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Establishment of a Disease‐Drug Trial Model for Postmenopausal Osteoporosis: A Zoledronic Acid Case Study
Author(s) -
Lien Yi Ting Kayla,
Madrasi Kumpal,
Samant Snehal,
Kim MyongJin,
Li Fang,
Li Li,
Wang Yaning,
Schmidt Stephan
Publication year - 2020
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1748
Subject(s) - zoledronic acid , medicine , osteoporosis , menopause , bone remodeling , clinical trial , placebo , bisphosphonate , oncology , bone mineral , tibolone , pathology , alternative medicine
Costly and lengthy clinical trials hinder the development of safe and effective treatments for postmenopausal osteoporosis. To reduce the expense associated with these trials, we established a mechanistic disease‐drug trial model for postmenopausal osteoporosis that can predict phase 3 trial outcome based on short‐term 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‐mg zoledronic acid in year 1 and saline in year 2, (2) 5‐mg zoledronic acid in year 1 and year 2, or (3) placebo (saline), calcium (500 mg), 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‐term biomarkers and fracture risk.