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Cathepsin K osteoporosis trials, pycnodysostosis and mouse deficiency models: Commonalities and differences
Dieter Brömme1,2,3, Preety Panwar1,3, Serap Turan4
1a Department of Oral Biological and Medical Sciences, Faculty of Dentistry , University of British Columbia , Vancouver , Canada.
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.
Insights
Novel cathepsin K inhibitors show promise for osteoporosis treatment by targeting bone matrix degradation. However, side effects and market competition have hindered development, necessitating further research for safer, more selective therapies.
Area of Science:
- Pharmacology
- Bone Biology
- Drug Development
Background:
- The osteoporosis market exceeded $11 billion in 2015.
- Current antiresorptive treatments include bisphosphonates, denosumab, and SERMs.
- Cathepsin K inhibitors represent a novel approach targeting bone matrix degradation.
Purpose of the Study:
- To review the development status of cathepsin K inhibitors.
- To analyze their side effects and compare with genetic deficiencies.
- To assess their therapeutic potential in osteoporosis.
Main Methods:
- Literature review of preclinical and clinical studies.
- Comparative analysis of mouse and human cathepsin K deficiency phenotypes.
- Evaluation of drug treatment outcomes and safety profiles.
Main Results:
- Several cathepsin K inhibitors demonstrated efficacy in reducing bone resorption markers.
- Development of some inhibitors was halted due to side effects or market issues.
- Odanacatib showed fracture reduction but has safety concerns.
Conclusions:
- Cathepsin K inhibitors offer a promising, selective mechanism for osteoporosis.
- Observed side effects require further investigation into treatment mechanisms.
- Future research needs to enhance osteoclast specificity or collagen-selective inhibition.
