caa a22 4500 605534020 CHVBK 20210128100840.0 cr unu---uuuuu 210128e20150801xx s 000 0 eng 10.1007/s10928-015-9423-3 doi (NATIONALLICENCE)springer-10.1007/s10928-015-9423-3 A semi-mechanistic model of bone mineral density and bone turnover based on a circular model of bone remodeling [Elektronische Daten] [Erno van Schaick, Jenny Zheng, Juan Ruixo, Ronald Gieschke, Philippe Jacqmin] Development of novel therapies for bone diseases can benefit from mathematical models that predict drug effect on bone remodeling biomarkers. Therefore, a bone cycle model (BCM) was developed that takes into consideration the concept of the basic multicellular unit and the dynamic equilibrium of bone remodeling. The model is a closed form cyclical model with four compartments representing resorption, formation, primary mineralization, and secondary mineralization. Equations describing the time course of bone turnover biomarkers were developed using the flow rate of bone cycle units (BCU) between the compartments or the amount of BCU in each compartment. A disease progression model representing bone loss in osteoporosis, a vitamin D and calcium supplementation (placebo) model, and a drug model for antiresorptive treatments were added to the model. Initial model parameter values were derived from published bone turnover data. The BCM accurately described biomarker-time profiles in postmenopausal women receiving either placebo or bisphosphonate treatment. The slow continual increase in bone mineral density (BMD) observed after 1year of treatment was accurately described when changes in bone turnover were combined with increases in mineralization. For this purpose, the secondary mineralization compartment was replaced by three catenary chain compartments representing increasing mineral content. The refined BCM satisfactorily predicted biomarker profiles after long-term (10-year) bisphosphonate treatment. Furthermore, the model successfully described individual bone turnover markers and BMD results following treatment with denosumab in postmenopausal women. Analyses with this model could be used to optimize dosing regimens and to predict effects of novel osteoporotic treatments. Springer Science+Business Media New York, 2015 Osteoporosis nationallicence Pharmacokinetics nationallicence Pharmacodynamics nationallicence Bone remodeling nationallicence van Schaick Erno SGS Exprimo NV, Generaal de Wittelaan 19A b5, 2800, Mechelen, Belgium aut Zheng Jenny Pharmacokinetics and Drug Metabolism Division, Amgen Inc., One Amgen Center Drive, 91320, Thousand Oaks, CA, USA aut Ruixo Juan Pharmacokinetics and Drug Metabolism Division, Amgen Inc., One Amgen Center Drive, 91320, Thousand Oaks, CA, USA aut Gieschke Ronald Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070, Basel, Switzerland aut Jacqmin Philippe SGS Exprimo NV, Generaal de Wittelaan 19A b5, 2800, Mechelen, Belgium aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/4(2015-08-01), 315-332 1567-567X 42:4<315 2015 42 10928 https://doi.org/10.1007/s10928-015-9423-3 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9423-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- van Schaick Erno SGS Exprimo NV, Generaal de Wittelaan 19A b5, 2800, Mechelen, Belgium aut NATIONALLICENCE 700 1- Zheng Jenny Pharmacokinetics and Drug Metabolism Division, Amgen Inc., One Amgen Center Drive, 91320, Thousand Oaks, CA, USA aut NATIONALLICENCE 700 1- Ruixo Juan Pharmacokinetics and Drug Metabolism Division, Amgen Inc., One Amgen Center Drive, 91320, Thousand Oaks, CA, USA aut NATIONALLICENCE 700 1- Gieschke Ronald Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070, Basel, Switzerland aut NATIONALLICENCE 700 1- Jacqmin Philippe SGS Exprimo NV, Generaal de Wittelaan 19A b5, 2800, Mechelen, Belgium aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/4(2015-08-01), 315-332 1567-567X 42:4<315 2015 42 10928