title: Bone turnover and the osteoprotegerin-RANKL pathway in tumor-induced osteomalacia: a longitudinal study of five cases.
abstract: To evaluate serum levels of osteoprotegerin (OPG), soluble receptor activator of the nuclear factor-kappaB (RANKL), and their relationship with FGF-23, lumbar bone mineral density (BMD), and bone turnover markers, five patients with tumor-induced osteomalacia (TIO) and 40 healthy controls were studied. TIO patients were followed for 360 days after surgical removal of underlying tumor (n = 2) or beginning of therapy with phosphate and calcitriol when surgical treatment was impossible (n = 3). At diagnosis, TIO patients had higher levels of FGF-23 and bone-specific alkaline phosphatase (bALP) and lower levels of cathepsin K (CathK), RANKL, and RANKL/OPG ratio compared to controls. During the follow-up, FGF-23 decreased significantly only in patients who underwent a surgical excision, while phosphate and BMD increased in all patients. The increases in BMD, phosphate, and renal phosphate reabsorption rate were directly related. In the first 60 days of follow-up, we observed a prolonged inhibition of RANKL, CathK, and bone resorption markers associated with a persistence of TIO symptoms and an increase in bALP. From day 60, levels of bone turnover markers returned progressively within the normal range and a clinical remission was observed. The inhibition of the RANKL/OPG pathway and the uncoupling of bone formation and resorption observed in patients with active TIO may be a compensatory mechanism, attempting to reduce worsening of osteomalacia. The BMD increase during TIO treatment is related to the improvement of phosphate rather than FGF-23 levels. A "hungry bone"-like syndrome was observed after surgical or pharmacological treatment.
authors.affiliation: Department of Clinical and Experimental Medicine, Federico II University, via Sergio Pansini, 5, 80131, Naples, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Rendina
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: De Filippo
authors.forename: Libuse
authors.initials: L
authors.lastname: Tauchmanovà
authors.forename: Luigi
authors.initials: L
authors.lastname: Insabato
authors.forename: Riccardo
authors.initials: R
authors.lastname: Muscariello
authors.forename: Fernando
authors.initials: F
authors.lastname: Gianfrancesco
authors.forename: Teresa
authors.initials: T
authors.lastname: Esposito
authors.forename: Michele
authors.initials: M
authors.lastname: Cioffi
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
authors.forename: Pasquale
authors.initials: P
authors.lastname: Strazzullo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mossetti
mesh_terms: D015519:Bone Density / Q000502:physiology; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006393:Hemangiopericytoma / Q000150:complications; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications*; D010012:Osteogenesis; D010018:Osteomalacia / Q000209:etiology* / Q000378:metabolism*; D053244:Osteoprotegerin / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C000717427:FGF23 protein, human; D053244:Osteoprotegerin; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23