Abstract
Bone remodeling consists of two phases—bone resorption and bone formation—that are normally balanced. When bone resorption exceeds bone formation, pathologic processes, such as osteoporosis, can result. Cathepsin K is a member of the papain family of cysteine proteases that is highly expressed by activated osteoclasts. Cathepsin K readily degrades type I collagen, the major component of the organic bone matrix. With such a major role in the initial process of bone resorption, cathepsin K has become a therapeutic target in osteoporosis. The antiresorptive properties of cathepsin K inhibitors have been studied in phase I and phase II clinical trials. Phase III studies are currently underway for odanacatib, a selective cathepsin K inhibitor.
Key Points
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Cathepsin K, a cysteine protease that is highly expressed in osteoclasts, degrades proteins present in the organic matrix of bone, and, therefore, has a fundamental role in bone resorption
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Loss-of-function mutations in the cathepsin K gene lead to pycnodysostosis, a disorder characterized by osteosclerosis, bone fragility, and decreased bone turnover
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In preclinical studies, cathepsin K inhibitors decreased bone resorption markers and prevented bone loss induced by ovariectomy
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The concerning off-target effects reported in early human clinical trials of cathepsin K inhibitors have not been observed with the newer, more-selective compounds currently in phase.III trials
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Clinical trials have demonstrated that cathepsin K inhibitors are potent antiresorptive drugs that act exclusively on bone resorption without perturbing bone formation or osteoclast survival, and demonstrate rapid reversibility
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Costa, A., Cusano, N., Silva, B. et al. Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis. Nat Rev Rheumatol 7, 447–456 (2011). https://doi.org/10.1038/nrrheum.2011.77
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DOI: https://doi.org/10.1038/nrrheum.2011.77
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