Download PDF
Aktuelle Rheumatologie 2012; 37(04): 243-247
DOI: 10.1055/s-0032-1304597
Übersichtsarbeit
© Georg Thieme Verlag KG Stuttgart · New York

Entzündliche Erkrankungen und Osteoporose – Potenzial der RANKL-Hemmung am Beispiel der Rheumatoiden Arthritis

Inflammatory Diseases and Osteoporosis – Potential of RANKL Inhibition in Rheumatoid Arthritis
G. E. Hein
1   MVZ Qsana Weimar und Rheumazentrum Jena
› Author Affiliations
Further Information

Publication History

Publication Date:
06 March 2012 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Die Rheumatoide Arthritis ist initial durch eine gelenknahe Osteoporose, im weiteren Verlauf durch eine zunehmende Gelenkdestruktion, aber auch durch eine der chronischen Entzündung geschuldete systemische Osteoporose charakterisiert. Beide Manifestationen werden wesentlich durch eine sowohl periartikulär als auch systemisch gesteigerte Osteoklastenaktivität verursacht. Verantwortlich hierfür ist eine relativ erhöhte Expression/Synthese von RANKL. Mit Denosumab, einem humanen RANKL-Antikörper, kann sowohl die knöcherne Gelenkdestruktion als auch die systemische Osteoporose aufgehalten werden. Denosumab vermag aber nicht die entzündliche Aktivität oder die damit verbundenen Schmerzen und funktionellen Einschränkungen zu beeinflussen.

Abstract

Rheumatoid arthritis is characterised by juxtaarticular osteoporosis in the early stage, and by increasing articular destruction in the further course, but also by systemic osteoporosis caused by chronic inflammation. These 2 manifestations are driven especially by increased activity of osteoclasts, both periarticular and systemic. The reason for this intensive osteoclast generation and functional activity is the high expression and synthesis of RANKL. With the application of denosumab, a fully human RANKL antibody, we are not only able to interrupt the articular destruction process but also to improve the bone mineral density. Denosumab, however, has no influence on inflammatory activity, pain and functional disability.

