Immune Biomarkers of BRONJ in High-Risk Cancer Patients

Saturday, September 15, 2012: 8:50 AM
Allan Leung DDS, MD Los Angeles, CA, USA
Peter Lee Los Angeles, CA, USA
Andrew Kiss Los Angeles, CA, USA
Simon Choyee DDS Los Angeles, CA, USA
Jettie Uyanne DDS Los Angeles, CA, USA
Kentaro Akiyama DDS, PhD Los Angeles, CA, USA
Parish Sedghizadeh DDS, MS Los Angeles, CA, USA
Songtao Shi DDS, PhD Los Angeles, CA, USA
Anh Le DDS, PhD Philadelphia, PA, USA
Background: Bisphosphonate related osteonecrosis of the jaws (BRONJ) is an adverse effect of bisphosphonate therapy, with highest incidence reported in the oncologic patients receiving intravenous bisphosphonates (BP). Our group previously established that Zolendronate, a potent intravenous BP, caused BRONJ-like disease in mice by suppressing the adaptive regulatory T cell (Tregs) and activating the inflammatory T helper producing interleukin 17 cells (Th17), thereby decreasing the ratio of Treg/Th17.  C-telopeptide (CTX), an indicator of bone turnover, is currently used by some clinicians to predict treatment response in BRONJ patients. Here, we determined whether the altered immune homeostasis elicited by bisphosphonate therapy, specifically a suppressed Treg/Th17 renders cancer patients susceptible to BRONJ,

Purpose: To identify novel immune biomarkers/predictors of BRONJ in the high-risk cancer patients.

Methods: We conducted a cross-sectional study using a well-defined group of cancer patients with history of chemotherapy and bisphosphonate treatment. The case controlled study evaluated patients who presented with osteonecrosis of the jaws (ONJ). Age and ethnically matched patients without ONJ were compared to the affected patients. Patients were screened from the Norris Cancer Center, the Ostrow School of Dentistry, and the LAC+USC medical center. Treg and Th17 cells were determined using flow cytometric analysis. Bone serum marker, C-telopeptide, was measured using ELISA.

Results: Data demonstrated that BRONJ patients showed a significantly higher level of Th17 cells than control patients (n=30, p<0.05) and the suppressed ratio of Treg/Th17 cells appears to correlate with the presence of active BRONJ lesion in these affected patients. In addition, the Treg/Th17 ratio also correlates with BRONJ disease severity following the established diagnosis guidelines by the American Association of Oral and Maxillofacial Surgeons. The differential immune cells profile between control and high-risk BRONJ groups were more significant than the currently used serum C-telopeptide assay.

Conclusions: The Treg/Th17 ratio appears to correlate with BRONJ disease severity and potentially serves as  an immune biomarker for prediction of BRONJ in cancer patients on IV bisphosphonate and chemotherapy.  

References:                                                                                                                                                                                                                                                                                                                          1. Kikuiri T, Kim I, Yamaza T, Akiyama K, Zhang Q, Li Y, Chen C, Chen W, Wang S, Le AD, Shi S. (2010) Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw-like disease in mice. J Bone Miner Res. 2010 Jan 29;25(7):1668-1679.

2. Ruggiero SL, Dodson TB, Assael LA et al (2009). American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws –2009 update. J Oral Maxillofac Surg 67(Suppl. 5): 2–12.

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