title: Increased osteoclastogenesis in patients with vertebral fractures following discontinuation of denosumab treatment.
abstract: OBJECTIVE
  To test the hypothesis that rebound of bone remodeling is responsible for clinical vertebral fractures reported in a few patients with osteoporosis after cessation of denosumab treatment.
  
  
  METHODS
  In this case-control study we compared clinical and biochemical characteristics of postmenopausal women with clinical vertebral fractures 8-16 months after the last injection of denosumab (Dmab/Fx+,n= 5) with those of treatment-naïve women with such fractures (Fx+,n= 5). In addition, 5 women who discontinued denosumab treatment but did not sustain vertebral fractures 18-20 months after the last injection were studied (Dmab/Fx-,n= 5).
  
  
  METHODS
  We measured serum microRNAs, gene expression of mRNAs of factors regulating formation and activity of osteoclasts and biochemical markers of bone and mineral metabolism. In Dmab/Fx+ and Fx+ women, blood was taken 4-8 weeks after the fracture.
  
  
  RESULTS
  Compared to Fx+ women, Dmab/Fx+ women had higher serum P1NP and CTx levels, and significantly lower serum miR-503 and miR-222-2 that downregulate osteoclastogenesis and osteoclast activity, and higher RANK (13-fold) andCTSK(2.6-fold) mRNA. The respective values of Dmab/Fx- women were in the same direction as those of Dmab/Fx+ women but of a lesser magnitude.
  
  
  CONCLUSIONS
  Bone fragility in women with clinical vertebral fractures after stopping denosumab therapy is pathophysiologically different from that of treatment-naïve women with osteoporosis and clinical vertebral fractures and it is associated with upregulation of markers of osteoclast formation and activity. The small number of women with this rare event studied is a limitation.
authors.affiliation: Department of Endocrinology424 General Military Hospital, Thessaloniki, Greece.
authors.forename: Athanasios D
authors.initials: AD
authors.lastname: Anastasilakis
authors.affiliation: 1st Department of Internal MedicineLaboratory of Clinical and Molecular Endocrinology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Yavropoulou
authors.affiliation: Department of Endocrinology and Diabetes251 Hellenic Air Force & VA General Hospital, Athens, Greece.
authors.forename: Polyzois
authors.initials: P
authors.lastname: Makras
authors.affiliation: Department of Rheumatology424 General Military Hospital, Thessaloniki, Greece.
authors.forename: Grigorios T
authors.initials: GT
authors.lastname: Sakellariou
authors.affiliation: Private PracticeThessaloniki, Greece.
authors.forename: Fotini
authors.initials: F
authors.lastname: Papadopoulou
authors.affiliation: Laboratories 'Analysis'Thessaloniki, Greece.
authors.forename: Spyridon
authors.initials: S
authors.lastname: Gerou
authors.affiliation: Center for Bone QualityLeiden University Medical Center, Leiden, The Netherlands.
authors.forename: Socrates E
authors.initials: SE
authors.lastname: Papapoulos
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D016723:Bone Remodeling / Q000235:genetics*; D016022:Case-Control Studies; D056657:Cathepsin K / Q000235:genetics; D024042:Collagen Type I / Q000378:metabolism; D000069448:Denosumab / Q000627:therapeutic use*; D000069340:Deprescriptions; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D010012:Osteogenesis / Q000235:genetics*; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D058866:Osteoporotic Fractures / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011347:Procollagen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics; D016103:Spinal Fractures / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D050071:Bone Density Conservation Agents; D056657:Cathepsin K; D024042:Collagen Type I; D000069448:Denosumab; D035683:MicroRNAs; D010446:Peptide Fragments; D010455:Peptides; D011347:Procollagen; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C525710:MIR222, human; C545473:MIRN503 microRNA, human; C505686:TNFRSF11A protein, human; C052929:collagen type I trimeric cross-linked peptide; C047202:procollagen Type I N-terminal peptide; C534130:CTSK protein, human