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Cathepsin K-Inhibitoren: präklinische und klinische Daten

Cathepsin K antagonists: preclinical and clinical data

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Zusammenfassung

Cathepsin K ist eine Cysteinproteinase und somit ein essentielles Enzym in der Degradation von Kollagen Typ I. Es wird fast ausschließlich in Osteoklasten exprimiert. Aufgrund des physiologischen Mechanismus stellt diese Protease einen pharmakologischen Angriffspunkt für die Entwicklung neuer Medikamente in der Osteologie dar. In den letzten Jahrzehnten wurde intensiv daran geforscht, hochwirksame, selektive und oral einnehmbare Cathepsin K-Inhibitoren zu entwickeln. Im Gegensatz zu Balicatib und Relacatib, deren Weiterentwicklung wegen kutaner Nebenwirkungen bei relativ geringer Spezifität eingestellt wurde, wendete sich die Forschung den spezifischeren Cathepsin K-Inhibitoren Odanacatib (ODN) und ONO-5334 zu. So hebt Odanacatib bei postmenopausalen Frauen sehr deutlich die Knochenmineraldichte und hemmt die Knochenresorption. Als Voraussetzung für die Weiterentwicklung konnte in einer Langzeituntersuchung die Sicherheit und Wirksamkeit des Medikaments bestätigt werden. Jedoch nehmen nach dessen Absetzen Knochenresorption und Knochenmasseverlust wieder zu. Eine Phase III Frakturpräventionsstudie an postmenopausalen Frauen mit Osteoporose befindet sich derzeit in der Endphase.

Summary

Cathepsin K, a cysteine protease, is an essential enzyme in degradation of collagen type I. Since cathepsin K is relatively specific to osteoclasts, it represents a promising candidate for drug development. In the past decades, 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 trials. Odanacatib progressively increases bone mineral density (BMD) and decreases bone resorption markers in postmenopausal women with low BMD. Its clinical efficacy and safety was confirmed by several clinical studies but indicates that odanacatib is characterized by a resolution-of-effect with increases in bone resorption and rapid decreases in BMD following treatment discontinuation. A phase III fracture prevention study in postmenopausal women with osteoporosis is currently in the final phase.

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Interessenkonflikt

M. Gamsjäger und H. Resch geben an, dass kein Interessenkonflikt besteht.

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  1. II. Medizinische Abteilung (Rheumatologie/Osteologie & Gastroenterologie), KH Barmherzige Schwestern, Akademisches Lehrkrankenhaus der MUW, 1060, Wien, Stumpergasse 13, Österreich

    Marion Gamsjäger MD &  Heinrich Resch

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Correspondence to Marion Gamsjäger MD.

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Gamsjäger, M., Resch, H. Cathepsin K-Inhibitoren: präklinische und klinische Daten. Wien Med Wochenschr 165, 65–70 (2015). https://doi.org/10.1007/s10354-014-0336-3

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