Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis

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

  • 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

  • Loss-of-function mutations in the cathepsin K gene lead to pycnodysostosis, a disorder characterized by osteosclerosis, bone fragility, and decreased bone turnover

  • In preclinical studies, cathepsin K inhibitors decreased bone resorption markers and prevented bone loss induced by ovariectomy

  • 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

  • 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

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mechanism of osteoclast-mediated bone resorption.
Figure 2: Effects of antiresorptive agents on bone remodeling, as assessed by bone turnover markers.
Figure 3: Graphic representation of the changes in bone markers in postmenopausal women treated with odanacatib 50 mg weekly for 3 years (ODN/ODN), odanacatib 50 mg weekly for 2 years followed by placebo for 1 year (ODN/PLB) or placebo for 3 years (PLB/PLB).

Similar content being viewed by others

References

  1. Ross, P. E. in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism (ed. Rosen, C. J.) 16–22 (American Society for Bone and Mineral Research, Washington, D. C., 2008).

    Book  Google Scholar 

  2. Rood, J. A., Van Horn, S., Drake, F. H., Gowen, M. & Debouck, C. Genomic organization and chromosome localization of the human cathepsin K gene (CTSK). Genomics 41, 169–176 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Drake, F. H. et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J. Biol. Chem. 271, 12511–12516 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Balkan, W. et al. Identification of NFAT binding sites that mediate stimulation of cathepsin K promoter activity by RANK ligand. Gene 446, 90–98 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Troen, B. R. The regulation of cathepsin K gene expression. Ann. N. Y. Acad. Sci. 1068, 165–172 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. McQueney, M. S. et al. Autocatalytic activation of human cathepsin K. J. Biol. Chem. 272, 13955–13960 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Rieman, D. J. et al. Biosynthesis and processing of cathepsin K in cultured human osteoclasts. Bone 28, 282–289 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Inaoka, T. et al. Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. Biochem. Biophys. Res. Commun. 206, 89–96 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Brömme, D. & Okamoto, K. Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution. Biol. Chem. Hoppe Seyler 376, 379–384 (1995).

    Article  PubMed  Google Scholar 

  10. Bühling, F. et al. Cathepsin K expression in human lung. Adv. Exp. Med. Biol. 477, 281–286 (2000).

    Article  PubMed  Google Scholar 

  11. Mandelin, J. et al. Human osteoblasts produce cathepsin K. Bone 38, 769–777 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Brubaker, K. D., Vessella, R. L., True, L. D., Thomas, R. & Corey, E. Cathepsin K mRNA and protein expression in prostate cancer progression. J. Bone Miner. Res. 18, 222–230 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Littlewood-Evans, A. J. et al. The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res. 57, 5386–5390 (1997).

    CAS  PubMed  Google Scholar 

  14. Sukhova, G. K., Shi, G. P., Simon, D. I., Chapman, H. A. & Libby, P. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J. Clin. Invest. 102, 576–583 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xiao, Y. et al. Cathepsin K in adipocyte differentiation and its potential role in the pathogenesis of obesity. J. Clin. Endocrinol. Metab. 91, 4520–4527 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Chiellini, C. et al. Identification of cathepsin K as a novel marker of adiposity in white adipose tissue. J. Cell Physiol. 195, 309–321 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Quintanilla-Dieck, M. J., Codriansky, K., Keady, M., Bhawan, J. & Runger, T. M. Expression and regulation of cathepsin K in skin fibroblasts. Exp. Dermatol. 18, 596–602 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Bou-Gharios, G. & de Crombrugghe, B. in Principles of Bone Biology (eds Bilezikian, J. P., Raisz, L. A. & Rodan, G. A.) 285–318 (Academic Press, San Diego, 2008).

    Book  Google Scholar 

  19. Cremers, S., Garnero, P. & Seibel, M. J. in Principles of Bone Biology (eds Bilezikian, J. P., Raisz, L. A. & Rodan, G. A.) 1857–1881 (Academic Press, San Diego, 2008).

