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: Morten A Karsdal, Georg Schett, Paul Emery, Olivier Harari, Inger Byrjalsen, Andy Kenwright, Anne C Bay-Jensen, Adam Platt
• Journal: Seminars in arthritis and rheumatism (Semin Arthritis Rheum) Vol. 42 Issue 2 Pg. 131-9 (Oct 2012) ISSN: 1532-866X [Electronic] United States
• PMID: 22397953 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antirheumatic Agents
• Biomarkers
• Collagen Type I
• Peptides
• Receptors, Interleukin-6
• Tumor Necrosis Factor-alpha
• collagen type I trimeric cross-linked peptide
• Osteocalcin
• C-Reactive Protein
• MMP3 protein, human
• Matrix Metalloproteinase 3
• tocilizumab
• Methotrexate

Topics

• Antibodies, Monoclonal, Humanized (adverse effects, therapeutic use)
• Antirheumatic Agents (adverse effects, therapeutic use)
• Arthritis, Rheumatoid (blood, drug therapy)
• Biomarkers (blood)
• Bone Resorption (drug therapy, metabolism)
• Bone and Bones (metabolism)
• C-Reactive Protein (metabolism)
• Collagen Type I (blood)
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Humans
• Injections, Intravenous
• Male
• Matrix Metalloproteinase 3 (blood)
• Methotrexate (therapeutic use)
• Middle Aged
• Osteocalcin (blood)
• Osteogenesis (drug effects, physiology)
• Peptides (blood)
• Receptors, Interleukin-6 (antagonists & inhibitors)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)