BARCELONA, Spain—The RANK ligand (RANKL) inhibitor denosumab (Amgen Inc) reduces the progression of bone erosions in rheumatoid arthritis (RA), even though it does not affect inflammation or clinical signs and symptoms," Desiree van der Heijde, MD, with Leiden University Medical Center, in The Netherlands, reported at EULAR 2007.^1,2

Lead author Dr. van der Heijde reported data from a double-blind, placebo-controlled, phase II study in which 227 RA patients were randomized to subcutaneous injections of placebo, or denosumab 60 mg or 180 mg (all with background methotrexate) every 6 months. Eligibility criteria included RA with at least six swollen joints or CRP above 2 mg/dL with positivity for anti-CCP antibodies.

"These data show the significant potential of denosumab, revealing that patients receiving denosumab experienced a reduced progression of erosions compared to control. Most significant was the difference observed between the control group and the group receiving denosumab 180 mg. The reduction in progression of erosions was apparent in this group as early as 6 months," she said.

Dr. van der Heijde and colleagues explained that RANKL signaling triggers differentiation and activation of osteoclasts and that denosumab, a fully human monoclonal antibody, blocks this signal. They reported 12-month X-ray data for 202 patients as well as 6-month MRI data for 199 patients using the van der Heijde-modified total Sharp score (TSS) and its components (erosion score and joint space narrowing [JSN] score) to evaluate changes from baseline.

Dr. van der Heijde said that increases in mean TSS from baseline were smaller in the denosumab 60 mg group than with placebo (P = .03) and nonsignificantly smaller in the denosumab 180 mg group than in placebo (P = .18). The mean erosion score also increased less in both denosumab groups (P <.05), a mean reduction of 75% and 86%, respectively. All three groups had similar adverse events, of which RA flare was the most common. As expected, since denosumab does not affect inflammation, there were no changes in the swollen joint count.

"This is the first RA trial to use MRI erosion score as a primary endpoint," Dr. van der Heijde said. The MRI data showed the bone-protective effects of denosumab even more clearly, with patients in the denosumab 180 mg group showing significantly less progression of bone erosions than patients on placebo at 6 months (P <.019). MRI progression was also slower in the denosumab 60 mg group, but not significantly (P = .247).

MRI erosion scores increased in 53% of placebo patients, in 42% of patients on 60 mg denosumab, and in 30% of patients on 180 mg of denosumab (P = .01 for 180-mg group vs placebo). At 6 months, treatment did not affect change in MRI osteitis (bone edema), ACR score, or DAS.

"A single dose of 180 mg denosumab significantly reduced progression of bone erosions and was quickly seen on MRI," Dr. van der Heijde concluded.

References

1. van der Heijde D, Cohen SB, Sharp JT, et al.  OP0120  The RANKL inhibitor denosumab reduces progression of the total sharp score and bone erosions in patients with rheumatoid arthritis: X-ray results at 12 months. Presented at: EULAR 2007 Meeting; June 13-16, 2007; Barcelona, Spain. Abstract OP0120.
2. Cohen SB, Valen PA, Ritchlin C, et al. Inhibiting RANKL with denosumab reduces progression of bone erosions in patients with rheumatoid arthritis: 6-month MRI results from a randomized, placebo-controlled study. Presented at: EULAR 2007 Meeting; June 13-16, 2007; Barcelona, Spain. Abstract OP0226.