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.