Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone

Arthritis Rheum. 2010 Jan;62(1):33-43. doi: 10.1002/art.25053.


Objective: To investigate the effects of tocilizumab (TCZ) added to a stable dosage of methotrexate (MTX) on biochemical markers of bone and cartilage metabolism in patients in the multicenter double-blind, placebo-controlled OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders) study who have moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to MTX.

Methods: Included in this study were 416 of the 623 patients with active RA enrolled in the OPTION study. Patients were randomized to receive TCZ (4 mg/kg or 8 mg/kg) or placebo intravenously every 4 weeks, with MTX continued at the stable prestudy doses (10-25 mg for 20 weeks, with a final followup at week 24). Serum biochemical markers of bone formation (osteocalcin, N-terminal propeptide of type I collagen [PINP]), bone resorption (C-terminal crosslinking telopeptide of type I collagen [CTX-I] and C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases [ICTP]), cartilage metabolism (N-terminal propeptide of type IIA collagen [PIIANP]), collagen helical peptide [HELIX-II]), and matrix metalloproteinase 3 (MMP-3) were measured at baseline and at weeks 4, 16, and 24.

Results: TCZ induced marked dose-dependent reductions in PIIANP, HELIX-II, and MMP-3 levels at week 4 that were maintained until week 24, an effect associated with increased levels of bone formation markers that were significant as compared with placebo only for PINP and only at 4 weeks (P < 0.01 for both TCZ doses). TCZ induced significant decreases in the bone degradation markers CTX-I and ICTP, providing initial evidence of a beneficial effect on bone turnover. TCZ-treated patients who met the American College of Rheumatology 50% improvement criteria (achieved an ACR50 response) or achieved clinical remission (as determined by a Disease Activity Score in 28 joints <2.6) at week 24 had greater reductions in ICTP, HELIX-II, and MMP-3 levels as compared with ACR50 nonresponders.

Conclusion: TCZ combined with MTX reduces systemic bone resorption, cartilage turnover, and proteolytic enzyme MMP-3 levels, which provides evidence of a limitation of joint damage and possible beneficial effects on skeletal structure in patients with established moderate-to-severe RA.

Trial registration: ClinicalTrials.gov NCT00106548.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / drug therapy*
  • Biomarkers / blood
  • Cartilage, Articular / drug effects
  • Cartilage, Articular / physiology
  • Chondrogenesis / drug effects*
  • Chondrogenesis / physiology
  • Collagen Type I
  • Collagen Type II / blood
  • Double-Blind Method
  • Drug Therapy, Combination
  • Drug Tolerance
  • Female
  • Health Status
  • Humans
  • Male
  • Matrix Metalloproteinase 3 / blood
  • Methotrexate / therapeutic use*
  • Middle Aged
  • Osteocalcin / blood
  • Osteogenesis / drug effects*
  • Osteogenesis / physiology
  • Peptide Fragments / blood
  • Peptides
  • Procollagen / blood


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Biomarkers
  • Collagen Type I
  • Collagen Type II
  • Peptide Fragments
  • Peptides
  • Procollagen
  • collagen type I trimeric cross-linked peptide
  • procollagen Type I N-terminal peptide
  • procollagen type IIA amino-terminal peptide
  • Osteocalcin
  • Matrix Metalloproteinase 3
  • tocilizumab
  • Methotrexate

Associated data

  • ClinicalTrials.gov/NCT00106548