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Cathepsin K Inhibition: A New Mechanism for the Treatment of Osteoporosis

Abstract

Cathepsin K (CatK), a cysteine protease, is highly expressed by osteoclasts and very efficiently degrades type I collagen, the major component of the organic bone matrix. Robust genetic and pharmacological preclinical studies consistently demonstrate that CatK inhibition increases bone mass, improves bone microarchitecture and strength. Recent advances in the understanding of the molecular and cellular mechanisms involved in bone modeling and remodeling suggest that inhibition of CatK decreases bone resorption, but increases the number of cells of osteoclast lineage. This in turn maintains the signals for bone formation, and perhaps may even increase bone formation on some cortical surfaces. Several CatK inhibitors, including relacatib, balicatib, odanacatib and ONO-5334 had entered clinical development for metabolic bone disorders with increased bone resorption, such as postmenopausal osteoporosis. However, odanacatib (ODN) is the only candidate continuing in development. ODN is a highly selective oral CatK inhibitor dosed once-weekly in humans. In a Phase 2 clinical trial, postmenopausal women treated with ODN had sustained reductions of bone resorption markers, while bone formation markers returned to normal after an initial decline within the first 2 years on treatment. In turn areal bone mineral density increased continuously at both spine and hip for up to 5 years. ODN has also been demonstrated to improve bone mass in women with postmenopausal osteoporosis previously treated with alendronate and in men with osteoporosis. ODN is currently in a worldwide Phase 3 fracture outcome trial for the treatment of postmenopausal osteoporosis with interim results supporting its anti-fracture efficacy at the spine, hip and non-vertebral sites.

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Acknowledgments

We thank Boyd B. Scott, Ph.D. (Merck & Co. Inc.) for his generous editorial support of the manuscript. We would also like to thank Jennifer Pawlowski, MS (Merck & Co. Inc.) for her logistical support and Sharon O’Brien (Merck & Co. Inc.) for her assistance in completing the figure design.

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Correspondence to Le T. Duong.

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Le T. Duong is an employee and Albert T. Leung is a former employee of Merck & Co. Inc. and owns stocks of the company. Bente Langdahl serves on advisory boards of Merck & Co, Eli Lilly & Co, Amgen and UCB and has received research support from Eli Lilly, Novartis, Novo Nordisk, and Orkla Health.

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Duong, L.T., Leung, A.T. & Langdahl, B. Cathepsin K Inhibition: A New Mechanism for the Treatment of Osteoporosis. Calcif Tissue Int 98, 381–397 (2016). https://doi.org/10.1007/s00223-015-0051-0

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  • DOI: https://doi.org/10.1007/s00223-015-0051-0

Keywords

  • Cathepsin K
  • Osteoclast
  • Bone resorption
  • Bone remodeling
  • Bone modeling
  • Osteoporosis