisted of marginal resection and/or debridement of clinically involved bone and exposure of clinically uninvolved bone identified by FDG uptake. Below the mandibular canal, mobile segments of bony sequestra were removed, but areas of clinically uninvolved bone with FDG uptake were not. Patients who did not heal underwent segmental resection and reconstruction with rigid fixation and a local or regional soft tissue flap or free fibular flap. The primary predictor variable was the FDG uptake pattern for each patient. The outcome variable was postoperative healing defined by mucosal closure without signs of infection or exposed bone at the time of evaluation. RESULTS Two risk groups were identified based on FDG uptake pattern. The low-risk group, type A, included 22 patients with activity limited to the alveolus, torus, and/or basal bone superior to the mandibular canal. The high-risk group, type B, included 11 patients with type A FDG activity with extension inferior to the mandibular canal. Treatment of type A MRONJ lesions was more successful than treatment of type B MRONJ lesions (100 vs 27%; P < .001). Seven of the type B failures were successfully retreated by segmental resection and reconstruction (1 patient refused further treatment). CONCLUSION These results showed that low-risk FDG PET-CT findings predicted successful healing with surgery above the mandibular canal. In contrast, high-risk FDG findings were associated with a greater than 50% risk of failure for treatment that extended below the mandibular canal. Although these failures suggest that FDG uptake indicates infected tissue, further research is needed to identify which high-risk patients are most likely to benefit from a conservative treatment protocol.

Comorbid Conditions are a Risk for Osteonecrosis of the Jaw Unrelated to Antiresorptive Therapy

OBJECTIVE Osteonecrosis of the jaw (ONJ) is commonly associated with antiresorptive therapy. There have been numerous reports of ONJ unrelated to antiresorptive therapy (ONJuat), confounding risk assessment. This study aimed to determine if ONJuat is associated with one or more particular comorbidities. STUDY DESIGN This was a retrospective case-control study of patients with ONJuat and delayed healing (DH). Each case was matched for patient age and gender, as well as location of ONJuat or DH lesion to a control patient who had a history of dentoalveolar surgery with uneventful healing and no history of antiresorptive therapy. Comorbidity data included medical conditions and smoking. RESULTS Of the 92 patients identified, 67 (73%) met the criteria for ONJuat and 25 (27%) for DH. The most common trigger for ONJ and DH was extraction (50%). The presence of any comorbidity (i.e., at least 1) was more prevalent in ONJuat than among controls (P = .04), and there were more comorbidities in patients with ONJuat and DH than in controls [M(SD) = 1.94 (1.2) and 2.0 (1.3) vs 1.26 (0.89); both P < .001]. CONCLUSIONS ONJ and DH are not limited to patients with a history of antiresorptive therapy. More comorbidities may signal increased risk for ONJuat and DH.