title: Pharmacogenetics of bisphosphonate-associated osteonecrosis of the jaw.
abstract: An undesirable effect associated with bisphosphonates is osteonecrosis of the jaw (ONJ). Case reports discussed ONJ development in patients with multiple myeloma or metastatic cancers receiving bisphosphonates as palliation for malignant bone disease. No causative relationship has been unequivocally demonstrated between ONJ and bisphosphonate therapy. To determine if a higher sensitivity to bisphosphonates could in part explain the development of ONJ, the segregation of A/C rs2297480 polymorphism of gene encoding for the farnesyl pyrophosphate synthase (FDPS) with ONJ was evaluated in a cohort of 68 Caucasian patients treated with zoledronic acid for multiple myeloma and metastatic mammary and prostate cancer. The AA and CC genotypes were highly differently distributed among ONJ patients and controls, matched for sex and type of malignant disease, with a positive correlation between AA carrier status and occurrence of ONJ (p=0.03) after 18-24 months of treatment. Because FDPS gene variants have been associated with bone morbidity, these pharmacogenetic association likely reflect the interaction of amino-bisphosphonates with germline sensitivity to drug actions, and might identify patients at highest risk to develop ONJ.
authors.affiliation: Department of Internal Medicine, University of Florence, Medical School, Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Marini
authors.forename: Paolo
authors.initials: P
authors.lastname: Tonelli
authors.forename: Loredana
authors.initials: L
authors.lastname: Cavalli
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cavalli
authors.forename: Laura
authors.initials: L
authors.lastname: Masi
authors.forename: Alberto
authors.initials: A
authors.lastname: Falchetti
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Brandi
mesh_terms: D050071:Bone Density Conservation Agents / Q000494:pharmacology; D004164:Diphosphonates / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D051228:Geranyltranstransferase / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007558:Italy; D007571:Jaw Diseases / Q000139:chemically induced*; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy*; D010020:Osteonecrosis / Q000139:chemically induced*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012189:Retrospective Studies; D044465:White People / Q000235:genetics; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D051228:Geranyltranstransferase