Rheumatoid arthritis (RA) represents an excellent model for gaining insights into the adverse effects of inflammatory arthritis on local articular as well as generalized systemic bone remodeling. Bone loss manifested by focal erosions at the margins of diarthrodial joints represents the radiographic hallmark of RA. These lesions are produced by resorption of cortical bone at the bone–pannus junction. Inflammatory pannus can also extend into the marrow space, with accompanying subcortical and trabecular bone destruction. In animal models of inflammatory arthritis, erosion of subchondral bone contributes significantly to cartilage loss, as the scaffolding bone is destroyed by the inflammatory process. Preservation of subchondral bone integrity would be predicted to have a cartilage sparing effect even in the presence of continued intra-articular joint inflammation. Recent studies employing magnetic resonance imaging have shown that marginal joint erosions occur very early in the course of RA and progress throughout the disease [1, 2]. The propensity of the inflamed pannus tissue in RA to induce bone resorption is probably related to its capacity to produce a variety of factors with potent osteoclast differentiation and activation activity. Particular attention has focused on receptor activator of NF-κB ligand (RANKL), a member of the tumor necrosis factor ligand family, because of the requirement of this factor for osteoclastogenesis. RANKL is expressed by synovial fibroblasts and activated T cells in RA synovial tissues [3]. In three different animal models of inflammatory arthritis, treatment with osteoprotegerin (the soluble receptor that inhibits RANKL activity) results in marked suppression of focal bone erosions [4–6]. In addition, mice possessing the null mutation for RANKL are protected from focal bone destruction in the serum transfer model of inflammatory arthritis [7]. These observations lend support to the concept that enhanced osteoclast-mediated bone resorption at the pannus–bone interface and in subchondral and trabecular bone play a critical role in the pathogenesis of focal articular bone erosions.

An additional observation in patients with active RA is the absence of bone repair radiographically. This finding suggests that the processes that regulate coupling of bone resorption and formation under physiologic conditions have been disrupted, and that the enhanced focal bone resorption associated with the synovial inflammatory lesion is not matched by a compensatory increase in bone formation. Of particular interest will be the determination of the effects of therapies that inhibit joint erosions on these focal bone remodeling events at the bone–pannus interface and in the subchondral bone.

In addition to the disordered focal bone remodeling associated with the synovitis, patients with RA also exhibit evidence of generalized axial and appendicular osteopenia at sites that are distant from inflamed joints [8]. The reduction in bone mass has been confirmed using multiple different techniques, and patients with RA have an increased risk of hip and vertebral fractures [9]. Assessment of biochemical markers of bone turnover indicates that there is a generalized increase in bone resorption, and that there is a correlation between disease activity and the rate of systemic bone resorption. Patients with greater disease activity exhibit enhanced rates of bone loss. It is likely that the disturbance in systemic bone remodeling is mediated by proinflammatory cytokines with osteoclastogenic activity that are released into the circulation from the inflamed joints. These factors probably then act systemically to produce a generalized increase in osteoclast-mediated bone resorption. Bisphosphonates have been shown to reverse systemic bone loss in patients with RA, but studies thus far have not shown that these treatment regimens reduce the progression of focal bone erosions [10]. It is likely, however, that new approaches for more effectively inhibiting osteoclast-mediated bone resorption will become available; for example, agents that specifically inhibit osteoclast formation or activity by targeting mediators such as RANKL. Whether preservation of the skeletal architecture, independent of, or in addition to suppression of joint and systemic inflammation, will impact on the progression of functional disability needs to be investigated in appropriately designed clinical trials.