Coping with time scales in disease systems analysis: application to bone remodeling

• Published in: Journal of pharmacokinetics and pharmacodynamics 2011-12, Vol.38 (6), p.873-900
• Main Authors: Schmidt, Stephan, Post, Teun M., Peletier, Lambertus A., Boroujerdi, Massoud A., Danhof, Meindert
• Format: Article
• Language: English
• Subjects: Aging - physiology; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Bone Remodeling - drug effects; Bone Remodeling - physiology; Cell Communication - drug effects; Cell Communication - physiology; Computer Simulation; Disease Progression; Estrogen Replacement Therapy - statistics & numerical data; Female; Glucocorticoids - pharmacology; Humans; Models, Biological; Osteoblasts - drug effects; Osteoblasts - physiology; Osteoclasts - drug effects; Osteoclasts - physiology; Osteoporosis - drug therapy; Osteoporosis - physiopathology; Pharmacology/Toxicology; Pharmacy; Signal Transduction - drug effects; Signal Transduction - physiology; Systems Analysis; Time Factors; Veterinary Medicine/Veterinary Science; Vitamin D Deficiency - physiopathology
• ISSN: 1567-567X; 1573-8744
• DOI: 10.1007/s10928-011-9224-2

In this study we demonstrate the added value of mathematical model reduction for characterizing complex dynamic systems using bone remodeling as an example. We show that for the given parameter values, the mechanistic RANK-RANKL-OPG pathway model proposed by Lemaire et al. (J Theor Biol 229:293–309, 2004) can be reduced to a simpler model, which can describe the dynamics of the full Lemaire model to very good approximation. The response of both models to changes in the underlying physiology and therapeutic interventions was evaluated in four physiologically meaningful scenarios: (i) estrogen deficiency/estrogen replacement therapy, (ii) Vitamin D deficiency, (iii) ageing, and (iv) chronic glucocorticoid treatment and its cessation. It was found that on the time scale of disease progression and therapeutic intervention, the models showed negligible differences in their dynamic properties and were both suitable for characterizing the impact of estrogen deficiency and estrogen replacement therapy, Vitamin D deficiency, ageing, and chronic glucocorticoid treatment and its cessation on bone forming (osteoblasts) and bone resorbing (osteoclasts) cells. It was also demonstrated how the simpler model could help in elucidating qualitative properties of the observed dynamics, such as the absence of overshoot and rebound, and the different dynamics of onset and washout.