Open AccessConnecting the Dots: Linking Osteocyte Activity and Therapeutic Modulation of Sclerostin by Extending a Multiscale Systems Model
Author(s) -
Eudy RJ,
Gastonguay MR,
Baron KT,
Riggs MM
Publication year - 2015
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12013
Subject(s) - sclerostin , osteocyte , rankl , bone remodeling , mechanism (biology) , bone resorption , bone formation , chemistry , signal transduction , microbiology and biotechnology , medicine , biology , osteoblast , receptor , wnt signaling pathway , in vitro , physics , biochemistry , activator (genetics) , quantum mechanics
The goal of this work was to extend a mathematical, multiscale systems model of bone function, remodeling, and health in order to explore hypotheses related to therapeutic modulation of sclerostin and quantitatively describe purported osteocyte activity within bone remodeling events. A pharmacokinetic model with first‐order absorption and dual elimination pathways was used to describe the kinetics of romosozumab, a monoclonal antibody (mAb) against sclerostin. To describe total circulating sclerostin, an extended indirect response model of inhibition of offset was developed. These models were subsequently linked to the systems model, with sclerostin signaling changes in resorption and formation through established osteocyte‐mediated mechanisms. The model proposes relative contributions of the osteocyte to the RANKL pool, a major player in feedback signaling, and is used to explore hypotheses surrounding attenuation of anabolic activity after multiple doses of sclerostin mAbs, a phenomenon whose mechanism is poorly understood.