{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:06:13Z","timestamp":1770815173508,"version":"3.50.1"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2013,7,22]],"date-time":"2013-07-22T00:00:00Z","timestamp":1374451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,2,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Cathepsin K inhibitors, such as ONO-5334, are being developed for the treatment of postmenopausal osteoporosis. However, their relative effects on bone resorption and formation, and how quickly the effects resolve after treatment cessation, are uncertain. The aim of this study was to examine the efficacy and safety of 24-month treatment with ONO-5334 and to assess the effect of treatment cessation over 2 months. We studied 197 postmenopausal women with osteoporosis or osteopenia with one fragility fracture. Patients were randomized to ONO-5334 50\u2009mg twice daily, 100\u2009mg or 300\u2009mg once daily, alendronate 70\u2009mg once weekly (positive control), or placebo for 24 months. After 24 months, all ONO-5334 doses were associated with increased bone mineral density (BMD) for lumbar spine, total hip, and femoral neck (p\u2009&amp;lt;\u20090.001). ONO-5334 300\u2009mg significantly suppressed the bone-resorption markers urinary (u) NTX and serum and uCTX-I throughout 24 months of treatment and to a similar extent as alendronate; other resorption marker levels remained similar to placebo (fDPD for ONO-5334 300\u2009mg qd) or were increased (ICTP, TRAP5b, all ONO-5334 doses). Levels of B-ALP and PINP were suppressed in all groups (including placebo) for approximately 6 months but then increased for ONO-5334 to close to baseline levels by 12 to 24 months. On treatment cessation, there were increases above baseline in uCTX-I, uNTX, and TRAP5b, and decreases in ICTP and fDPD. There were no clinically relevant safety concerns. Cathepsin K inhibition with ONO-5334 resulted in decreases in most resorption markers over 2 years but did not decrease most bone formation markers. This was associated with an increase in BMD; the effect on biochemical markers was rapidly reversible on treatment cessation. \u00a9 2014 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2047","type":"journal-article","created":{"date-parts":[[2013,7,22]],"date-time":"2013-07-22T05:46:21Z","timestamp":1374471981000},"page":"458-466","source":"Crossref","is-referenced-by-count":69,"title":["Effect of ONO-5334 on Bone Mineral Density and Biochemical Markers of Bone Turnover in Postmenopausal Osteoporosis: 2-Year Results From the OCEAN Study"],"prefix":"10.1093","volume":"29","author":[{"given":"Richard","family":"Eastell","sequence":"first","affiliation":[{"name":"Academic Unit of Bone MetabolismUniversity of SheffieldSheffieldUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinichi","family":"Nagase","sequence":"additional","affiliation":[{"name":"Ono Pharma UK Ltd.LondonUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Small","sequence":"additional","affiliation":[{"name":"Ono Pharma UK Ltd.LondonUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Boonen","sequence":"additional","affiliation":[{"name":"Division of Gerontology and GeriatricsLeuven UniversityLeuvenBelgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Spector","sequence":"additional","affiliation":[{"name":"King's College LondonLondonUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michiyo","family":"Ohyama","sequence":"additional","affiliation":[{"name":"Ono Pharmaceutical Co., Ltd.OsakaJapan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohiro","family":"Kuwayama","sequence":"additional","affiliation":[{"name":"Ono Pharma UK Ltd.LondonUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve","family":"Deacon","sequence":"additional","affiliation":[{"name":"Ono Pharma UK Ltd.LondonUK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,7,22]]},"reference":[{"key":"2024020318572258100_jbmr2047-bib-0001","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1210\/jc.2009-1947","article-title":"Long-term use of bisphosphonates in osteoporosis","volume":"95","author":"Watts","year":"2010","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020318572258100_jbmr2047-bib-0002","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1007\/s00198-005-1945-x","article-title":"Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies","volume":"16","author":"Boonen","year":"2005","journal-title":"Osteoporos Int."},{"key":"2024020318572258100_jbmr2047-bib-0003","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1056\/NEJMoa067312","article-title":"Once-yearly zoledronic acid for treatment of post-menopausal osteoporosis","volume":"356","author":"Black","year":"2007","journal-title":"N Engl J Med."},{"key":"2024020318572258100_jbmr2047-bib-0004","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1056\/NEJMoa0809493","article-title":"Denosumab for prevention of fractures in postmenopausal women with osteoporosis","volume":"361","author":"Cummings","year":"2009","journal-title":"N Engl J Med."},{"key":"2024020318572258100_jbmr2047-bib-0005","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/ncprheum0977","article-title":"Potential new drug targets for osteoporosis","volume":"5","author":"Deal","year":"2009","journal-title":"Nat Clin Pract Rheumatol."},{"key":"2024020318572258100_jbmr2047-bib-0006","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.addr.2004.12.013","article-title":"The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics","volume":"57","author":"Yasuda","year":"2005","journal-title":"Adv Drug Deliv Rev."},{"key":"2024020318572258100_jbmr2047-bib-0007","doi-asserted-by":"crossref","first-page":"12511","DOI":"10.1074\/jbc.271.21.12511","article-title":"Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts","volume":"271","author":"Drake","year":"1996","journal-title":"J Biol Chem."},{"key":"2024020318572258100_jbmr2047-bib-0008","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1126\/science.273.5279.1236","article-title":"Pycnodysostosis, a lysosomal disease caused by cathepsin K 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ascending multiple-dose","volume":"97","author":"Nagase","year":"2012","journal-title":"Phase 1 study. J Clin Endocrinol Metab."},{"key":"2024020318572258100_jbmr2047-bib-0016","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1002\/jbmr.341","article-title":"Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: the OCEAN study","volume":"26","author":"Eastell","year":"2011","journal-title":"J Bone Miner Res."},{"key":"2024020318572258100_jbmr2047-bib-0017","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1001\/jama.282.14.1344","article-title":"Effects of risedronate treatment on vertebral and nonvertebral fractures in women with post-menopausal osteoporosis: a randomized controlled trial","volume":"282","author":"Harris","year":"1999","journal-title":"JAMA."},{"key":"2024020318572258100_jbmr2047-bib-0018","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1002\/jbmr.212","article-title":"Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect","volume":"26","author":"Eisman","year":"2011","journal-title":"J Bone Miner Res."},{"key":"2024020318572258100_jbmr2047-bib-0019","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1359\/jbmr.2002.17.11.1988","article-title":"Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis","volume":"17","author":"Rizzoli","year":"2002","journal-title":"J Bone Miner Res."},{"key":"2024020318572258100_jbmr2047-bib-0020","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1359\/JBMR.040920","article-title":"Fosamax Actonel Comparison Trial Investigators. Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study","volume":"20","author":"Rosen","year":"2005","journal-title":"J Bone Miner Res."},{"key":"2024020318572258100_jbmr2047-bib-0021","first-page":"1","article-title":"Comparison of the effect of denosumab and alendronate on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded","volume":"14","author":"Brown","year":"2009","journal-title":"Phase 3 trial. 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