PMID- 22397953
OWN - NLM
STAT- MEDLINE
DCOM- 20130228
LR  - 20220330
IS  - 1532-866X (Electronic)
IS  - 0049-0172 (Linking)
VI  - 42
IP  - 2
DP  - 2012 Oct
TI  - 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).
PG  - 131-9
LID - S0049-0172(12)00018-2 [pii]
LID - 10.1016/j.semarthrit.2012.01.004 [doi]
AB  - 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.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Karsdal, Morten A
AU  - Karsdal MA
AD  - Nordic Bioscience, Herlev, Denmark. mk@nordicbioscience.com
FAU - Schett, Georg
AU  - Schett G
FAU - Emery, Paul
AU  - Emery P
FAU - Harari, Olivier
AU  - Harari O
FAU - Byrjalsen, Inger
AU  - Byrjalsen I
FAU - Kenwright, Andy
AU  - Kenwright A
FAU - Bay-Jensen, Anne C
AU  - Bay-Jensen AC
FAU - Platt, Adam
AU  - Platt A
LA  - eng
SI  - ClinicalTrials.gov/NCT00106522
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20120306
PL  - United States
TA  - Semin Arthritis Rheum
JT  - Seminars in arthritis and rheumatism
JID - 1306053
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Biomarkers)
RN  - 0 (Collagen Type I)
RN  - 0 (Peptides)
RN  - 0 (Receptors, Interleukin-6)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (collagen type I trimeric cross-linked peptide)
RN  - 104982-03-8 (Osteocalcin)
RN  - 9007-41-4 (C-Reactive Protein)
RN  - EC 3.4.24.17 (MMP3 protein, human)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - I031V2H011 (tocilizumab)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Antibodies, Monoclonal, Humanized/adverse effects/*therapeutic use
MH  - Antirheumatic Agents/adverse effects/*therapeutic use
MH  - Arthritis, Rheumatoid/blood/*drug therapy
MH  - Biomarkers/blood
MH  - Bone Resorption/drug therapy/metabolism
MH  - Bone and Bones/*metabolism
MH  - C-Reactive Protein/metabolism
MH  - Collagen Type I/blood
MH  - Double-Blind Method
MH  - Drug Therapy, Combination
MH  - Female
MH  - Humans
MH  - Injections, Intravenous
MH  - Male
MH  - Matrix Metalloproteinase 3/blood
MH  - Methotrexate/therapeutic use
MH  - Middle Aged
MH  - Osteocalcin/blood
MH  - Osteogenesis/*drug effects/physiology
MH  - Peptides/blood
MH  - Receptors, Interleukin-6/*antagonists & inhibitors
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors
EDAT- 2012/03/09 06:00
MHDA- 2013/03/01 06:00
CRDT- 2012/03/09 06:00
PHST- 2011/10/26 00:00 [received]
PHST- 2012/01/13 00:00 [revised]
PHST- 2012/01/16 00:00 [accepted]
PHST- 2012/03/09 06:00 [entrez]
PHST- 2012/03/09 06:00 [pubmed]
PHST- 2013/03/01 06:00 [medline]
AID - S0049-0172(12)00018-2 [pii]
AID - 10.1016/j.semarthrit.2012.01.004 [doi]
PST - ppublish
SO  - Semin Arthritis Rheum. 2012 Oct;42(2):131-9. doi: 
      10.1016/j.semarthrit.2012.01.004. Epub 2012 Mar 6.