Establishment of a Disease-Drug Trial Model for Postmenopausal Osteoporosis: A Zoledronic Acid Case Study.

Abstract

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.

• Authors: Yi Ting Kayla Lien, Kumpal Madrasi, Snehal Samant, Myong-Jin Kim, Fang Li, Li Li, Yaning Wang, Stephan Schmidt
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 60 Suppl 2 Pg. S86-S102 (12 2020) ISSN: 1552-4604 [Electronic] England
• PMID: 33274518 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
• Copyright: © 2020, The American College of Clinical Pharmacology.

Chemical References

• Biomarkers
• Bone Density Conservation Agents
• Collagen Type I
• Peptides
• collagen type I trimeric cross-linked peptide
• Vitamin D
• Zoledronic Acid
• ALPL protein, human
• Alkaline Phosphatase
• Calcium

Topics

• Aged
• Alkaline Phosphatase (blood)
• Biomarkers (metabolism)
• Bone Density (drug effects)
• Bone Density Conservation Agents (pharmacology, therapeutic use)
• Bone Remodeling (drug effects)
• Calcium (therapeutic use)
• Clinical Trials as Topic
• Collagen Type I (blood)
• Female
• Humans
• Middle Aged
• Models, Biological
• Osteoporosis, Postmenopausal (prevention & control)
• Peptides (blood)
• Vitamin D (therapeutic use)
• Zoledronic Acid (pharmacology, therapeutic use)