    Book  Google Scholar 

  20. Rosen, H. N. et al. Specificity of urinary excretion of cross-linked N-telopeptides of type I collagen as a marker of bone turnover. Calcif. Tissue Int. 54, 26–29 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Rosen, H. N. et al. Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy. Calcif. Tissue Int. 66, 100–103 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Garnero, P. et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J. Biol. Chem. 273, 32347–32352 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Atley, L. M., Mort, J. S., Lalumiere, M. & Eyre, D. R. Proteolysis of human bone collagen by cathepsin K: characterization of the cleavage sites generating by cross-linked N-telopeptide neoepitope. Bone 26, 241–247 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Bossard, M. J. et al. Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J. Biol. Chem. 271, 12517–12524 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Lecaille, F., Brömme, D. & Lalmanach, G. Biochemical properties and regulation of cathepsin K activity. Biochimie 90, 208–226 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Kafienah, W., Brömme, D., Buttle, D. J., Croucher, L. J. & Hollander, A. P. Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem. J. 331, 727–732 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hou, W. S. et al. Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation. Am. J. Pathol. 159, 2167–2177 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dejica, V. M. et al. Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage. Am. J. Pathol. 173, 161–169 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hou, W. S. et al. Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum. 46, 663–674 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Gelb, B. D., Edelson, J. G. & Desnick, R. J. Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping. Nat. Genet. 10, 235–237 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Gelb, B. D., Shi, G. P., Chapman, H. A. & Desnick, R. J. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273, 1236–1238 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Polymeropoulos, M. H. et al. The gene for pycnodysostosis maps to human chromosome 1cen-q21. Nat. Genet. 10, 238–239 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Bertola, D. et al. Craniosynostosis in pycnodysostosis: broadening the spectrum of the cranial flat bone abnormalities. Am. J. Med. Genet. A 152, 2599–2603 (2010).

    Article  Google Scholar 

  34. Schilling, A. F. et al. High bone mineral density in pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K. Osteoporos. Int. 18, 659–669 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Khan, B., Ahmed, Z. & Ahmad, W. A novel missense mutation in cathepsin K (CTSK) gene in a consanguineous Pakistani family with pycnodysostosis. J. Investig. Med. 58, 720–724 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Li, H. Y., Ma, H. W., Wang, H. Q. & Ma, W. H. Molecular analysis of a novel cathepsin K gene mutation in a Chinese child with pycnodysostosis. J. Int. Med. Res. 37, 264–269 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Hou, W. S. et al. Characterization of novel cathepsin K mutations in the pro and mature polypeptide regions causing pycnodysostosis. J. Clin. Invest. 103, 731–738 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Maroteaux, P. & Lamy, M. 2 cases of a condensing osseous disease: pynodysostosis [French]. Arch. Fr. Pediatr. 19, 267–274 (1962).

    CAS  PubMed  Google Scholar 

  39. Motyckova, G. & Fisher, D. E. Pycnodysostosis: role and regulation of cathepsin K in osteoclast function and human disease. Curr. Mol. Med. 2, 407–421 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Shuler, S. E. Pycnodysostosis. Arch. Dis. Child. 38, 620–625 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chavassieux, P. et al. Mechanisms of the anabolic effects of teriparatide on bone: insight from the treatment of a patient with pycnodysostosis. J. Bone Miner. Res. 23, 1076–1083 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Sedano, H. D., Gorlin, R. J. & Anderson, V. E. Pycnodysostosis. Clinical and genetic considerations. Am. J. Dis. Child. 116, 70–77 (1968).

    Article  CAS  PubMed  Google Scholar 

  43. Maroteaux, P. & Lamy, M. The malady of Toulouse-Lautrec. JAMA 191, 715–717 (1965).

    Article  CAS  PubMed  Google Scholar 

  44. Nishi, Y. et al. Determination of bone markers in pycnodysostosis: effects of cathepsin K deficiency on bone matrix degradation. J. Bone Miner. Res. 14, 1902–1908 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Everts, V., Aronson, D. C. & Beertsen, W. Phagocytosis of bone collagen by osteoclasts in two cases of pycnodysostosis. Calcif. Tissue Int. 37, 25–31 (1985).

