Kathepsin-K-Inhibitoren in der Osteoporosetherapie

Zusammenfassung

Kathepsin K, eine in Osteoklasten exprimierte Cysteinprotease, ist ein wichtiges Enzym in der Degradation von Kollagen Typ I. Da Kathepsin K relativ spezifisch für Osteoklasten ist, ist diese Protease ein interessanter Angriffspunkt für die Entwicklung neuer Osteoporosepräparate. Im vergangenen Jahrzehnt wurden große Anstrengungen unternommen, hochwirksame, selektive und oral einnehmbare Kathepsin-K-Inhibitoren zu entwickeln. Im Gegensatz zu Balicatib und Relacatib, deren Arzneimittelentwicklung wegen kutaner Nebenwirkungen (bedingt durch eine zu geringe Spezifität des Arzneimittels) eingestellt wurde, wurden die spezifischeren Kathepsin-KInhibitoren Odanacatib (ODN) und ONO-5334 weiterentwickelt und bereits in ersten klinischen Studien untersucht. ODN erhöht bei postmenopausalen Frauen mit niedriger Knochenmasse progressiv die Knochenmineraldichte und hemmt die Knochenresorption. Eine kürzlich veröffentlichte Langzeitstudie bestätigt die klinische Wirksamkeit und Sicherheit von ODN, weist aber auch darauf hin, dass die Wirkung reversibel ist, d. h. nach dem Absetzen von ODN nimmt die Knochenresorption und der Knochenmassenverlust wieder rapid zu. Diese Beobachtungen sind vergleichbar mit dem zeitlich limitierten Effekt von Östrogenen, Denosumab und Parathormon, stehen jedoch im Gegensatz zu den nach dem Absetzen von Bisphosphonaten beobachteten residuellen Langzeitwirkungen. Derzeit wird eine Frakturpräventionsstudie an postmenopausalen Frauen mit Osteoporose, die mit ODN behandelt werden, durchgeführt.

Summary

Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Since cathepsin K is relatively specific to osteoclasts, it represents a promising candidate for drug development. In the past decade, a lot of efforts have been made in developing highly potent, selective and orally applicable cathepsin K inhibitors. In contrast to balicatib and relacatib, whose drug development programmes were stopped due to cutaneous side-effects related to limited drug specificity, the more specific cathepsin K inhibitors odanacatib (ODN) and ONO-5334 have entered clinical trial programs. ODN progressively increases bone mineral density (BMD) and decreases bone resorption markers in postmenopausal women with low BMD. A recently published extension study confirms clinical efficacy and safety but indicates that ODN is characterized by a resolution-of-effect with increases in bone resorption and rapid decreases in BMD following treatment discontinuation. These observations are similar to the findings with hormone-replacement therapy, denosumab and parathyroid hormone but in contrast to changes observed after discontinuation of bisphosphonates. From a clinical perspective further studies are needed to elucidate whether rapid bone loss and sustained increases in bone turnover following cessation of ODN modifies fracture risk. A fracture prevention study in postmenopausal women with osteoporosis using ODN is currently underway.

Schlüsselwörter

Osteoporose - Kathepsin-K-Inhibitoren - Cysteinprotease - Kollagen Typ I

Keywords

Osteoporosis - cathepsin K inhibitor - cysteine protease - type 1 collagen

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