Evidenz von Bisphosphonaten bei entzündlich-rheumatischen Erkrankungen

Zusammenfassung

Die häufigsten entzündlich-rheumatischen Erkrankungen, Rheumatoide Arthritis (RA), ankylosierende Spondylitis und Arthritis psoriatica als auch das seltene SAPHO-Syndrom gehen in der Regel mit Knochendestruktion bzw. Veränderungen des Knochenumbaus einher. Insbesondere im Fall der RA kommt es häufig zu einer systemischen Osteoporose. Aus diesem Grunde sind für die Behandlung der genannten Erkrankungen Medikamente, welche sowohl die Knochenresorption und den Knochenumbau hemmen als auch potentiell in der Lage sind, entzündliche Prozesse zu supprimieren, von besonderem Interesse. Basierend auf den Ergebnissen Plazebo-kontrollierter Studien haben Bisphosphonate einen festen Platz in der Prävention und Therapie des Glukokortikoid-begünstigten Knochenmasseverlustes bei entzündlich-rheumatischen Erkrankungen und können das Frakturrisiko in diesem Zusammenhang reduzieren. Eine Hemmung der Destruktion des periartikulären Knochens bei der RA ist dagegen offensichtlich nicht mit den in der Osteoporose-Therapie üblichen Dosierungen der meisten Bisphosphonate möglich und gelingt nur mit dem hoch potenten intravenösen Bisphosphonat Zoledronat. Für andere Bisphosphonate sind zur Suppression von Destruktion und entzündlicher Aktivität im Arthritis-Modell Dosierungen notwendig, welche die beim Menschen übliche Dosis überschreiten. Zoledronat bewirkte bei Arthritis psoriatica eine Reduktion des die Osteitis reflektierenden Knochenmarködems, jedoch keine Hemmung der Knochen-Erosion. Bei ankylosierender Spondylitis und SAPHO-Syndrom konnte insbesondere für Pamidronat im Rahmen von offenen Studien eine Reduktion der entzündlichen Aktivität und Wirbelsäulen-Funktion repräsentierenden Scores sowie teilweise auch der paraklinischen Entzündungsparameter nachgewiesen werden. Unterschiedliche molekulare Mechanismen des systemischen und gelenknahen Knochenmasseverlustes sowie des Knochenumbaus bei RA einerseits sowie ankylosierender Spondylitis und SAPHO-Syndrom andererseits dürften für die differente Wirksamkeit von Bisphosphonaten im Hinblick auf Entzündung und Entzündungs-assoziierte Knochenveränderungen verantwortlich sein.

Abstract

The most common inflammatory rheumatic diseases, i. e., rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis as well as SAPHO syndrome are regularly associated with bone destruction or disturbance of bone turnover. Especially in rheumatoid arthritis, systemic osteoporosis frequently occurs. Therefore, drugs that suppress bone resorption as well as bone turnover and potentially reduce inflammatory processes are of critical interest in the treatment of these diseases. Based on the results of randomised, placebo-controlled trials, bisphosphonates are the treatment of choice in the prevention of and therapy for glucocorticoid-induced osteoporosis in inflammatory rheumatic diseases including the reduction of fracture risk. In contrast, an inhibition of destruction of periarticular bone in rheumatoid arthritis is not possible using the normal doses for treatment of osteoporosis of most bisphosphonates, except for the highly potent intravenous bisphosphonate zoledronate. In animal models of rheumatoid arthritis high doses of different bisphosphonates are necessary for the suppression of bone destruction and inflammatory disease activity. Zoledronate reduces bone marrow oedema as a sign reflecting osteitis in psoriatic arthritis but is not able to prevent bone erosion. In the case of ankylosing spondylitis and the SAPHO syndrome, especially pamidronate has been shown to reduce different scores reflecting disease activity and function of the spine and also laboratory parameters of inflammation in part in different open-label studies. Different molecular mechanisms of systemic and periarticular bone loss and of bone turnover in rheumatoid arthritis on the one hand and in ankylosing spondylitis and SAPHO syndrome on the other may contribute to the different effectivity of bisphosphonates with respect to inflammation and inflammation-associated bone changes.

