title: Vitamin D receptor gene polymorphisms predict acquired resistance to clodronate treatment in patients with Paget's disease of bone.
abstract: Bisphosphonates are first-choice drugs for treatment of Paget's disease of bone (PDB); nevertheless, acquired resistance to bisphosphonate therapy has been described in PDB patients. The 1,25(OH)(2)D(3)/vitamin D receptor (VDR) system influences the effectiveness of antiresorptive treatments in metabolic bone disorders. This study evaluated the relationship between acquired resistance to clodronate treatment and BsmI, TaqI, and FokI VDR polymorphisms in Caucasian patients with polyostotic PDB (n = 84). We also evaluated the influence of mutations in exons 7 and 8 of the sequestosome 1 (SQSTM1) gene on the occurrence of this phenomenon. All patients were treated from diagnosis for several cycles with intravenous clodronate infusion (1500 mg/cycle). Acquired resistance to clodronate treatment was defined as the failure of total alkaline phosphatase serum levels to be suppressed to at least 50% of the patient's previous highest levels during a subsequent treatment course with the same compound, which produced a >50% response after the first exposure. During an observation period of 10.6 +/- 2.7 years, 31 PDB patients (36.9%) showed acquired resistance to clodronate. It was observed that the bb and TT VDR genotypes as well as a lower persistence of the biochemical response to the first treatment course were significantly and independently associated with the risk of developing resistance to clodronate treatment. SQSTM1 gene mutations, considered altogether, did not influence the occurrence of this phenomenon. Our results indicate that 3'VDR allelic variants and duration of biochemical response to the first treatment course are independent predictors of acquired resistance to clodronate treatment in patients with polyostotic PDB.
authors.affiliation: Department of Clinical and Experimental Medicine, Federico II University Medical School, Via S. Pansini 5, Naples, 80131, Italy. giumosse@unina.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mossetti
authors.forename: Luigi
authors.initials: L
authors.lastname: Gennari
authors.forename: Domenico
authors.initials: D
authors.lastname: Rendina
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: De Filippo
authors.forename: Daniela
authors.initials: D
authors.lastname: Merlotti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Paola
authors.forename: Pina
authors.initials: P
authors.lastname: Fusco
authors.forename: Teresa
authors.initials: T
authors.lastname: Esposito
authors.forename: Fernando
authors.initials: F
authors.lastname: Gianfrancesco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Martini
authors.forename: Ranuccio
authors.initials: R
authors.lastname: Nuti
authors.forename: Pasquale
authors.initials: P
authors.lastname: Strazzullo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D004002:Clodronic Acid / Q000627:therapeutic use*; D015331:Cohort Studies; D004351:Drug Resistance; D005091:Exons; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010001:Osteitis Deformans / Q000188:drug therapy* / Q000235:genetics*; D011110:Polymorphism, Genetic; D018167:Receptors, Calcitriol / Q000235:genetics*; D012306:Risk; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018167:Receptors, Calcitriol; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D004002:Clodronic Acid