Background/Purpose: Tocilizumab (TCZ) is a humanized monoclonal anti-IL-6 receptor antibody. TCZ has demonstrated efficacy in moderate to severe active rheumatoid arthritis (RA) with inadequate clinical response to disease-modifying anti-rheumatic drugs (DMARDs) or TNF inhibitors. Moreover, it is reported that TCZ combined with MTX reduces systemic bone resorption in RA. However, the detailed mechanism about improvement effect by TCZ on abnormal bone homeostasis in RA is poorly understood. In this study, we investigated the effect of TCZ on biomarkers of bone metabolism, soluble receptor activator of NF-kappa B ligand (sRANKL), osteoprotegerin (OPG), Dickkopf-1 (DKK-1), and osteopontin (OPN) in active RA.

Methods: Thirty four patients with active RA (25 females, 9 males; age 51.9±7.9 years; disease duration 12.4±12.6 years; DAS28-ESR 5.6±1.6) were started on treatment with TCZ 8mg/kg intravenously every 4 weeks. All patients were treated with methotrexate, other DMARDs and prednisolone, and the treatments continued at the stable pretreatment doses. After 12 weeks of treatment with TCZ, we evaluated an effectiveness using DAS28-ESR. We appreciated DAS28-ESR<2.6 as a remission group and DAS28-ESR³a2.6 as a no-remission group, respectively. Additionally, we measured serum biochemical markers such as osteocalcin, type I collagen cross-linked N-telopeptides (NTx), sRANKL, OPG, and DKK-1 and plasma OPN by ELISA at baseline and 12 weeks.

Results: At 12 weeks after the treatment of TCZ, a disease activity reduced significantly from the baseline (DAS28-ESR 5.6±1.6 vs 3.1±1.7; p<0.01). Fifteen patients achieved the remission. In the analysis of bone metabolic markers at 12 weeks, average of serum NTx levels decreased significantly from the baseline (18.91nmol BCE/l vs 17.16nmol BCE/l; p<0.05) and osteocalcin levels increased significantly from the baseline (5.78ng/ml vs 6.68ng/ml; p<0.05). In addition, average of serum sRANKL, DKK-1, and plasma OPN levels decreased significantly from the baseline (sRANKL: 0.570pmol/l vs 0.480pmol/l; p<0.05, DKK-1: 2806pg/ml vs 2282pg/ml; p<0.01, and OPN: 117.0ng/ml vs 77.1ng/ml; p<0.01 respectively), however average of OPG levels did not change significantly from the baseline. TCZ decreased NTx, sRANKL, DKK-1, and OPN levels and increased osteocalcin levels regardless of remission group or no-remission group. Moreover, average of OPG levels in remission group increased significantly from the base line. Therefore, OPG/RANKL ratio tended to increase in remission group compared with no-remission group.

Conclusion: These findings suggest that TCZ therapy improves abnormal bone homeostasis in patient with active RA. We consider that this mechanism may result from the regulation of osteoclastic-bone destruction via the control of RANKL induced-osteoclastogenesis and OPN induced-osteoclast attachment of bone surface and the promotion of osteoblastic-bone formation via the regulation of DKK-1.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-6-signaling-inhibition-improves-abnormal-bone-homeostasis-in-active-rheumatoid-arthritis/