Einfluss von Bisphosphonaten auf die entzündliche Gelenkdestruktion bei rheumatoider Arthritis und in Arthritismodellen

Zusammenfassung

Mit zunehmenden Erkenntnissen über die Bedeutung der osteoklastären Knochenresorption, vermittelt über das RANKL-RANK-OPG-System bei postmenopausaler, glukokortikoidinduzierter und entzündungsassoziierter Osteoporose und im Prozess der Destruktion des periartikulären Knochens bei rheumatoider Arthritis (RA) wächst das Interesse an einer Kombination von antiinflammatorischen und antiosteoklastären Therapieprinzipien zur Hemmung der Gelenkdestruktion bei Patienten mit RA. Aufgrund suppressiver Effekte auf die osteoklastäre Knochenresorption sowie zusätzlicher antiinflammatorischer Effekte, wie Hemmung der Sekretion von proinflammatorischen Zytokinen und Matrix-Metalloproteinasen, bieten sich die relativ nebenwirkungsarmen Bisphosphonate als antiosteoklastäres und potenziell antiinflammatorisches adjuvantes Therapieprinzip bei RA an. Bisphosphonate wurden in verschiedenen Arthritismodellen als auch in kleineren Studien bei Patienten mit RA hinsichtlich ihrer Wirksamkeit auf Entzündung, Gelenkdestruktion und periartikuläre Knochenresorption untersucht. Während im Tiermodell übereinstimmend für verschiedene Bisphosphonate eine Hemmung des periartikulären Knochenmasseverlusts bzw. der Knochenresorption nachgewiesen werden konnte, sind die Befunde hinsichtlich der Suppression von Gelenkdestruktion und Entzündung nicht einheitlich. Für neu entwickelte hochpotente Bisphosphonate wie Zoledronat konnte nicht nur im Tiermodell, sondern auch bei RA-Patienten ein hemmender Effekt auf die Knochenerosion gezeigt werden. Die Beurteilung der in Tiermodellen gewonnenen Ergebnisse wird dadurch erschwert, dass verschiedene Substanzen in Arthritis-Modellen mit unterschiedlicher Pathogenese in differenten Dosierungen zum Einsatz kamen. Außerdem wurden Bisphosphonat-Effekte auf Knochen, Entzündung und Gelenkdestruktion mit unterschiedlichen Methoden und Methodenkombinationen untersucht. Sowohl tierexperimentelle Daten als auch Untersuchungen bei RA-Patienten weisen darauf hin, dass für die Hemmung von Gelenkdestruktion und Entzündung wesentlich höhere Dosierungen erforderlich sind als für die Hemmung der osteoklastären Knochenresorption. Unklar ist, inwieweit die zur Hemmung der Entzündung erforderlichen Dosierungen eine Übersuppression des Knochenumbaus bedingen. Die vorliegende Übersicht gibt einen Überblick über die in Tiermodellen und bei RA gewonnen Erkenntnisse über Bisphosphonat-Effekte auf Entzündung und die arthritisassoziierte Knochendestruktion.

Abstract

In context with the increasing evidence for the significance of osteoclastic bone resorption mediated by the RANKL-RANK-OPG system in the pathogenesis of postmenopausal, glucocorticoid-induced and inflammation-associated osteoporosis as well as in joint destruction in rheumatoid arthritis (RA), there is an increasing interest in the combination of anti-inflammatory and anti-osteoclastic therapies in RA. Because of their suppressive effects on both osteoclastic bone resorption and inflammation due to inhibitory effects on the secretion of pro-inflammatory cytokines and matrix metalloproteinases, bisphosphonates are implicated to be a useful adjuvant therapy in RA. Furthermore, these substances are relatively cheap and have only few side effects. The effects of various bisphosphonates on inflammation, joint destruction and periarticular bone resorption were investigated in different animal models of RA and also in some small studies in RA patients. In various animal models, a suppressive effect of different non-amino- and aminobisphosphonates on periarticular bone resorption was found. But the results with respect to the inhibition of joint and cartilage destruction and inflammation are inconsistent. Newly developed, highly potent aminobisphosphonates such as zoledronate have been shown to inhibit articular bone erosion not only in animal models but also in RA. The assessment of data from animal models is difficult because various bisphosphonates were administered in different doses in heterogeneous animal models with a partly different pathogenesis. Furthermore, the effects of bisphophonates on bone and joint destruction were investigated using different methods or combinations of these methods. Data from animal models and from RA patients have shown that the doses of bisphosphonates necessary for the suppression of inflammation and joint destruction are significantly higher than those needed for the inhibition of osteoclastic bone resorption. It is not clear whether or not these relatively high bisphosphonate doses may result in an oversuppression of bone turnover. The effects of various bisphosphonates on joint destruction and inflammation in RA and animal models of RA are reviewed systematically and discussed in this contribution.

Schlüsselwörter

rheumatoide Arthritis - Arthritismodelle - Gelenkdestruktion - Bisphosphonate

Key words

rheumatoid arthritis - animal models of rheumatoid arthritis - joint destruction - bisphosphonates

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