title: IL-6 receptor inhibition positively modulates bone balance in rheumatoid arthritis patients with an inadequate response to anti-tumor necrosis factor therapy: biochemical marker analysis of bone metabolism in the tocilizumab RADIATE study (NCT00106522).
abstract: OBJECTIVE
  To evaluate changes in biochemical markers of bone metabolism in response to tocilizumab in patients with anti-tumor necrosis factor-refractory rheumatoid arthritis (RA).
  
  
  METHODS
  RADIATE was a randomized, double-blind, placebo-controlled, parallel-group phase 3 trial. C-reactive protein, osteocalcin (OC), C-terminal telopeptides of type-I collagen (C-terminal telopeptides of type-1 collagen (CTX-I) and type-I collagen degradation product), and matrix metalloproteinase-3 (MMP-3) serum levels were analyzed from 299 RA patients. Patients were randomly assigned to either tocilizumab (4 or 8 mg/kg) or placebo intravenously every 4 weeks, along with concomitant stable methotrexate (10 to 25 mg weekly) in all treatment arms. The change in biochemical markers CTX-I and OC in combination was evaluated as a measure of net bone balance, a reflection of the change in equilibrium between resorption and formation.
  
  
  RESULTS
  Both tocilizumab doses decreased C-reactive protein levels and significantly inhibited cathepsin K-mediated bone resorption in RADIATE subjects, as measured by a decrease in CTX-I. There was a significant overall improvement in net bone balance at week 16 as measured by a decrease in the CTX-I:OC ratio (-25%, P < 0.01). Furthermore, a significant reduction in MMP-3 (43%, P < 0.001) and type-I collagen degradation product levels (18%, P < 0.001) were observed following treatment, both consistent with decreased MMP-mediated type-I collagen catabolism in joint tissue.
  
  
  CONCLUSIONS
  In anti-tumor necrosis factor-refractory patients, tocilizumab significantly reduced the levels of biochemical markers of cathepsin K-mediated bone resorption and MMP-mediated tissue degradation and remodeling. These observations suggest that tocilizumab has a positive effect on bone balance, which could in part explain the retardation of progressive structural damage observed with tocilizumab. Clinical trial registry number: NCT00106522.
authors.affiliation: Nordic Bioscience, Herlev, Denmark. mk@nordicbioscience.com
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Olivier
authors.initials: O
authors.lastname: Harari
authors.forename: Inger
authors.initials: I
authors.lastname: Byrjalsen
authors.forename: Andy
authors.initials: A
authors.lastname: Kenwright
authors.forename: Anne C
authors.initials: AC
authors.lastname: Bay-Jensen
authors.forename: Adam
authors.initials: A
authors.lastname: Platt
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism*; D002097:C-Reactive Protein / Q000378:metabolism; D024042:Collagen Type I / Q000097:blood; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000097:blood; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D010455:Peptides / Q000097:blood; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; D024042:Collagen Type I; D010455:Peptides; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C052929:collagen type I trimeric cross-linked peptide; D015675:Osteocalcin; D002097:C-Reactive Protein; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C502936:tocilizumab; D008727:Methotrexate