Study of the combined effects of PTH treatment and mechanical loading in postmenopausal osteoporosis using a new mechani
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ORIGINAL PAPER
Study of the combined effects of PTH treatment and mechanical loading in postmenopausal osteoporosis using a new mechanistic PK‑PD model Maxence Lavaill1 · Silvia Trichilo2 · Stefan Scheiner3 · Mark R. Forwood4 · David M. L. Cooper5 · Peter Pivonka1 Received: 10 December 2019 / Accepted: 7 February 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract One of only a few approved and available anabolic treatments for severe osteoporosis is daily injections of PTH (1-34). This drug has a specific dual action which can act either anabolically or catabolically depending on the type of administration, i.e. intermittent or continuous, respectively. In this paper, we present a mechanistic pharmacokinetic–pharmacodynamic model of the action of PTH in postmenopausal osteoporosis. This model accounts for anabolic and catabolic activities in bone remodelling under intermittent and continuous administration of PTH. The model predicts evolution of common bone biomarkers and bone volume fraction (BV/TV) over time. We compared the relative changes in BV/TV resulting from a daily injection of 20 μ g of PTH with experimental data from the literature. Simulation results indicate a site-specific bone gain of 8.66% (9.4 ± 1.13% ) at the lumbar spine and 3.14% (2.82 ± 0.72% ) at the femoral neck. Bone gain depends nonlinearly on the administered dose, being, respectively, 0.68% , 3.4% and 6.16% for a 10, 20 and 40 μ g PTH dose at the FN over 2 years. Simulations were performed also taking into account a bone mechanical disuse to reproduce elderly frail subjects. The results show that mechanical disuse ablates the effects of PTH and leads to a 1.08% reduction of bone gain at the FN over a 2-year treatment period for the 20 μ g of PTH. The developed model can simulate a range of pathological conditions and treatments in bones including different PTH doses, different mechanical loading environments and combinations. Consequently, the model can be used for testing and generating hypotheses related to synergistic action between PTH treatment and physical activity. Keywords Postmenopausal osteoporosis · Dual action of PTH · Bone remodelling model · Pharmacokinetics pharmacodynamics · Mechanical feedback · Site-specific bone response
1 Introduction
* Maxence Lavaill [email protected] 1
Biomechanics and Spine Research Group, Queensland University of Technology, Brisbane, QLD, Australia
2
St Vincent’s Department of Surgery, University of Melbourne, Melbourne, VIC, Australia
3
Institute for Mechanics of Materials and Structures, Vienna University of Technology (TU Wien), Vienna, Austria
4
School of Medical Science, Griffith University, Gold Coast, QLD, Australia
5
Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada
Bone remodelling is the lifelong process of bone resorption and bone formation maintaining bone health (Langdahl et al. 2016). In osteoporosis, bone resorption prevails over bone formation and leads to low bone mineral d
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