Skip to main content

Advertisement

Adverse effects of rheumatoid arthritis on bone remodeling

Article metrics

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 [46]. 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.

References

  1. 1.

    McQueen FM, Stewart N, Crabbe J, Robinson E, Yeoman S, Tan PL, McLean L: Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom onset. Ann Rheum Dis. 1998, 57: 350-356.

  2. 2.

    McGonagle D, Conaghan PG, O'Connor P, Gibbon W, Green M, Wakefield R, Ridgway J, Emery P: The relationship between synovitis and bone changes in early untreated rheumatoid arthritis: a controlled magnetic resonance imaging study. Arthritis Rheum. 1999, 42: 1706-1711. 10.1002/1529-0131(199908)42:8<1706::AID-ANR20>3.0.CO;2-Z.

  3. 3.

    Gravallese EM, Manning C, Tsay A, Naito A, Pan C, Amento E, Goldring SR: Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 2000, 43: 250-258. 10.1002/1529-0131(200002)43:2<250::AID-ANR3>3.0.CO;2-P.

  4. 4.

    Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM: Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999, 402: 304-309. 10.1038/46303.

  5. 5.

    Redlich K, Hayer S, Maier A, Dunstan CR, Tohidast-Akrad M, Lang S, Turk B, Pietschmann P, Woloszczuk W, Haralambous S, Kollias G, Steiner G, Smolen JS, Schett G: Tumor necrosis factor alpha-mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin. Arthritis Rheum. 2002, 46: 785-792. 10.1002/art.10097.

  6. 6.

    Romas E, Sims NA, Hards DK, Lindsay M, Quinn JW, Ryan PF, Dunstan CR, Martin TJ, Gillespie MT: Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am J Pathol. 2002, 161: 1419-1427.

  7. 7.

    Pettit AR, Ji H, von Stechow D, Muller R, Goldring SR, Choi Y, Benoist C, Gravallese EM: TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol. 2001, 159: 1689-1699.

  8. 8.

    Haugeberg G, Uhlig T, Falch JA, Halse JI, Kvien TK: Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo County Rheumatoid Arthritis register. Arthritis Rheum. 2000, 43: 522-530. 10.1002/1529-0131(200003)43:3<522::AID-ANR7>3.0.CO;2-Y.

  9. 9.

    Peel NF, Moore DJ, Barrington NA, Bax DE, Eastell R: Risk of vertebral fracture and relationship to bone mineral density in steroid treated rheumatoid arthritis. Ann Rheum Dis. 1995, 54: 801-806.

  10. 10.

    Eggelmeijer F, Papapoulos SE, van Paassen HC, Dijkmans BA, Valkema R, Westedt ML, Landman JO, Pauwels EK, Breedveld FC: Increased bone mass with pamidronate treatment in rheumatoid arthritis. Results of a three-year randomized, double-blind trial. Arthritis Rheum. 1996, 39: 396-402.

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Goldring, S., Gravallese, E. Adverse effects of rheumatoid arthritis on bone remodeling. Arthritis Res Ther 6, 38 (2004) doi:10.1186/ar1373

Download citation

Keywords

  • Rheumatoid Arthritis
  • Bone Resorption
  • Subchondral Bone
  • Inflammatory Arthritis
  • Rheumatoid Arthritis Synovial Tissue