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Mathematically represent the integration of pharmacology, physiology and pathophysiology associated with bone health and bone mineral (calcium and phosphate) homeostatic balance mechanisms at the levels of cell signaling, organ function and clinical outcome. This model is intended to provide a research platform for assessing clinical changes associated with disease, aging and pharmacologic interventions.
Please use Issues to comment on desired applications and extensions (e.g., disease states, regulating pathways, new drug targets) to this platform or to report bugs, propose improvements and suggest other developments to the model and underlying science.
Background and Motivation
The model was originally developed to describe the bone marker changes associated with denosumab administration from a then ongoing clinical trial. Associated changes in serum calcium and PTH were also considered of interest at the time and so justified the development of a 'systems' model that included bone remodeling and bone mineral (calcium and phosphate) homeostatic mechanisms. Other therapeutics (e.g., teriparatide) and disease states (kidney failure, parathyroid-related abnormalities) were also considered at the time to further inform the parameterization and estimation of the model (Peterson and Riggs, Bone 2010).
Extensibility, and so re-use and repurposing, of the model has been perhaps its greatest attribute, particularly when integrated with pharmacometrics. For example, pharmacokinetic (PK) models have been included to drive pharmacologic effects of parathyroid analogue (teriparatide, Peterson and Riggs, Bone 2010), calcium sensing receptor modulators (Baron et al. J Bone Miner Res 2013), exogenous vitamin D (Ocampo-Pelland et al. J PK PD 2016), and sclerostin inhibition (Eudy et al. CPT:PSP 2015).
Many of these applications have lead to, or taken advantage of “middle-up” extensions added to describe, for example, BMD changes associated with bone marker changes and fracture risk associated with BMD (Eudy et al. J PK PD 2015). These, along with disease progression effects such as kidney failure (Riggs et al. J Clin Pharmacol 2012) and estrogen depletion, enabled a range of drug development evaluations including proof of mechanism and concept, dose ranging, disease state implications and off-treatment effects. Predicted BMD change partnered with proportional odds modeling for efficacy was used in this way to evaluate GnRH modulating therapies (Riggs et al. CPT:PSP 2012). Notably, external validation and use by FDA during regulatory review to recommend further dose regimen optimizations, stands as the first known use of this kind for a QSP model (Peterson and Riggs CPT:PSP 2015).
An overview of the model and many of the extensions was reviewed in this presentation:
- Riggs, M. Systems pharmacology model development to provide physiologically based interpretation and drug development decision support in osteoporosis and other bone mineral-related diseases. Presented at Pharmacology 2016, annual meeting of the British Pharmacological Society, London, December 2016. download slides
The Bone Health and Mineral Model in mrgsolve
Although already 'publically-available', the implementation represented herein takes advantage of mrgsolve (Baron 2017), an R package for simulation from hierarchical, ordinary differential equation (ODE) based models typically employed in drug development. See https://github.com/metrumresearchgroup/mrgsolve and http://mrgsolve.github.io/ for complete information on mrgsolve.
In this implementation, the model is written and compiled from a C++ (.cpp) file (located here in inst) which can be run separately in R or using the packaged model as described here: https://github.com/metrumresearchgroup/cabone#usage. Of note, the packaged version includes pre-configured dosing functions for teriparatide and denosumab.
Alternative public-source model implementations
- Using R / LSODA: https://github.com/riggsmm/calciumhomeostasis-boneresorption-model
- Externally coded (not evaluated by publication authors): http://biomodels.caltech.edu/static-pages.do?page=ModelMonth%2F2016-07
- Berkeley-Madonna format: http://onlinelibrary.wiley.com/doi/10.1038/psp.2012.10/suppinfo
Kyle T Baron (2017). mrgsolve: Simulate from ODE-Based Population PK/PD and Systems Pharmacology Models. R package version 0.8.6. https://CRAN.R-project.org/package=mrgsolve
Peterson MC and Riggs MM, A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling. Bone, Volume 46, Issue 1, 2010, Pages 49-63, ISSN 8756-3282, publication link
Peterson, M. and Riggs, M. (2015), FDA Advisory Meeting Clinical Pharmacology Review Utilizes a Quantitative Systems Pharmacology (QSP) Model: A Watershed Moment?. CPT Pharmacometrics Syst. Pharmacol., 4: 189–192. publication link
Riggs MM, Peterson MC and Gastonguay MR. (2012), Multiscale Physiology-Based Modeling of Mineral Bone Disorder in Patients With Impaired Kidney Function. J Clin Pharmacol., 52: 45S–53S. publication link
Riggs M, Bennetts M, van der Graaf P, and Martin S. (2012), Integrated Pharmacometrics and Systems Pharmacology Model-Based Analyses to Guide GnRH Receptor Modulator Development for Management of Endometriosis. CPT: Pharmacometrics & Systems Pharmacology, 1: 1–9, 11. publication link
K. Baron, M. Riggs, R. Sawamura, T. Shimizu, F. Okada, J. Zhou, T. Shibayama, and M. Jansen. An evaluation of calcilytic effects on parathyroid hormone and bone mineral density response using a physiologically-based, multiscale systems pharmacology model. Presented at American Society of Bone Mineral Research (ASBMR) Annual Meeting, Abstract SU0407; Baltimore, MD; 06-October 2013. J Bone Miner Res, 28(Suppl 1), 2013. poster link
M. M. Riggs, K. T. Baron, E. L. Plan, and M. R. Gastonguay. Qualification of a physiologically-based model for predicted bone marker and bone mineral density changes associated with denosumab treatment. Presented at American Society of Bone Mineral Research (ASBMR) Annual Meeting, Abstract SU0363, Minneapolis, MN, October 2012. J Bone Miner Res, 27 (Suppl 1), 2012 poster link
M. Riggs, M. Bennetts, P. van der Graaf, and S. Martin. Integrated pharmacometrics and systems pharmacology model-based analyses to guide GnRH receptor modulator development for management of endometriosis. CPT Pharmacomet Syst Pharmacol, 1(e10), 2012. publication link
M. C. Peterson and R. M. M. Predicting nonlinear changes in bone mineral density over time using a multiscale systems pharmacology model. CPT Pharmacomet Syst Pharmacol, 1(e14), 2012 publication link
Eudy R, Gillespie WR, Riggs MM, Gastonguay MR. Linking a Mechanistic Model of Bone Mineral Density to a Time-to-Event Model to Evaluate Effects of Various Therapies on Fracture Risk in Postmenopausal Women with Osteoporosis. Journal of Pharmacokinetics and Pharmacodynamics 42:S87-S87 2015 poster link
Ocampo-Pelland AS, Gastonguay MR, Riggs MM. Extension of multi-scale systems pharmacology model to evaluate effect of vitamin D3 pharmacokinetics on bone health. Journal of Pharmacokinetics and Pharmacodynamics 43(1) 2016 poster link
Eudy-Byrne RJ, Gillespie WR, Riggs MM, Gastonguay MR. A mathematical model to quantify links between bone mineral density, patient factors and therapeutic interventions on fracture risk in patients with osteoporosis. Presented at: American Society for Bone and Mineral Research Annual Meeting; September 2016 J Bone Miner Res, (Suppl 1), 2016 poster link
R. Eudy, M. Gastonguay, K. Baron, and M. Riggs. Connecting the dots: Linking osteocyte activity and therapeutic modulation of sclerostin by extending a multiscale systems model. CPT Pharmacomet Syst Pharmacol, 2015 publication link