title: Osteoprotegerin and RANKL in the pathogenesis of thalassemia-induced osteoporosis: new pieces of the puzzle.
abstract: Osteoporosis represents an important cause of morbidity in adult thalassemic patients, and its pathogenesis has not, as yet, been completely clarified. In our study, we observed that thalassemic patients showed a significantly lower OPG/RANKL ratio than normal subjects. These data are extremely important for the possible therapeutic use of RANKL antagonists such as OPG in thalassemia-induced osteoporosis.
  
  
  BACKGROUND
  Osteoporosis represents an important cause of morbidity in adult thalassemic patients who display increased fracture risk. The etiology of this bone disease is multifactorial, but it is thought that the main role is played by hypogonadism. The mechanisms by which the skeletal effects of sex steroids are mediated are still not fully understood. Recently, two new cytokines, osteoprotegerin (OPG) and RANKL, have been implicated in the pathogenesis of postmenopausal osteoporosis and other metabolic bone diseases. Thus, the aim of this study was to characterize the possible role of the OPG/RANKL system in thalassemia-related bone loss.
  
  
  METHODS
  We measured, in 30 thalassemic patients and in 20 healthy control subjects, serum OPG and RANKL levels, and determined their correlations with bone turnover markers, BMD, sex steroid levels, erythropoietin, and hemoglobin.
  
  
  RESULTS
  Thalassemic patients had an unbalanced bone turnover with an increased resorption phase (shown by high levels of pyridinium cross-links) and a decreased neoformation phase (shown by the slightly low levels of osteocalcin). Moreover, they displayed lower BMD values than controls both at the lumbar and femoral level. As far as the OPG/RANKL system is concerned, thalassemic patients showed no differences in plasma levels of OPG compared with controls, and significantly higher plasma levels of RANKL, with a consequent significantly lower OPG/RANKL ratio.
  
  
  CONCLUSIONS
  Our data suggest that, in thalassemic patients, an altered modulation of the OPG/RANKL system, resulting in increased expression of RANKL by stromal or osteoblastic cells, could contribute to the enhanced osteoclastic bone resorption and bone loss characteristic of these patients.
authors.affiliation: Department of Internal Medicine, University of Messina, Messina, Italy. nancynat@libero.it
authors.forename: Nunziata
authors.initials: N
authors.lastname: Morabito
authors.forename: Agostino
authors.initials: A
authors.lastname: Gaudio
authors.forename: Antonino
authors.initials: A
authors.lastname: Lasco
authors.forename: Marco
authors.initials: M
authors.lastname: Atteritano
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Pizzoleo
authors.forename: Maria
authors.initials: M
authors.lastname: Cincotta
authors.forename: Mariangela
authors.initials: M
authors.lastname: La Rosa
authors.forename: Roberta
authors.initials: R
authors.lastname: Guarino
authors.forename: Anna
authors.initials: A
authors.lastname: Meo
authors.forename: Nicola
authors.initials: N
authors.lastname: Frisina
mesh_terms: D000328:Adult; D000596:Amino Acids / Q000652:urine; D015415:Biomarkers; D015519:Bone Density; D001862:Bone Resorption; D002352:Carrier Proteins / Q000097:blood*; D016022:Case-Control Studies; D004958:Estradiol / Q000097:blood; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging; D006023:Glycoproteins / Q000097:blood*; D006454:Hemoglobins; D006801:Humans; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood*; D010024:Osteoporosis / Q000097:blood / Q000209:etiology* / Q000473:pathology / Q000652:urine; D053244:Osteoprotegerin; D053245:RANK Ligand; D011859:Radiography; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood*; D018124:Receptors, Tumor Necrosis Factor; D012044:Regression Analysis; D013739:Testosterone / Q000097:blood; D017086:beta-Thalassemia / Q000097:blood / Q000150:complications* / Q000652:urine
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D002352:Carrier Proteins; D006023:Glycoproteins; D006454:Hemoglobins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D013739:Testosterone; D004958:Estradiol; C036020:deoxypyridinoline