title: Mathematical Model of Bone Remodeling Captures the Antiresorptive and Anabolic Actions of Various Therapies.
abstract: A better understanding of the molecular pathways regulating the bone remodeling process should help in the development of new antiresorptive regulators and anabolic regulators, that is, regulators of bone resorption and of bone formation. Understanding the mechanisms by which parathyroid hormone (PTH) influences bone formation and how it switches from anabolic to catabolic action is important for treating osteoporosis (Poole and Reeve in Curr Opin Pharmacol 5:612-617, 2005). In this paper we describe a mathematical model of bone remodeling that incorporates, extends, and integrates several models of particular aspects of this biochemical system (Cabal et al. in J Bone Miner Res 28(8):1830-1836, 2013; Lemaire et al. in J Theor Biol 229:293-309, 2004; Peterson and Riggs in Bone 46:49-63, 2010; Raposo et al. in J Clin Endocrinol Metab 87(9):4330-4340, 2002; Ross et al. in J Disc Cont Dyn Sys Series B 17(6):2185-2200, 2012). We plan to use this model as a bone homeostasis platform to develop anabolic and antiresorptive compounds. The model will allow us to test hypotheses about the dynamics of compounds and to test the potential benefits of combination therapies. At the core of the model is the idealized account of osteoclast and osteoblast signaling given by Lemaire et al. (J Theor Biol 229:293-309, 2004). We have relaxed some of their assumptions about the roles of osteoprotegerin, transforming growth factor [Formula: see text], and receptor activator of nuclear factor [Formula: see text]B ligand; we have devised more detailed models of the interactions of these species. We have incorporated a model of the effect of calcium sensing receptor antagonists on remodeling (Cabal et al. in J Bone Miner Res 28(8):1830-1836, 2013). We have also incorporated a basic model of the effects of vitamin D on calcium homeostasis. We have included a simple model of the mechanism proposed by Bellido et al. (2003), Ross et al. (J Disc Cont Dyn Sys Series B 17(6):2185-2200, 2012), of the influence of PTH on osteoblast apoptosis, a mechanism that accounts for the anabolic response to pulsatile PTH administration. Finally, we have devised a simple model of the administration and effects of bisphosphonates. The biomarkers in the model are procollagen type 1 amino-terminal propeptide and C-terminal telopeptide. Bone mineral density is the model's principal endpoint.
authors.affiliation: Center for Applied and Computational Mathematics, Rochester Institute of Technology, Rochester, NY, 14623, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Ross
authors.affiliation: Quantitative Pharmacology and Pharmacometrics, Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ, USA.
authors.forename: Khamir
authors.initials: K
authors.lastname: Mehta
authors.affiliation: Quantitative Pharmacology and Pharmacometrics, Merck Research Laboratories, Merck & Co. Inc., Kenilworth, NJ, USA. antonio.cabal@merck.com.|, 351 N Sumneytown Pike, P. O. Box 1000, North Wales, PA, 19454, USA. antonio.cabal@merck.com.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cabal
mesh_terms: D045930:Anabolic Agents / Q000627:therapeutic use; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D016723:Bone Remodeling / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D055641:Mathematical Concepts; D008954:Models, Biological; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D010024:Osteoporosis / Q000188:drug therapy / Q000503:physiopathology; D053244:Osteoprotegerin / Q000502:physiology; D010281:Parathyroid Hormone / Q000502:physiology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000502:physiology; D015398:Signal Transduction
chemical_list: D045930:Anabolic Agents; D050071:Bone Density Conservation Agents; D053244:Osteoprotegerin; C470125:PTH protein, human; D010281:Parathyroid Hormone; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human
keywords: Anabolic window; Mechanistic model; Osteoblast; Osteoclast; Osteoporosis