The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction

Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in debilitating joint deformities with destruction of bone and cartilage. Inflammation is still considered the pivotal inducer of both components of joint damage. Results of recent animal studies suggested a prominent contribution of osteoclastic bone resorption that could be dissociated from inflammation. RANKL and its natural decoy receptor, osteoprotegerin (OPG), play key roles in osteoclast activation. In a group of patients with early RA not treated with disease-modifying drugs, we tested the hypothesis that osteoclast activation, reflected by the serum OPG:RANKL ratio at baseline, is negatively associated with progression of bone damage, independent of inflammation.

OPG and RANKL levels, together with a parameter of inflammation (first-year time-averaged erythrocyte sedimentation rate [tESR]), were measured in 92 patients with newly diagnosed early active RA who were participants in a randomized study. The tESR and the OPG:RANKL ratio were evaluated for the ability to predict 5-year radiographic progression of joint damage.

The first-year tESR and the OPG:RANKL ratio, as measured at baseline, independently predicted 5-year radiographic progression of joint damage (both P < or = 0.001). Progression of radiographic damage was greatest in patients with a high tESR and a low OPG:RANKL ratio and was lowest in patients with a low tESR and a high OPG:RANKL ratio.

This study in patients with early untreated RA is the first to confirm the findings in animal models of arthritis, that radiographic progression of the bone component of joint destruction is dependent on both inflammation (tESR) and osteoclast activation (the OPG:RANKL ratio).