Modeling osteoporosis to design and optimize pharmacological therapies comprising multiple drug types

David J. Jörg, Doris Fuertinger, Alhaji Cherif, David Bushinsky, Ariella Mermelstein, Jochen G Raimann, Peter Kotanko


For the treatment of postmenopausal osteoporosis, several drug classes with different mechanisms of action are available. Since only a limited set of dosing regimens and drug combinations can be tested in clinical trials, it is currently unclear whether common medication strategies achieve optimal bone mineral density gains or are outperformed by alternative dosing schemes and combination therapies that have not been explored so far. Here, we develop a mathematical framework of drug interventions for postmenopausal osteoporosis that unifies fundamental mechanisms of bone remodeling and the mechanisms of action of four drug classes: bisphosphonates, parathyroid hormone analogs, sclerostin inhibitors, and receptor activator of NF-κB ligand inhibitors. Using data from several clinical trials, we calibrate and validate the model, demonstrating its predictive capacity for complex medication scenarios, including sequential and parallel drug combinations. Via simulations, we reveal that there is a large potential to improve gains in bone mineral density by exploiting synergistic interactions between different drug classes, without increasing the total amount of drug administered.

About the Contributors

Ariella Mermelstein, MA

Data Analyst

Ariella joined RRI as a data analyst in 2020 while completing her master's degree in mathematics from the Katz School at Yeshiva University. As an integral part of the research division at RRI, Ariella collaborates across all teams on various projects, particularly the physiological effects of hemodialysis on a variety of patient populations. The scope of her work includes predictive modeling, outcome analysis, and data extraction and processing. She has submitted manuscripts for publication and is looking forward to her continued career at RRI.

Jochen G. Raimann, MD, PhD, MPH

Director, Data Analytics

Jochen has worked as a full-time scientist at RRI since his start as a postdoctoral research fellow in 2007. As Senior Manager of Clinical Data Analytics, Jochen conducts epidemiological research in dialysis and oversees many analytical projects. He has first- and co-authored numerous papers and also serves as Associate Editor of the journals Trials and Scientific Reports. ochen earned his MD from the Medical University Graz, his PhD from Maastricht University, and his MPH with a focus on epidemiology and biostatistics from the City University of New York School of Public Health.

Dr. Peter Kotanko, MD

RRI Research Director

SVP, Corporate Research & Development

Peter Kotanko, MD, is Research Director at the Renal Research Institute (RRI), New York. Prior to joining RRI, from 1997 to 2007 he served as vice chair of a department of internal medicine at an academic teaching hospital in Graz, Austria. Prior to moving to Graz in 1989, he worked from 1982 to 1989 in the Department of Physiology and the University Clinic of Internal Medicine in Innsbruck, Austria. From 1995 to 1996 he trained in nephrology at the Hammersmith Hospital, London, United Kingdom.

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