title: Incidence of bisphosphonate-related osteonecrosis of the jaw in consideration of primary diseases and concomitant therapies.
abstract: BACKGROUND
  Since its first description by Marx in 2003, the etiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is the subject of numerous scientific discussions for oral and maxillofacial surgeons. Many retrospective studies on its etiology and pathogenesis have been carried out to explain pathological mechanisms; most of them just take a close look at the issue of dosage and application. Recently, attempts have been made, to identify co-factors which might promote the development of BRONJ.
  
  
  METHODS
  The present study is based on data of 169 patients with osseous metastatic malignancies. All patients received intravenous bisphosphonate therapy. On the basis of medical history, malignancy, and primary treatment, the modality of bisphosphonate therapy, and existing comorbidities and medication were analyzed. The role of immunosuppressive drugs, influence of underlying diseases, and general factors such as age and gender were examined. The predictability of necrotic involvement, influenced by the underlying malignancy and its specific therapy, e.g. radiation and cytostatic therapy were analyzed and statistically evaluated.
  
  
  RESULTS
  A total of 8.9% (n=15) of patients developed BRONJ. The average time between diagnosis of malignancy and BRONJ was 80 months. Nine patients suffered from breast cancer, five had prostate cancer and one renal cancer. Separation into stage and histological subtype did not show any significant correlation, nor did age or gender, to the occurrence of BRONJ. However statistical analysis did show a significant correlation concerning monocytostatic (p=0.0215) and triple-cytostatic therapy (p=0.0137). The majority of patients with BRONJ (60%) received a bisphosphonate therapy including zoledronate. Single application with one bisphosphonate was administered in 28 cases; 44 patients had a medical history of different use of bisphosphonate. Concomitant medication did not suggest possible correlation, nor did accompanying diseases, arterial hypertension (33.33%) or arterial microcirculatory disturbances (20%).
  
  
  CONCLUSIONS
  The evaluation of our results is pioneering. The influence of cytostatics and combined therapy of cytotoxic drugs on the pathogenesis of BRONJ is demonstrated here statistically. We confirmed a drug- and dose-dependent occurrence of BRONJ. Further prospective studies should be performed to elucidate the role of tissue perfusion and oxygen saturation, and the influence of immunosuppressive drugs in relation to the occurrence of BRONJ, as well as on wound healing of initial lesions.
authors.affiliation: DMD, Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. a.assaf@uke.uni-hamburg.de.
authors.forename: Alexandre T
authors.initials: AT
authors.lastname: Assaf
authors.forename: Ralf
authors.initials: R
authors.lastname: Smeets
authors.forename: Björn
authors.initials: B
authors.lastname: Riecke
authors.forename: Eva
authors.initials: E
authors.lastname: Weise
authors.forename: Alexander
authors.initials: A
authors.lastname: Gröbe
authors.forename: Marco
authors.initials: M
authors.lastname: Blessmann
authors.forename: Tim
authors.initials: T
authors.lastname: Steiner
authors.forename: Johannes
authors.initials: J
authors.lastname: Wikner
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Friedrich
authors.forename: Max
authors.initials: M
authors.lastname: Heiland
authors.forename: Frank
authors.initials: F
authors.lastname: Hoelzle
authors.forename: Frank
authors.initials: F
authors.lastname: Gerhards
mesh_terms: D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000150:complications / Q000453:epidemiology*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
keywords: Bisphosphonate; cytostatic therapy; mandible; osteonecrosis; risk factors