Denosumab is a fully human monoclonal antibody that binds to and inhibits RANK Ligand (RANKL), a key mediator of osteoclast formation, function, and survival. There is no detectable binding to TNFα, TNFβ, TRAIL, or CD40L. RANKL-driven osteoclast activity has been implicated in the bone erosions that are characteristic of rheumatoid arthritis (RA).

This ongoing, double-blind, placebo-controlled, phase 2 study was conducted to determine if denosumab treatment could reduce the progression of bone erosions in patients with RA who were on background methotrexate (MTX). Based on previous pharmacokinetic studies of denosumab in postmenopausal women, a 6 month dosing schedule was selected for this initial trial [Bekker PJ et al. J Bone Miner Res 2004; Peterson M et al. J Bone Miner Res 2003].

A total of 227 patients (9 patients never received test article) were randomly assigned to receive subcutaneous injections of denosumab 60 mg (n=71) or 180 mg (n=72) or placebo (n=75) every 6 months. Of this group, 2 patients discontinued from the 60 mg group, 6 discontinued from the 180 mg group, and 6 discontinued from the placebo group. Radiographs of the hands and feet were taken at baseline, 6, and 12 months. Randomization was stratified for prior use of biologics and current steroid use. Change from baseline in MRI erosion scores at 6 months was the primary endpoint. Key secondary endpoints included changes in the modified Sharp erosion score (ES), modified Sharp joint space narrowing score (JSN), and modified total Sharp score (TSS) from baseline and at months 6 and 12. Radiographs of the hands/wrist and feet were analyzed using the van der Heijde-modified Sharp method. Increasing scores reflected increased damage. Safety was monitored throughout the study.

The mean change in ES at 6 months was significantly (p=0.02) less for patients treated with 180 mg of denosumab vs placebo. Data for 209 patients are included in the 12 month analysis. At 12 months, the change was significantly (p≤0.01) less for both doses of denosumab.

No significant differences were noted for any treatment group for ACR response. Modeling of data for collagen C-telopeptide Type II (CTX-II, a biomarker of cartilage turnover) suggests that the dose/frequency used in this study may not have been sufficient to preserve cartilage. The radiographic erosion scores were consistent with MRI erosion scores analyzed at the primary endpoint of the study.

Adverse events were similar across the 3 treatment groups. The most frequent, occurring at ≥10%, were flare, upper respiratory infection, sinusitis, nasopharyngitis, and influenza.

Denosumab treatment (60 mg and 180 mg) every 6 months reduced progression of TSS and ES, but not JSN vs placebo. No change in ACR response was noted. The incidence of adverse events was similar among the placebo and denosumbab 60 mg and 180 mg treatment groups.

Professor Désirée van der Heijde, MD, Leiden University Medical Center and lead author of the study commented, “These data show the significant potential of denosumab, revealing that patients receiving denosumab experienced a reduced progression of erosions compared to control…”