Schlüsselwörter

Entzündung - Knochendestruktion - Osteoporose - Bisphosphonate

Key words

inflammation - bone destruction - osteoporosis - bisphosphonates

• Literatur

• 1 Kong YY, 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
• 2 Takayanagi H, Iizuka H, Juji T et al. Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum 2000; 43: 259-269
• 3 Diarra D, Stolina M, Polzer K et al. Dickkopf-1 is a master regulator of joint remodeling. Nature Medicine 2007; 13: 156-163
• 4 Schett G, Rudwaleit M. Can we stop progression in ankylosing spondylitis. Best Pract Res Clin Rheumatol 2010; 24: 363-371
• 5 Gravallese EM, Manning C, Tsay A et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 2000; 43: 250-258
• 6 Compston JE, Vedi S, Croucher PI et al. Bone turnover in non-steroid treated rheumatoid arthritis. Ann Rheum Dis 1994; 53: 163-166
• 7 Nakashima T, Hayashi M, Fukunaga T et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011; 17: 1231-1234
• 8 Xiong J, Onal M, Jilka RL et al. Matrix-embedded cells control osteoclast formation. Nat Med 2011; 17: 1235-1241
• 9 Baron R, Ferrari S, Russell RGR. Denosumab and bisphosphonates: Different mechanisms of action and effects. Bone 2011; 48: 677-692
• 10 Pederson L, Ruan M, Westendorf JJ et al. Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci USA 2008; 105: 20764-20769
• 11 Sims N. EPHs and ephrins: many pathways to regulate osteoblasts and osteoclasts. IBMS BoneKEy 2010; 7: 304-313
• 12 Russel RG, Watts NB, Ebetino FH et al. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 2008; 19: 733-759
• 13 Corrado A, Santoro N, Cantatore FP. Extra-skeletal effects of bisphosphonates. Joint Bone Spine 2007; 74: 32-38
• 14 Evans CE. Bisphosphonates modulate the effect of macrophage-like cells on osteoblast. Int J Biochem Cell Biol 2002; 34: 554-563
• 15 Abe Y, Kawakami A, Nakashima T et al. Etidronate inhibits human osteoblast apoptosis by inhibition of pro-apoptotic factor(s) produced by activated T cells. J Lab Clin Med 2000; 136: 344-354
• 16 Weinstein RS. Glucocorticoid-induced bone disease. N Engl J Med 2011; 365: 62-70
• 17 Bellido T, Plotkin LI. Novel actions of bisphosphonates in bone: Preservation of osteoblast and osteocyte viability. Bone 2011; 49: 50-55
• 18 Barrera P, Blom A, van Lent PLEM et al. Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis. Arthritis Rheum 2000; 43: 1951-1959
• 19 Jarrett SJ, Conaghan PG, Sloan VS et al. Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis. Arthritis Rheum 2006; 54: 1410-1414
• 20 Maccagno A, Di Giorgio E, Roldan EJA et al. Double blind radiological assessment of continuous oral pamidronic acid in patients with rheumatoid arthritis. J Rheumatol 1994; 23: 211-214
• 21 Dombrecht EJ, De Tollenaere CB, Aerts K et al. Antioxidant effect of bisphosphonates and simvastatin on chondrocyte lipid peroxidation. Biochem Biophys Res Commun 2006; 348: 459-464
• 22 Van Offel JF, Schuerwegh AJ, Bridts CH et al. Effect of bisphosphonates on viability, proliferation, and dexamethasone-induced apoptosis of articular chondrocytes. Ann Rheum Dis 2002; 61: 925-928
• 23 Saag KG, Emkey R, Schnitzer TJ et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med 1998; 339: 292-299
• 24 Adachi JD, Saag KG, Delmas PD et al. Two-Year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids. A randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum 2001; 44: 202-211
• 25 De Nijs RNJ, Jacobs JWG, Lems WF et al. Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. N Engl J Med 2006; 355: 675-684
• 26 Saag KG, Shane E, Boonen S et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 2007; 357: 2028-2039
• 27 Langdahl BL, Marin F, Shane E et al. Teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis. An analysis by gender and menopausal status. Osteoporos Int 2009; 20: 2095-2104
• 28 Reid DM, Devogelaer JP, Saag K et al. Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomized controlled trial. Lancet 2009; 373: 1253-1263