    Article  CAS  PubMed  Google Scholar 

  46. Fratzl-Zelman, N. et al. Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis. J. Clin. Endocrinol. Metab. 89, 1538–1547 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Saftig, P. et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc. Natl Acad. Sci. USA 95, 13453–13458 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gowen, M. et al. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J. Bone Miner. Res. 14, 1654–1663 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Pennypacker, B. et al. Bone density, strength, and formation in adult cathepsin K (−/−) mice. Bone 44, 199–207 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Pennypacker, B. L. et al. Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits. J. Bone Miner. Res. 26, 252–262 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Chen, W. et al. Novel pycnodysostosis mouse model uncovers cathepsin K function as a potential regulator of osteoclast apoptosis and senescence. Hum. Mol. Genet. 16, 410–423 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Yasuda, Y., Kaleta, J. & Brömme, D. The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. Adv. Drug Deliv. Rev. 57, 973–993 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Fuller, K. et al. Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts. Bone 42, 200–211 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Yang, M. et al. Deficiency and inhibition of cathepsin K reduce body weight gain and increase glucose metabolism in mice. Arterioscler. Thromb. Vasc. Biol. 28, 2202–2208 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Funicello, M. et al. Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores. PLoS One 42, e683 (2007).

    Article  CAS  Google Scholar 

  56. Samokhin, A. O., Wong, A., Saftig, P. & Brömme, D. Role of cathepsin K in structural changes in brachiocephalic artery during progression of atherosclerosis in apoE-deficient mice. Atherosclerosis 200, 58–68 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Lutgens, E. et al. Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation. Circulation 113, 98–107 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Guo, J. et al. Leucocyte cathepsin K affects atherosclerotic lesion composition and bone mineral density in low-density lipoprotein receptor deficient mice. Cardiovasc. Res. 81, 278–285 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Hofnagel, O. & Robenek, H. Cathepsin K: boon or bale for atherosclerotic plaque stability? Cardiovasc. Res. 81, 242–243 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Bühling, F. et al. Pivotal role of cathepsin K in lung fibrosis. Am. J. Pathol. 164, 2203–2216 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Srivastava, M. et al. Overexpression of cathepsin K in mice decreases collagen deposition and lung resistance in response to bleomycin-induced pulmonary fibrosis. Respir. Res. 9, 54 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yamashita, D. S. & Dodds, R. A. Cathepsin K and the design of inhibitors of cathepsin K. Curr. Pharm. Des. 6, 1–24 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Podgorski, I. Future of anticathepsin K drugs: dual therapy for skeletal disease and atherosclerosis? Future Med. Chem. 1, 21–34 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Stoch, S. A. & Wagner, J. A. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin. Pharmacol. Ther. 83, 172–176 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Yamane, H. et al. The anabolic action of intermittent PTH in combination with cathepsin K inhibitor or alendronate differs depending on the remodeling status in bone in ovariectomized mice. Bone 44, 1055–1062 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Kumar, S. et al. A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys. Bone 40, 122–131 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Le Gall, C. et al. A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden. Cancer Res. 67, 9894–9902 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. McDougall, J. J., Schuelert, N. & Bowyer, J. Cathepsin K inhibition reduces CTXII levels and joint pain in the guinea pig model of spontaneous osteoarthritis. Osteoarthritis Cartilage 18, 1355–1357 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Seeman, E. Advances in Therapeutics: Meeting Report from the 31st Annual Meeting of the American Society for Bone and Mineral Research: September 11–15, 2009 in Denver, Colorado. IBMS BoneKEy 6, 496–502 (2009).

    Article  Google Scholar 

  70. Kassahun, K. et al. Pharmacokinetics and metabolism in rats, dogs and monkeys of the cathepsin K inhibitor odanacatib: demethylation of a methylsulfonyl moiety as a major metabolic pathway. Drug Metab. Dispos. doi:10.1124/dmd.110.037184.

