title: Major histocompatibility complex class II polymorphisms are associated with the development of anti-resorptive agent-induced osteonecrosis of the jaw.
abstract: The aetiology of anti-resorptive agent-induced osteonecrosis of the jaw (ARONJ) is still under debate. Clinical and genetic risk factors are currently being investigated to help understand its pathogenesis. This case-control study analysed a large number of cancer patients (n = 230) under therapy with intravenous bisphosphonates, half of which were diagnosed with ARONJ. Multiple myeloma, greater patient age and the use of more than one bisphosphonate were identified as clinical risk factors on logistic regression analysis. In addition, 204 patients were genotyped for HLA-DRB1 and DQB1 and the allele frequencies were compared between ARONJ (n = 94) and unaffected cancer patients (n = 110). For the HLA class II alleles, a strong increase in the frequency of DRB1*15, DQB1*06:02, DRB1*01 and DQB1*05:01 was observed in the ARONJ group. These results were reinforced on analysis of the respective haplotypes, with DRB1*15-DQB1*06:02 being significantly associated with the development of ARONJ (odds ratio [OR] 2.5; 95% confidence interval [CI] 1.3-5.0). The presence of at least one of the haplotypes DRB1*15-DQB1*06:02 and DRB1*01-DQB1*05:01 was highly associated with the development of ARONJ (OR 3.0; 95% CI 1.7-5.5). The data in this study of a large number of cancer patients receiving intravenous bisphosphonates suggest that MHC class II polymorphisms represent genetic risk factors for the development of ARONJ. This result supports recent findings that inflammation and infection might play an important role in the pathogenesis of ARONJ.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Erlangen, Erlangen, Germany. philipp.stockmann@uk-erlangen.de
authors.forename: Philipp
authors.initials: P
authors.lastname: Stockmann
authors.forename: Emeka
authors.initials: E
authors.lastname: Nkenke
authors.forename: Matthias
authors.initials: M
authors.lastname: Englbrecht
authors.forename: Tilo
authors.initials: T
authors.lastname: Schlittenbauer
authors.forename: Falk
authors.initials: F
authors.lastname: Wehrhan
authors.forename: Claudia
authors.initials: C
authors.lastname: Rauh
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.forename: Thomas
authors.initials: T
authors.lastname: Kreusch
authors.forename: Andreas
authors.initials: A
authors.lastname: Mackensen
authors.forename: Bernd
authors.initials: B
authors.lastname: Wullich
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Bernd M
authors.initials: BM
authors.lastname: Spriewald
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000235:genetics / Q000276:immunology*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage; D016022:Case-Control Studies; D004338:Drug Combinations; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D059866:HLA-DQ beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D007275:Injections, Intravenous; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors; D012737:Sex Factors
chemical_list: D050071:Bone Density Conservation Agents; D004338:Drug Combinations; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; C497841:HLA-DRB1*01 antigen; C507799:HLA-DRB1*15 antigen; D000949:Histocompatibility Antigens Class II