• 29 DVO Leitlinie 2009 zur Prophylaxe . Diagnostik und Therapie der Osteoporose im Erwachsenenalter. Osteologie 2009; 18: 304-328
• 30 Oelzner P, Wolf G, Hein G et al. Einfluss von Bisphosphonaten auf die entzündliche Gelenkdestruktion bei rheumatoider Arthritis und in Arthritismodellen. Akt Rheumatol 2008; 33: 290-299
• 31 Oelzner P, Kunze A, Henzgen S et al. High-dose clodronate therapy prevents joint destruction in chronic antigen-induced arthritis of the rat but inhibits bone formation at the axial skeleton. Inflamm Res 2000; 49: 424-433
• 32 Valleala H, Laasonen L, Koivula MK et al. Two year randomized controlled trial of etidronate in rheumatoid arthritis: changes in serum aminoterminal telopeptides correlate with radiographic progression of disease. J Rheumatol 2003; 30: 468-473
• 33 Hasegawa J, Nagashima M, Yamamoto M et al. Bone resorption and inflammatory inhibition efficacy of intermittent cyclical etidronate therapy in rheumatoid arthritis. J Rheumatol 2003; 30: 474-479
• 34 Yamamoto K, Yoshino S, Shue G et al. Inhibitory effect of bone resorption and inflammation with etidronate therapy in patients with rheumatoid arthritis for 3 years and in vitro assay in arthritis models. Rheumatol Int 2006; 26: 627-632
• 35 Morishita M, Nagashima M, Wauke K et al. Osteoclast inhibitory effects of vitamin K2 alone or in combination with etidronate or risedronate in patients with rheumatoid arthritis: 2-year results. J Rheumatol 2008; 35: 407-435
• 36 Valleala H, Laitinen K, Pylkkanen L et al. Clinical and biochemical response to single infusion of clodronate in active rheumatoid arthritis – a double blind placebo controlled study. Inflamm Res 2001; 50: 598-601
• 37 Ferraccioli GF, Salaffi F, Carotti M et al. Cl2MDP improves rheumatoid inflammation. In: 5^th INWIN, Interscience World Conference of Inflammation, Antirheumatics, Analgetics, Immunomodulators, Geneva, Switzerland 25–28 April 1993 abstract 208
• 38 Cantatore FP, Ingrosso AM, Carozzo M. Effects of bisphosphonates on interleukin-1, tumor necrosis factor α and ß2 microglobulin in rheumatoid arthritis. J Rheumatol 1993; 23: 1117-1118
• 39 Ralston SH, Hacking L, Willocks L et al. Clinical, biochemical, and radiographic effects of aminohydroxypropylidene bisphosphonate treatment in rheumatoid arthritis. Ann Rheum Dis 1989; 48: 396-399
• 40 Lodder MC, van Pelt PA, Lems WF et al. Effects of high dose IV pamidronate on disease activity and bone metabolism in patients with active RA: a randomized, double-blind placebo-controlled trial. J Rheumatol 2003; 30: 2080-2081
• 41 Eggelmeijer F, Papapoulos SE, van Paassen HC et al. Clinical and biochemical response to single infusion of pamidronate in patients with active rheumatoid arthritis: a double blind placebo controlled study. J Rheumatol 1994; 21: 2016-2020
• 42 Van Offel JF, Schuerwegh AJ, Bridts CH et al. Influence of cyclic intravenous pamidronate on proinflammatory monocytic cytokine profiles and bone density in rheumatoid arthritis treated with low dose prednisolone and methotrexate. Clin Exp Rheumatol 2001; 19: 13-20
• 43 Cantatore FP, Acquista CA, Pipitone V. Evaluation of bone turnover and osteoclastic cytokines in early rheumatoid arthritis treated with alendronate. J Rheumatol 1999; 26: 2318-2323
• 44 Mazzantini M, Di Munno O, Metelli MR et al. Single infusion of neridronate (6-amino-1-hydroxyhexylidene-1,1-bisphosphonate) in patients with active rheumatoid arthritis: effects on disease activity and bone resorption markers. Aging Clin Exp Res 2002; 14: 197-201
• 45 Zhang Q, Badell IR, Schwarz EM et al. Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2. Arthritis Rheum 2005; 52: 2708-2718
• 46 Sutherland KA, Rogers HL, Tosh D et al. RANKL increases the level of Mcl-1 in osteoclasts and reduces bisphosphonate-induced osteoclast apoptosis in vitro. Arthritis Res Ther 2009; 11 [Epub ahead of print]
