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To reduce the expense associated with these trials, we established a mechanistic disease\u2010drug trial model for postmenopausal osteoporosis that can predict phase 3 trial outcome based on short\u2010term bone turnover marker data. To this end, we applied a previously developed model for tibolone to bisphosphonates using zoledronic acid as paradigm compound by (1) linking the mechanistic bone cell interaction model to bone turnover markers as well as bone mineral density in lumbar spine and total hip, (2) employing a mechanistic disease progression function, and (3) accounting for zoledronic acid's mechanism of action. Once developed, we fitted the model to clinical trial data of 581 postmenopausal women receiving (1) 5\u2010mg zoledronic acid in year 1 and saline in year 2, (2) 5\u2010mg zoledronic acid in year 1 and year 2, or (3) placebo (saline), calcium (500\u00a0mg), and vitamin D (400 IU). All biomarker data was fitted reasonably well, with no apparent bias or model misspecification. Age, years since menopause, and body mass index at baseline were identified as significant covariates. In the future, the model can be modified to explore the link between short\u2010term biomarkers and fracture risk.<\/jats:p>","DOI":"10.1002\/jcph.1748","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T04:56:32Z","timestamp":1607057792000},"update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Establishment of a Disease\u2010Drug Trial Model for Postmenopausal Osteoporosis: A Zoledronic Acid Case Study"],"prefix":"10.1002","volume":"60","author":[{"given":"Yi Ting (Kayla)","family":"Lien","sequence":"first","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida  Orlando Florida USA"},{"name":"Office of Clinical Pharmacology Office of Translational Sciences (OTS) Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kumpal","family":"Madrasi","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida  Orlando Florida USA"},{"name":"Office of Clinical Pharmacology Office of Translational Sciences (OTS) Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Snehal","family":"Samant","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida  Orlando Florida USA"},{"name":"Office of Clinical Pharmacology Office of Translational Sciences (OTS) Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myong\u2010Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology Office of Translational Sciences (OTS) Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Li","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology Office of Translational Sciences (OTS) Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology Office of Translational Sciences (OTS) Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaning","family":"Wang","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology Office of Translational Sciences (OTS) Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA)  Silver Spring Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,12,3]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"Foundation NO.What is osteoporosis and what causes it?https:\/\/www.nof.org\/patients\/what-is-osteoporosis\/. 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