  71. Yamashita, D. S. et al. Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors. J. Med. Chem. 49, 1597–1612 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Lin, J. H. Bisphosphonates: a review of their pharmacokinetic properties. Bone 18, 75–85 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Cremers, S. & Papapoulos, S. Pharmacology of bisphosphonates. Bone doi:10.1016/j.bone.2011.01.014.

  74. Cremers, S. C., Pillai, G. & Papapoulos, S. E. Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin. Pharmacokinet. 44, 551–570 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Body, J. J. et al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin. Cancer Res. 12, 1221–1228 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Russell, R. G., Watts, N. B., Ebetino, F. H. & Rogers, M. J. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos. Int. 19, 733–759 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Gauthier, J. Y. et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 18, 923–928 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Isabel, E. et al. The discovery of MK-0674, an orally bioavailable cathepsin K inhibitor. Bioorg. Med. Chem. Lett. 20, 887–892 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Stoch, S. A. et al. Effect of the cathepsin K inhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women: two double-blind, randomized, placebo-controlled phase I studies. Clin. Pharmacol. Ther. 86, 175–182 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Eastell, R. et al. Safety and efficacy of the cathepsin K inhibitor, ONO-5334, in postmenopausal osteoporosis—the OCEAN study. J. Bone Miner. Res. doi:10.1002/jbmr.341 (2011).

  81. Adami, S. et al. Effect of one year treatment with the cathepsin-K inhibitor, balicatib, on bone mineral density (BMD) in postmenopausal women with osteopenia/osteoporosis. J. Bone Miner. Res. 21 (Suppl. 1) S24 (2006).

    Google Scholar 

  82. Black, W. C. Peptidomimetic inhibitors of cathepsin K. Curr. Top. Med. Chem. 10, 745–751 (2010).

    Article  CAS  PubMed  Google Scholar 

  83. Falgueyret, J. P. et al. Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. J. Med. Chem. 48, 7535–7543 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Peroni, A. et al. Drug-induced morphea: report of a case induced by balicatib and review of the literature. J. Am. Acad. Dermatol. 59, 125–129 (2008).

    Article  PubMed  Google Scholar 

  85. Desmarais, S. et al. Effect of cathepsin k inhibitor basicity on in vivo off-target activities. Mol. Pharmacol. 73, 147–156 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Engelke, K. et al. Effects of the cathepsin K inhibitor, ONO-5334, on BMD as measured by 3D QCT in the hip and the spine after 12 months treatment. Presented at the 32nd Annual Meeting of the American Society for Bone and Mineral Research, Toronto, ON, Canada, October 2010.

  87. Bone, H. G. et al. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J. Bone Miner. Res. 25, 937–947 (2010).

    PubMed  Google Scholar 

  88. Eisman, J. A. et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J. Bone Miner. Res. 26, 242–251 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Alatalo, S. L. et al. Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in Albers–Schonberg disease (type II autosomal dominant osteopetrosis). Clin. Chem. 50, 883–890 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Neele, S. J., Evertz, R., De Valk-De Roo, G., Roos, J. C. & Netelenbos, J. C. Effect of 1 year of discontinuation of raloxifene or estrogen therapy on bone mineral density after 5 years of treatment in healthy postmenopausal women. Bone 30, 599–603 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Bone, H. G. et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J. Clin. Endocrinol. Metab. 96, 972–980 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Miller, P. D. et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43, 222–229 (2008).

    Article  CAS  PubMed  Google Scholar 

  93. Bauer, D. C. Discontinuation of odanacatib and other osteoporosis treatments: here today and gone tomorrow? J. Bone Miner. Res. 26, 239–241 (2011).

    Article  PubMed  Google Scholar 

  94. US National Library of Medicine. ClinicalTrials.gov[online]. (2011).

  95. US National Library of Medicine. ClinicalTrials.gov[online]. (2011).

  96. US National Library of Medicine. ClinicalTrials.gov[online]. (2011).

  97. Jensen, A. B. et al. The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial. Clin. Breast Cancer 10, 452–458 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed equally to researching data, discussing the content, writing the article and performing review/editing of the manuscript before submission.

Corresponding author

Correspondence to John P. Bilezikian.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2011.77

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research