{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:42:27Z","timestamp":1789753347625,"version":"4.0.1"},"reference-count":21,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2013,3,7]],"date-time":"2013-03-07T00:00:00Z","timestamp":1362614400000},"content-version":"vor","delay-in-days":371,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2012,3]]},"abstract":"<jats:p>Selective inhibitors of cathepsin K, which has a major role in the degradation of bone collagen, are potential new treatments for osteoporosis. The pharmacokinetics and the pharmacodynamic effects on biochemical markers of bone turnover of the new cathepsin K inhibitor, ONO\u20105334, were investigated in a multiple ascending dose, phase 1 study. A total of 120 healthy postmenopausal women were enrolled, and doses of 10 to 600 mg once daily and 50 and 300 mg twice daily were evaluated in 15\u2010 and 28\u2010day multiple\u2010dosing cohorts. Plasma ONO\u20105334 concentration reached steady state within 2 days. Twenty\u2010four hours after the last dose in the 15\u2010day multiple\u2010dose cohort, 100, 300, and 600 mg once daily reduced urinary C\u2010terminal telopeptide of type I collagen by a mean (\u00b1 standard deviation) 44.9% \u00b1 13.6%, 84.5% \u00b1 4.4%, and 92.5% \u00b1 1.3%, respectively. The 28\u2010day cohort showed similar effects. There were far smaller effects on bone\u2010specific alkaline phosphatase (B\u2010ALP), tartrate\u2010resistant acid phosphatase 5b (TRAP5b), or osteocalcin (OC) (measured after 28 days). ONO\u20105334 was well tolerated up to 600 mg\/d and for up to 28 days of multiple dosing. Multiple dosing with ONO\u20105334 100 mg resulted in considerable suppression of bone resorption markers with no appreciable effects on bone formation markers (B\u2010ALP, OC) or osteoclast number (TRAP5b).<\/jats:p>","DOI":"10.1177\/0091270011399080","type":"journal-article","created":{"date-parts":[[2011,7,1]],"date-time":"2011-07-01T03:52:21Z","timestamp":1309492341000},"page":"306-318","source":"Crossref","is-referenced-by-count":22,"title":["Pharmacodynamic Effects on Biochemical Markers of Bone Turnover and Pharmacokinetics of the Cathepsin K Inhibitor, ONO\u20105334, in an Ascending Multiple\u2010Dose, Phase 1 Study"],"prefix":"10.1002","volume":"52","author":[{"given":"Shinichi","family":"Nagase","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiyo","family":"Ohyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Small","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Kuwayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Deacon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,3,7]]},"reference":[{"key":"e_1_2_5_2_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1994.0083"},{"key":"e_1_2_5_3_2","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.1999.14.11.1902"},{"key":"e_1_2_5_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5279.1236"},{"key":"e_1_2_5_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.23.13453"},{"key":"e_1_2_5_6_2","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.1999.14.10.1654"},{"key":"e_1_2_5_7_2","unstructured":"AdamiS SupronikJ HalaT et al.Effect of one year treatment with the cathepsin\u2010K inhibitor balicatib on bone mineral density (BMD) in postmenopausal women with osteopenia\/osteoporosis. Paper presented at: American Society for Bone and Mineral Research2006. Philadelphia PA. Abstract 1085."},{"key":"e_1_2_5_8_2","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.091035"},{"key":"e_1_2_5_9_2","volume-title":"Inhibitory effect of ONO\u20105334 on human recombinant cathepsin K (E05QA012)","author":"Data on file."},{"key":"e_1_2_5_10_2","volume-title":"Inhibitory effect of ONO\u20105334 on 6 cystein proteases (E05QA025)","author":"Data on file."},{"key":"e_1_2_5_11_2","volume-title":"An investigation of Ono's compound (ONO\u20105334) on 9 enzyme and 3 receptor binding assays (1056356)","author":"Data on file."},{"key":"e_1_2_5_12_2","unstructured":"YamadaH MoriH NakanishiY et al.Orally active cathepsin K inhibitor ONO\u20105334 potently improved bone mineral density not only in trabecular bone but also in cortical bone in ovariectomized cynomolgus monkeys. Paper presented at: American Society for Bone and Mineral Research2009. Denver CO. Abstract A09002146."},{"key":"e_1_2_5_13_2","volume-title":"A phase I, three\u2010part, study to investigate the safety, tolerability, pharmacokinetic profile and pharmacodynamic effect of single and multiple doses of ONO\u20105334 in post\u2010menopausal females, ONO\u20105334POE001 study","author":"Data on file."},{"key":"e_1_2_5_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2009.60"},{"key":"e_1_2_5_15_2","doi-asserted-by":"publisher","DOI":"10.2165\/00044011-200626020-00002"},{"key":"e_1_2_5_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa067312"},{"key":"e_1_2_5_17_2","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.0809010"},{"key":"e_1_2_5_18_2","article-title":"Cathepsin K inhibitors prevent bone loss in estrogen\u2010deficient rabbits [published online ahead of print August 23, 2010]","author":"Pennypacker BL","journal-title":"J Bone Miner Res"},{"key":"e_1_2_5_19_2","unstructured":"YamadaH MoriH NakanishiY et al.Orally active cathepsin K inhibitor ONO\u20105334 potently improved bone mineral density not only in trabecular bone but also in cortical bone in ovariectomized cynomolgus monkeys. Paper presented at: American Society for Bone and Mineral Research2009Annual Meeting Denver CO. Abstract A09002146."},{"key":"e_1_2_5_20_2","unstructured":"TanakaM YamadaH MoriH et al.Efficacy of ONO\u20105334 a cathepsin K inhibitor on bone geometry and histomorphometry in cortical bone in ovariectomized cynomolgus monkeys. Paper presented at: American Society for Bone and Mineral Research2010Annual Meeting. Toronto OT Canada. 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