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

Publication date: Available online 19 April 2019Source: Journal of Theoretical BiologyAuthor(s): Silvia Trichilo, Stefan Scheiner, Mark Forwood, David M.L. Cooper, Peter PivonkaAbstractThis 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 μg/kg/day to 160 μg/kg/day induced a 1.3-fold increase of the bone volume-to-total vo...
Source: Journal of Theoretical Biology - Category: Biology Source Type: research