Computational model of the dual action of PTH — Application to a rat model of osteoporosis

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Author(s)
Trichilo, S
Scheiner, S
Forwood, M
Cooper, DML
Pivonka, P
Griffith University Author(s)
Year published
2019
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This paper presents a pharmacokinetic/pharmacodynamic (PK/PD) model of the action of PTH(1-34) on bone modelling and remodelling, developed for quantitatively investigating the dose- and administration pattern-dependency of the bone tissue response to this drug. Firstly, a PK model of PTH(1-34) was developed, accounting for administration via subcutaneous injections. Subsequently, the PK model was coupled to a (mechanistic) bone cell population model of bone modelling and remodelling, taking into account the effects of PTH(1-34) on the differentiation of lining cells into active osteoblasts, on the apoptosis of active ...
View more >This paper presents a pharmacokinetic/pharmacodynamic (PK/PD) model of the action of PTH(1-34) on bone modelling and remodelling, developed for quantitatively investigating the dose- and administration pattern-dependency of the bone tissue response to this drug. Firstly, a PK model of PTH(1-34) was developed, accounting for administration via subcutaneous injections. Subsequently, the PK model was coupled to a (mechanistic) bone cell population model of bone modelling and remodelling, taking into account the effects of PTH(1-34) on the differentiation of lining cells into active osteoblasts, on the apoptosis of active osteoblasts, and on proliferation of osteoblast precursors, as well as on the key regulatory pathways of bone cell activities. Numerical simulations show that the coupled PK/PD model is able to distinguish between continuous and intermittent administration patterns of PTH(1-34), in terms of yielding both catabolic bone responses (if drug administration is carried out continuously) and anabolic bone responses (if drug administration is carried out intermittently). The model also features a non-linear relation between bone gain and drug dose (as known from experiments); doubling the dose from 80 g/kg/day to 160 g/kg/day induced a 1.3-fold increase of the bone volume-to-total volume ratio. Furthermore, the model presented in this paper confirmed that bone modelling represents an essential mechanism of the anabolic response of bone to PTH(1–34) administration in rat models, and that the large amount of bone formation observed in such models cannot be explained via remodelling alone.
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View more >This paper presents a pharmacokinetic/pharmacodynamic (PK/PD) model of the action of PTH(1-34) on bone modelling and remodelling, developed for quantitatively investigating the dose- and administration pattern-dependency of the bone tissue response to this drug. Firstly, a PK model of PTH(1-34) was developed, accounting for administration via subcutaneous injections. Subsequently, the PK model was coupled to a (mechanistic) bone cell population model of bone modelling and remodelling, taking into account the effects of PTH(1-34) on the differentiation of lining cells into active osteoblasts, on the apoptosis of active osteoblasts, and on proliferation of osteoblast precursors, as well as on the key regulatory pathways of bone cell activities. Numerical simulations show that the coupled PK/PD model is able to distinguish between continuous and intermittent administration patterns of PTH(1-34), in terms of yielding both catabolic bone responses (if drug administration is carried out continuously) and anabolic bone responses (if drug administration is carried out intermittently). The model also features a non-linear relation between bone gain and drug dose (as known from experiments); doubling the dose from 80 g/kg/day to 160 g/kg/day induced a 1.3-fold increase of the bone volume-to-total volume ratio. Furthermore, the model presented in this paper confirmed that bone modelling represents an essential mechanism of the anabolic response of bone to PTH(1–34) administration in rat models, and that the large amount of bone formation observed in such models cannot be explained via remodelling alone.
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Journal Title
Journal of Theoretical Biology
Volume
473
Copyright Statement
© 2019 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
Subject
Mathematical Sciences
Biological Sciences
Information and Computing Sciences