Cathepsin K osteoporosis trials, pycnodysostosis and mouse deficiency models: Commonalities and differences

ABSTRACT

Introduction: The osteoporosis market reached a value of more than $11 billion in 2015. Current treatments remain mostly antiresorptive and comprise of bisphosphonates, the anti-RANKL antibody, denusomab, and selective estrogen receptor modulators (SERMs). The most promising novel antiresorptives are cathepsin K inhibitors, which selectively target the bone matrix, degrading protease without interfering with osteoclast viability or formation as all other antiresorptives do.

Areas covered: This review analyses the current status of cathepsin K inhibitor development, its side effects, and compares the phenotypes of mouse and human cathepsin K deficiencies with drug treatment outcomes.

Expert opinion: Several selective cathepsin K inhibitors have been developed and evaluated in preclinical and clinical studies. Although all compounds were effective in reducing bone resorption markers, the development of some compounds was terminated either due to side effects or market competition. The most advanced compound is odanacatib, which significantly reduced bone fracture rates in a 5-year trial but still exhibits safety concerns. The analysis of mouse and human catK deficiencies sheds some light on the consequences of a cathepsin K inhibitor treatment. How predictive the knockout phenotypes are regarding long-term cathepsin K treatment remains unclear. Clearly, more studies are needed to understand the mechanism of the observed side effects and novel approaches are needed to make CatK inhibitors either osteoclast-specific or selective for the inhibition of the collagen matrix without affecting the other activities of the protease.

KEYWORDS:

• Cathepsin K
• cathepsin K knockout
• odanacatib
• osteoporosis
• protease inhibitors
• pycnodysostosis

Article highlights

• Cathepsin K (CatK) is a major pharmaceutical target for the development of anti-resorptive drugs.

• Several selective cathepsin K inhibitors have been developed and evaluated in preclinical and clinical trials.

• The efficacy and safety concerns regarding CatK inhibitors in osteoporosis trials and the phenotypic consequences of genetic knockouts of this protease in mice and men are described.

• The phenotypes of mouse and human cathepsin K deficiencies are compared with drug treatment outcomes and there are significant overlaps but also major differences.

• More studies are needed to understand the mechanism of the observed side effects and new approaches are needed to make CatK inhibitors either osteoclast-specific or selective for the inhibition of the collagen matrix without affecting the other activities of the protease.

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Acknowledgements

We thank Ingrid Ellis from the Faculty of Dentistry at UBC for her careful language editing. The Marmara University ethics committee approved the study for pycnodysostosis cases and, written informed consents were obtained from the patients and parents for the studies.

Financial & competing interests disclosure

This work was supported in part by the Canadian Institutes of Health Research (MOP89974 to D. Brömme) and the Scientific Research Project Committee of Marmara University (SAG-B-090409-0071). It was also supported in part by the Turkish Society of Pediatric Endocrinology and Diabetes (S. Turan). Furthermore, D Brömme was supported by a Canada Research Chair Award. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.