• 47 Maksymowych WP, Jhangri GS, Leclercq S et al. An open study of pamidronate in the treatment of refractory ankylosing spondylitis. J Rheumatol 1998; 25: 714-717
• 48 Maksymowych WP, Lambert R, Jhangri GS et al. Clinical and radiological ameloriation of refractory peripheral spondyloarthritis by pulse intravenous pamidronate therapy. J Rheumatol 2001; 28: 144-155
• 49 Haibel H, Brandt J, Rudwaleit M et al. Treatment of active ankylosing spondylitis with pamidronate. Rheumatology 2003; 42: 1018-1020
• 50 Cairns AP, Wright SA, Taggart AJ et al. An open study of pulse pamidronate treatment in severe ankylosing spondylitis and its effect on biochemical parameters of bone turnover. Ann Rheum Dis 2005; 64: 338-339
• 51 Grover R, Shankar S, Aneja R et al. Treatment of ankylosing spondylitis with pamidronate: an open label study. Ann Rheum Dis 2006; 65: 688-689
• 52 Toussirot E, Le Huede G, Lohse A et al. Transient efficacy of pulse pamidronate in active spondyloarthropathies: an open study of 35 cases. Clin Exp Rheumatol 2006; 24: 348
• 53 Santra G, Sarkar RN, Phaujdar S et al. Assessment of the efficacy of pamidronate in ankylosing spondylitis: an open prospective trial. Singapore Med J 2011; 51: 883-887
• 54 Maksymowych WP, Jhangri GS, Fitzgerald AA et al. A six-month randomized, controlled, double-blind, dose response comparison of intravenous pamidronate (60 mg versus 10 mg) in the treatment of nonsteroidal antiinflammatory drug-refractory ankylosing spondylitis. Arthritis Rheum 2002; 46: 766-773
• 55 Toussirot E, Wendling D. Antiinflammatory treatment with bisphosphonates in ankylosing spondylitis. Curr Opin Rheumatol 2007; 19: 340-345
• 56 Polyzos SA, Anastasilakis AD, Efstathiadou Z et al. The effect of zoledronic acid on serum dickkopf-1, osteoprotegerin, and RANKL in patients with paget’s disease of bone. Horm Metab Res 2009; 41: 846-850
• 57 Chung YE, Lee SH, Lee SY et al. Long-term treatment with raloxifene, but not bisphosphonates, reduces circulating sclerostin levels in postmenopausal women. Osteoporos Int 2011; [Epub ahead of print]
• 58 Li X, Ominsky MS, Warmington KS et al. Increased bone formation and bone mass is not affected by pretreatment or cotreatment with alendronate in osteopenic, ovariectomized rats. Endocrinology 2011; 152: 3312-3322
• 59 Mensah KA, Schwarz EM, Ritchlin CT. Altered bone remodeling in psoriatic arthritis. Curr Rheumatol Rep 2008; 10: 311-317
• 60 Mc Queen F, Lloyd R, Doyle A et al. Zoledronic acid does not reduce MRI erosive progression in PsA but may suppress bone oedema: the zoledronic acid in psoriatic arthritis (ZAPA) study. Ann Rheum Dis 2011; 70: 1091-1094
• 61 Olivieri I, Padula A, Palazzi C. Pharmacological management of SAPHO syndrome. Expert Opin Investig Drugs 2006; 15: 1229-1233
• 62 Wipff J, Adamsbaum C, Kahan A et al. Chronic recurrent multifocal osteomyelitis. Joint Bone Spine 2011; 78: 555-560
• 63 Amital Y, Applbaum H, Aamar S et al. SAPHO syndrome treated with pamidronate: an open-label study of 10 patients. Rheumatology 2004; 43: 658-661
• 64 Guignard S, Job-Deslandre C, Savage-Boukris V et al. Pamidronate treatment in SAPHO syndrome. Joint Bone Spine 2001; 69: 392-396
• 65 Kopterides P, Pikazis D, Koufos C. Successful treatment of SAPHO syndrome with zoledronic acid. Arthritis Rheum 2004; 50: 2970-2973
• 66 Ichikawa J, Sato E, Haro H et al. Successful treatment of SAPHO syndrome with an oral bisphosphonate. Rheumatol Int 2009; 29: 713-715
• 67 Miettunen PM, Wei X, Kaura D et al. Dramatic pain relief and resolution of bone inflammation following pamidronate in in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol J 2009; 7: 2
• 68 Rech J, Manger B, Lang B et al. Adult-onset Still’s disease and chronic recurrent multifocal osteomyelitis: a hithero undescribed manifestation of autoinflammation. Rheumatol Int 2012; 32: 1827-1829