Schlüsselwörter

Rheumatoide Arthritis - Entzündung - Osteoporose - RANKL - Denosumab

Key words

rheumatoid arthritis - inflammation - osteoporosis - RANKL - denosumab
 

  • Literatur

  • 1 Jakob F, Benisch P, Ebert R. Pathophysiologie der Osteoporose. DBI 2010; 30: 110-118
    PubMedGoogle Scholar
  • 2 Hofbauer LC, Heufelder AE. Role of receptor activator of nuclear factor -kB ligand and osteoprotegerin in bone cell biology. J Mol Med 2001; 79: 243-253
    CrossrefPubMedGoogle Scholar
  • 3 Kong Y-Y, Yoshida H, Sarosi I et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999; 397: 315-323
    CrossrefPubMedGoogle Scholar
  • 4 Wong BR, Rho J, Arron J et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinases in T-cells. J Biol Chem 1997; 272: 25190-25194
    CrossrefPubMedGoogle Scholar
  • 5 Kong Y-Y, Feige U, Sarosi I et al. Activated T-cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999; 402: 304-309
    CrossrefPubMedGoogle Scholar
  • 6 Yeo L, Toellner KM, Salmon M et al. Cytokine mRNA profiling identifies B-cells as the major source of RANKL in rheumatoid arthritis. Ann Rheum Dis 2011; 70: 2022-2024
    CrossrefPubMedGoogle Scholar
  • 7 Lam J, Takeshita S, Barker JE et al. TNF alpha induces osteoclasto-genesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000; 106: 1481-1488
    CrossrefPubMedGoogle Scholar
  • 8 Lacey DL, Timms E, Tan HL et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165-176
    CrossrefPubMedGoogle Scholar
  • 9 Bekker PJ, Holloway DL, Rasmussen AS et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Mineral Res 2004; 19: 1059-1066
    CrossrefPubMedGoogle Scholar
  • 10 Hofbauer LC, Khosla S, Dunstan CR et al. The roles of osteoprotegerin and osteoprotegerinligand in the paracrine regulation of bone resorption. J Bone Mineral Res 2000; 15: 2-12
    CrossrefPubMedGoogle Scholar
  • 11 Schett G. Review: Immune cells and mediators of inflammatory arthritis. Autoimmunity 2008; 41: 224-229
    CrossrefPubMedGoogle Scholar
  • 12 Hein G, Meister M, Oelzner P et al. SRANKL and OPG in serum and syn-ovial fluid in patients with rheumatoid arthritis in comparison to non-destructive chronic arthritis. Rheumatol Intern 2008; 28: 765-769
    PubMedGoogle Scholar
  • 13 Stolina M, Adamu S, Ominsky M et al. RANKL is a marker and medi-ator of local and systemic bone loss in two rat models of inflammatory arthritis. J Bone Mineral Res 2005; 20: 1756-1765
    CrossrefPubMedGoogle Scholar
  • 14 Neumann T, Oelzner P, Petrow PK et al. Osteoprotegerin reduces the loss of periartikular bone mass in primary and secundary spongiosa but does not influence inflammation in rat antigen-induced arthritis. Inflamm Res 2006; 55: 32-39
    CrossrefPubMedGoogle Scholar
  • 15 Oelzner P, Franke S, Lehmann G et al. Soluble receptor activator of Nfkappa B ligand and osteoprotegerin in rheumatoid arthritis – relatioship with bone mineral density, disease activity and bone turnover. Clin Rheumatol 2007; 26: 2127-2135
    CrossrefPubMedGoogle Scholar
  • 16 Gough AK, Lilley J, Eyre S et al. Generalized bone loss in patients with early rheumatoid arthritis. Lancet 1994; 344: 23-27
    CrossrefPubMedGoogle Scholar
  • 17 Böttcher JA, Pfeil A, Petrovitch A et al. Metacarpal index estimated by digital x-ray radiogrammetry as a tool for differentiating rheumatoid arthritis related periarticular osteopenia. IJBS 2006; 2: 241-250
    PubMedGoogle Scholar
  • 18 Foley-Nolan D, Stack JP, Ryan M et al. Magnetic resonance imaging in assessment of rheumatoid arthritis in comparison with plain film radiographs. Br J Rheumatol 1991; 30: 101-106
    CrossrefPubMedGoogle Scholar
  • 19 McQueen FM, Steward N, Crabbe J et al. 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
    CrossrefPubMedGoogle Scholar
  • 20 McGonagle Conaghan PG, O’Connor P. et al. The ralationship between synovitis and bone changes in early untreated rheumatoid arthritis: a control-magnetic resonance imaging study. Arthritis Rheum 1999; 42: 1706-1711
    CrossrefPubMedGoogle Scholar
  • 21 Shigeyama Y, Pap T, Kunzler P et al. Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum 2000; 43: 2523-2530
    CrossrefPubMedGoogle Scholar
  • 22 Gravallese EM, Manning C, Tsay A et al. Synovial tissue in rheumatoid arthritis is a sorce of osteoclast differentation factor. Arthritis Rheum 2000; 43: 250-258
    CrossrefPubMedGoogle Scholar
  • 23 Rau R, Herborn G. Healing phenomena of erosive changes in rheumatoid arthritis patients undergoing disease modifying antirheumatic drug therapy. Arthritis Rheum 1996; 39: 162-168
    CrossrefPubMedGoogle Scholar
  • 24 Strand V, Cohen S, Schiff M et al. Treatment of active rheumatoid ar-thritis with leflunomide compared with placebo and methotrexate. Arch Intern Med 1999; 159: 2542-2550
    CrossrefPubMedGoogle Scholar
  • 25 Mandema JW, Salinger DH, Baumgartner SW et al. A dose-response meta-analysis for quantifying relative efficacy of biologics in rheumatoid arthritis. Clin Pharmacol Ther 2011; 90: 828-835
    CrossrefPubMedGoogle Scholar
  • 26 Emery P, Dörner T. Optimising treatment in rheumatoid arthritis: a review of potential biological markers of response. Ann Rheum Dis 2011; 70: 2063-2070
    CrossrefPubMedGoogle Scholar
  • 27 Deodhar AA, Woolf AD. Bone mass measurement and bone metabolism in rheumatoid arthritis. A review. Br J Rheumatol 1996; 35: 309-322
    CrossrefPubMedGoogle Scholar
  • 28 Wang SY, Lin YY, Ye H et al. Circulating Dickkopf-1 is correlated with bone erosion and inflammation in rheumatoid arthritis. J Rheumatol 2011; 38: 821-827
    CrossrefPubMedGoogle Scholar
  • 29 Schett G, Sieper J. Inflammation and repair mechanisms. Clin Exp Rheumatol 2009; 27 (Suppl. 55) S33-S35
    PubMedGoogle Scholar
  • 30 Toritsuka Y, Nakamura N, Lee SB et al. Osteoclastogenesis in iliac bone marrow of patients with rheumatoid arthritis. J Rheumatol 1997; 24: 1690-1696
    PubMedGoogle Scholar
  • 31 Lobo ED, Hansen JR, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 2004; 93: 2645-2668
    CrossrefPubMedGoogle Scholar
  • 32 Miller PD, Bolognese MA, Lewiecki EM et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 2008; 43: 222-229
    CrossrefPubMedGoogle Scholar
  • 33 Cummings SR, San Martin J, McClung MR et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 261: 756-765
    PubMedGoogle Scholar
  • 34 Cohen SB, Dore RK, Lane NE et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum 2008; 58: 1299-1309
    CrossrefPubMedGoogle Scholar
  • 35 Van der Hejde DM. Joint erosions and patients with early rheumatoid arthritis. Br J Rheumatol 1995; 34: 74-76
    PubMedGoogle Scholar
  • 36 Deodhar A, Dore RK, Mandel D et al. Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients. Arthritis Care Res (Hoboken) 2010; 62: 569-574
    CrossrefPubMedGoogle Scholar
  • 37 Sharp JT, Tsuji W, Ory P et al. Denosumab prevents metacarpal shaft cortical bone loss in patients with erosive rheumatoid arthritis. Arthritis Care Res (Hoboken) 2010; 62: 537-544
    CrossrefPubMedGoogle Scholar
  • 38 Dore RK, Cohen SB, Lane NE et al. Effect of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates. Ann Rheum Dis 2010; 69: 872-875
    CrossrefPubMedGoogle Scholar
  • 39 Ferrari-Lacraz S, Ferrari S. Do RANKL inhibitors (denosumab) affect inflammation and immunity?. Osteoporos Int 2011; 22: 435-446
    CrossrefPubMedGoogle Scholar
  • 40 Steger BB, Bartsch R. Denosumab for the treatment of bone metastasis in breast cancer: evidence and opinion. Ther Adv Med Oncol 2011; 3: 233-243
    CrossrefPubMedGoogle Scholar