Calcium Homeostasis and Bone Remodeling: Development of an Integrated Model for Evaluation and Simulation of Therapeutic Responses to Bone-Related Therapies
M.C. Peterson(1), M.M. Riggs(2)
(1)Amgen Inc., Thousand Oaks, CA USA, (2)Metrum Research Group, LLC, Tariffville, CT USA
Objectives: Calcium (Ca) homeostasis and bone remodeling are complexly integrated, highly regulated processes involving multiple organs and endocrine pathways. Published attempts to develop a generalized model have failed to provide an adequate platform for describing multiple therapeutic class effects on the system. We describe the development of a model that characterizes and predicts longitudinal Ca homeostasis and related co-factors (including phosphate, PTH and calcitriol), as well as expected rates of bone turnover due to natural progression, therapeutic intervention, or disease states.
Methods: Our approach is based on physiologic requirements to maintain Ca balance with the general model predicated on 3 manuscripts [1-3]. Significant modifications and additional feedback mechanisms, based on literature reports and Amgen internal data, have been added to appropriately integrate the model. The model includes the RANK-RANKL-OPG system to enable characterization of osteoclast (OC) and osteoblast (OB) genesis and survival. PTH-mediated anti-apoptotic signaling in OB allows for description of both anabolic and catabolic effects of PTH on bone remodeling. TGFbeta-mediated feedback mechanisms are incorporated to capture homeostatic observations. The model has enabled evaluation of various affecting mechanisms and ramifications of therapeutic interventions and disease states, including the following: (1) OPG infusion, (2) intermittent- and (3) constant-PTH infusion, (4) hyper- and (5) hypo-calcemia, and (6) progressive renal insufficiency.
Results: The integrated model appears to provide a generalizable structure with known or plausible cell signaling concepts and physiologically consistent parameters. Model predictions under conditions (1) - (6) provide results consistent with clinical observations.
Conclusion: We have developed a robust physiologic model that provides continuous descriptions of biomarkers and electrolytes including calcium, phosphate, PTH, and markers of bone turnover consistent with literature and Amgen internal data. This model may allow for investigation of therapeutics under development, prediction of cytokine mediators of bone homeostasis, and provide a platform for hypothesis testing prior to clinical investigations.
References:
[1]Raposo et. al, J Clin Endocrin Metab, 2002; 87(9):4330-40.
[2] Lemaire et. al, J Theor Biol, 2004; 229(3):293-309.
[3] Bellido et. al, J Biological Chem, 2003; 278(50):50259-72.
