title: Mathematical modeling of postmenopausal osteoporosis and its treatment by the anti-catabolic drug denosumab.
abstract: Denosumab, a fully human monoclonal antibody, has been approved for the treatment of postmenopausal osteoporosis. The therapeutic effect of denosumab rests on its ability to inhibit osteoclast differentiation. Here, we present a computational approach on the basis of coupling a pharmacokinetics model of denosumab with a pharmacodynamics model for quantifying the effect of denosumab on bone remodeling. The pharmacodynamics model comprises an integrated systems biology-continuum micromechanics approach, including a bone cell population model, considering the governing biochemical factors of bone remodeling (including the action of denosumab), and a multiscale micromechanics-based bone mechanics model, for implementing the mechanobiology of bone remodeling in our model. Numerical studies of postmenopausal osteoporosis show that denosumab suppresses osteoclast differentiation, thus strongly curtailing bone resorption. Simulation results also suggest that denosumab may trigger a short-term bone volume gain, which is, however, followed by constant or decreasing bone volume. This evolution is accompanied by a dramatic decrease of the bone turnover rate by more than one order of magnitude. The latter proposes dominant occurrence of secondary mineralization (which is not anymore impeded through cellular activity), leading to higher mineral concentration per bone volume. This explains the overall higher bone mineral density observed in denosumab-related clinical studies.
authors.affiliation: Institute for Mechanics of Materials and Structures, Vienna University of Technology, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Scheiner
authors.forename: P
authors.initials: P
authors.lastname: Pivonka
authors.forename: D W
authors.initials: DW
authors.lastname: Smith
authors.forename: C R
authors.initials: CR
authors.lastname: Dunstan
authors.forename: C
authors.initials: C
authors.lastname: Hellmich
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002138:Calibration; D003198:Computer Simulation; D000069448:Denosumab; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008962:Models, Theoretical; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D017698:Postmenopause
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000069448:Denosumab
keywords: bone remodeling; micromechanics; pharmacokinetics; systems biology
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