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).
Author(s): Karsdal MA, Schett G, Emery P, Harari O, Byrjalsen I, Kenwright A, Bay-Jensen AC,
Affiliation(s): Nordic Bioscience, Herlev, Denmark. firstname.lastname@example.org
Publication date & source: 2012, Semin Arthritis Rheum. , 42(2):131-9
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.