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Connecting the Dots: Linking Osteocyte Activity and Therapeutic Modulation of Sclerostin by Extending a Multiscale Systems Model.

Eudy RJ, Gastonguay MR, Baron KT, Riggs MM - CPT Pharmacometrics Syst Pharmacol (2015)

Bottom Line: To describe total circulating sclerostin, an extended indirect response model of inhibition of offset was developed.These models were subsequently linked to the systems model, with sclerostin signaling changes in resorption and formation through established osteocyte-mediated mechanisms.The model proposes relative contributions of the osteocyte to the RANKL pool, a major player in feedback signaling, and is used to explore hypotheses surrounding attenuation of anabolic activity after multiple doses of sclerostin mAbs, a phenomenon whose mechanism is poorly understood.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, University of Connecticut Storrs, Connecticut, USA ; Metrum Institute Tariffville, Connecticut, USA.

ABSTRACT
The goal of this work was to extend a mathematical, multiscale systems model of bone function, remodeling, and health in order to explore hypotheses related to therapeutic modulation of sclerostin and quantitatively describe purported osteocyte activity within bone remodeling events. A pharmacokinetic model with first-order absorption and dual elimination pathways was used to describe the kinetics of romosozumab, a monoclonal antibody (mAb) against sclerostin. To describe total circulating sclerostin, an extended indirect response model of inhibition of offset was developed. These models were subsequently linked to the systems model, with sclerostin signaling changes in resorption and formation through established osteocyte-mediated mechanisms. The model proposes relative contributions of the osteocyte to the RANKL pool, a major player in feedback signaling, and is used to explore hypotheses surrounding attenuation of anabolic activity after multiple doses of sclerostin mAbs, a phenomenon whose mechanism is poorly understood.

No MeSH data available.


Simulations of dose-equivalent sclerostin mAb administered at different dosing intervals demonstrate that changing the dosing interval may alter clinical outcomes. P1NP (a), osteoblast precursors (b), CTx (c), total hip BMD (d). Colored marks indicate the final dose in each arm.
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fig04: Simulations of dose-equivalent sclerostin mAb administered at different dosing intervals demonstrate that changing the dosing interval may alter clinical outcomes. P1NP (a), osteoblast precursors (b), CTx (c), total hip BMD (d). Colored marks indicate the final dose in each arm.

Mentions: In order to demonstrate how the model can be used to investigate the role of dosing protocol on clinical outcomes, dose-matched administrations of sclerostin mAb were simulated at several dosing intervals (Figure4). Simulations of larger dosing intervals promote greater increases in P1NP (Figure4a), due to precursors also achieving higher levels (Figure4b). Maximum simulated resorption activity, however, is also increased with a larger dosing interval (Figure4c), resulting in lower increases in total hip BMD when compared to smaller dosing intervals (Figure4d).


Connecting the Dots: Linking Osteocyte Activity and Therapeutic Modulation of Sclerostin by Extending a Multiscale Systems Model.

Eudy RJ, Gastonguay MR, Baron KT, Riggs MM - CPT Pharmacometrics Syst Pharmacol (2015)

Simulations of dose-equivalent sclerostin mAb administered at different dosing intervals demonstrate that changing the dosing interval may alter clinical outcomes. P1NP (a), osteoblast precursors (b), CTx (c), total hip BMD (d). Colored marks indicate the final dose in each arm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592532&req=5

fig04: Simulations of dose-equivalent sclerostin mAb administered at different dosing intervals demonstrate that changing the dosing interval may alter clinical outcomes. P1NP (a), osteoblast precursors (b), CTx (c), total hip BMD (d). Colored marks indicate the final dose in each arm.
Mentions: In order to demonstrate how the model can be used to investigate the role of dosing protocol on clinical outcomes, dose-matched administrations of sclerostin mAb were simulated at several dosing intervals (Figure4). Simulations of larger dosing intervals promote greater increases in P1NP (Figure4a), due to precursors also achieving higher levels (Figure4b). Maximum simulated resorption activity, however, is also increased with a larger dosing interval (Figure4c), resulting in lower increases in total hip BMD when compared to smaller dosing intervals (Figure4d).

Bottom Line: To describe total circulating sclerostin, an extended indirect response model of inhibition of offset was developed.These models were subsequently linked to the systems model, with sclerostin signaling changes in resorption and formation through established osteocyte-mediated mechanisms.The model proposes relative contributions of the osteocyte to the RANKL pool, a major player in feedback signaling, and is used to explore hypotheses surrounding attenuation of anabolic activity after multiple doses of sclerostin mAbs, a phenomenon whose mechanism is poorly understood.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, University of Connecticut Storrs, Connecticut, USA ; Metrum Institute Tariffville, Connecticut, USA.

ABSTRACT
The goal of this work was to extend a mathematical, multiscale systems model of bone function, remodeling, and health in order to explore hypotheses related to therapeutic modulation of sclerostin and quantitatively describe purported osteocyte activity within bone remodeling events. A pharmacokinetic model with first-order absorption and dual elimination pathways was used to describe the kinetics of romosozumab, a monoclonal antibody (mAb) against sclerostin. To describe total circulating sclerostin, an extended indirect response model of inhibition of offset was developed. These models were subsequently linked to the systems model, with sclerostin signaling changes in resorption and formation through established osteocyte-mediated mechanisms. The model proposes relative contributions of the osteocyte to the RANKL pool, a major player in feedback signaling, and is used to explore hypotheses surrounding attenuation of anabolic activity after multiple doses of sclerostin mAbs, a phenomenon whose mechanism is poorly understood.

No MeSH data available.