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Osteoporosis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Mazen Nasrallah, Marcy B. Bolster
While the past decade has led to the development of numerous agents with novel mechanisms of action, several agents have been developed and abandoned, including odanacatib, a cathepsin K inhibitor antiresorptive agent. Odanacatib was investigated in the Long-Term Odanacatib Fracture Trial (LOFT), which showed reduced fracture risk; however, it was associated with an increased risk of cardiovascular events, including stroke in postmenopausal women. As a result of these data, the study sponsor abandoned its further development.26
Osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
Ippokratis Pountos, Peter V. Giannoudis
Cathepsin K is a catalytic enzyme of collagen type I expressed in osteoclasts. A small amount of cathepsin K is released in the circulation but is degraded quickly by other enzymes like cathepsin S. There is some evidence to suggest that cathepsin K is increased in postmenopausal women with osteoporosis, but its clinical relevance should be further elucidated as this molecule is involved in pathologies like osteoarthritis, atherosclerosis, and cardiovascular diseases (39).
Metabolic and endocrine bone disorders
Published in Ashley W. Blom, David Warwick, Michael R. Whitehouse, Apley and Solomon’s System of Orthopaedics and Trauma, 2017
Recent advances in drug treatment Cathepsin K is a lysosomal cysteine proteinase with high collagenase activity. Cathepsin K inhibition (Odanacatib) is a promising new treatment to reduce fracture risk (Chapurlat, 2015), with a phase III trial, unpublished but reported at scientific meetings, showing a reduction in vertebral, hip and non-vertebral fractures. Sclerostin is a glycoprotein inhibitor of osteoblast Wnt signalling produced by osteocytes that has been recognized as a new target for therapeutic intervention in patients with osteoporosis. Romosozumab is a humanized anti- sderostin monoclonal antibody that has been demonstrated to increase bone formation. A large phase III controlled study is currently underway. Abaloparatide is a new synthetic peptide analog of human parathyroid hormone-related peptide (PTHrP), and a phase III trial for this is also awaited.
Highly potent inhibitors of cathepsin K with a differently positioned cyanohydrazide warhead: structural analysis of binding mode to mature and zymogen-like enzymes
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Jakub Benýšek, Michal Buša, Petra Rubešová, Jindřich Fanfrlík, Martin Lepšík, Jiří Brynda, Zuzana Matoušková, Ulrike Bartz, Martin Horn, Michael Gütschow, Michael Mareš
Cathepsin K (CatK) is one of the most investigated cysteine cathepsins, both by academia and pharmaceutical companies. It is expressed in high levels in osteoclasts, where it serves as the principal protease involved in bone remodelling. It has been validated as a therapeutic target for osteoporosis, an increasing health problem in the modern world1–4. This disorder is caused by progressive loss of bone mass due to excessive activity of osteoclastic CatK. Several anti-remodelling inhibitors of CatK, such as odanacatib or balicatib5–7 (Figure 1), have been developed for the treatment of osteoporosis but have not yet been approved. CatK has also been implicated in the pathophysiology of two common forms of arthritis, osteoarthritis and rheumatoid arthritis8,9. In bone and cartilage disorders, CatK functions as a potent collagen degrading enzyme with the unique ability to cleave the triple helix of collagen molecules at multiple locations, an activity that is unparalleled among human collagenases10,11. This activity is induced by glycosaminoglycans, foremost chondroitin-4-sulphate, which mediates the formation of a complex between CatK and the collagen substrate10,12,13.
A patent review of bisphosphonates in treating bone disease
Published in Expert Opinion on Therapeutic Patents, 2019
Teriparatide (recombinant parathyroid hormone) and abaloparatide (a parathyroid hormone-related protein analog) are approved for the treatment of osteoporosis. It should be noted that in animals, abaloparatide caused an increase in the incidence of osteosarcoma [103], and therefore, this agent is not to be used in patients who are at increased risk for osteosarcoma. In addition, a cumulative use of either teriparatide or abaloparatide for more than 2 years during a patient’s lifetime is not recommended. Lasofoxifene, a nonsteroidal selective estrogen receptor modulator, did reduce the risk of vertebral and nonvertebral fracture in postmenopausal women with osteoporosis, but this treatment was also associated with an increased risk of venous thromboembolic events [104]. Development of the cathepsin K inhibitor odanacatib as an osteoporosis drug was abandoned due to an increased risk of strokes. Finally, romosozumab, a monoclonal antibody-targeting sclerostin, was recently approved by the Food and Drug Administration (FDA) for the treatment of osteoporosis. This was accompanied by a black box warning because of the increased risk of myocardial infarction, stroke and cardiovascular death. In addition, treatment is limited to 12 monthly doses. Thus overall, the agents with the best-understood safety profiles continue to be the NBPs and denosumab. Further studies and clinical experience are required to establish the role that the newer drugs such as romosozumab will play in the treatment of bone diseases.
Advances in the discovery of cathepsin K inhibitors on bone resorption
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Jun Lu, Maolin Wang, Ziyue Wang, Zhongqi Fu, Aiping Lu, Ge Zhang
Cathepsin K (Cat K), a member of cysteine proteases, is predominantly expressed in osteoclasts and plays crucial roles in degradation of bone matrix composited of hydroxyapatite and protein, especially type I collagen1. Both decalcification of hydroxyapatite in an acidic microenvironment and degradation of the protein matrix are inevitable during the bone resorption process. Furthermore, the imbalance between bone resorption (influenced by osteoclasts) and bone formation (influenced by osteoblasts) ultimately results in bone loss, which is significantly associated with osteoporosis2,3. Cat K with a relatively restricted expression pattern exhibits high activity against elastin and type I collagen and is obviously responsible for the relation of osteoclastic bone resorption, which leads to the development of Cat K inhibitors for the treatment of diseases characterised by excessive bone, loss such as osteoporosis4,5.