Establishment of a Disease-Drug Trial Model for Postmenopausal Osteoporosis: A Zoledronic Acid Case Study.
Aged
Alkaline Phosphatase
/ blood
Biomarkers
/ metabolism
Bone Density
/ drug effects
Bone Density Conservation Agents
/ pharmacology
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
biomarkers
bisphosphonates
bone turnover marker
disease-drug trial model
fracture
postmenopausal osteoporosis
Journal
Journal of clinical pharmacology
ISSN: 1552-4604
Titre abrégé: J Clin Pharmacol
Pays: England
ID NLM: 0366372
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
26
05
2020
accepted:
31
08
2020
entrez:
4
12
2020
pubmed:
5
12
2020
medline:
22
9
2021
Statut:
ppublish
Résumé
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.
Substances chimiques
Biomarkers
0
Bone Density Conservation Agents
0
Collagen Type I
0
Peptides
0
collagen type I trimeric cross-linked peptide
0
Vitamin D
1406-16-2
Zoledronic Acid
6XC1PAD3KF
ALPL protein, human
EC 3.1.3.1
Alkaline Phosphatase
EC 3.1.3.1
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
S86-S102Informations de copyright
© 2020, The American College of Clinical Pharmacology.
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