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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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ☑ The current systems pharmacology models that include osteocyte activity or sclerostin mAb intervention are not designed to predict quantitative clinical outcomes.

• WHAT QUESTIONS DID THIS STUDY ADDRESS? ☑ Is it possible to leverage the clinical study data available with sclerostin mAbs to extend a systems model to predict responses to therapeutic modulation of sclerostin and describe osteocyte activity within bone remodeling events?

• WHAT THIS STUDY ADDS TO OUR KNOWLEDGE ☑ The extended systems model can be used to examine hypotheses surrounding the mechanism for attenuation of anabolic activity after multiple doses of sclerostin mAbs. This has not been fully explored by laboratory experimentation. Age of empires 3 update 1.14 crack. It is also used to investigate the relative contribution of osteocytes to feedback regulation within the bone. • HOW THIS MIGHT CHANGE CLINICAL PHARMACOLOGY AND THERAPEUTICS ☑ The extended model can be used to explore therapeutic target modulation in order to maximize and maintain increased BMD in osteoporosis patients. Sclerostin has been identified as a target for osteoporosis treatment because preventing sclerostin inhibition of Wnt has been shown to both increase markers of bone formation and decrease markers of resorption, expanding net gain of bone calcification and increasing bone mineral density (BMD).

This mechanism, which “decouples” bone formation and resorption, is differentiated from other osteoporosis treatment mechanisms that are either purely anabolic (both formation and resorption increase, e.g., intermittent parathyroid hormone (PTH)) or catabolic (both formation and resorption decrease, e.g., bisphosphonates, RANKL-inhibition). Furthermore, sclerostin is mainly expressed in the osteocyte, limiting off-target effects of inhibition in other tissues.

Questions remain about the mechanism of sclerostin inhibition and how this is linked to osteocyte activity and feedback regulation in bone remodeling. One clinical question is whether or not efficacy can be maintained after multiple doses of an anti-sclerostin monoclonal antibody (mAb). Identification of appropriate dosing regimens of sclerostin mAb and/or its combination with an antiresorptive to promote greater formation and prolonged maintenance of strong bone is a critical step in the advancement of this therapy.

Potential for a model that is aimed at elucidating the mechanisms of sclerostin modulation includes exploration of dosing regimen and trial design considerations. Such inputs, although not meant at this stage to generate statistical probabilities, could generate hypotheses (learnings) for further experimental confirmation, e.g., through clinical investigation. A multiscale bone model has been published that combines important aspects of three previous models of bone in order to combine quantitative aspects of bone physiology: all major organ systems involved in calcium handling, feedback control between osteoblasts (OB) and osteoclasts (OC) through the Receptor Activator of Nuclear Factor κ#/RANK-ligand/Osteoprogerin (RANK/RANKL/OPG) axis, and dynamics of intermittent PTH administration.

In its current construct, the model lacks the osteocyte and sclerostin-related components necessary to predict effects of sclerostin mAb treatment on clinical outcomes like BMD. Other published models of sclerostin, osteocytes (OCY), and Wnt signaling are either qualitative in nature, with model variables lacking physiological meaning, or they are focused on mechanical strain analysis., The “strain” models depict quantitative changes in a single bone unit during loading, but they do not account for feedback signaling between bone cells, which largely contribute to signal transduction and remodeling. In contrast with other models, the multiscale bone model provides an evaluated platform to predict changes in BMD based on clinical markers of formation and resorption. It has already been used to predict changes in BMD after treatment with denosumab. The new model components were developed by incorporating knowledge of the Wnt/β-catenin signaling and its role in bone formation by leveraging data from recent clinical studies.,, The updated model promotes understanding of how OCY signals contribute to remodeling within the bone and how sclerostin mAbs can be used to harness these signals to maximize bone formation in patients with osteoporosis. Data A phase I study reporting time–concentration profiles of romosozumab after a single dose was used to build the pharmacokinetic (PK) model. Total sclerostin concentrations measured in two phase I studies over a range of single and multiple doses of blosozumab were used to estimate parameters in the pharmacodynamics (PD) model.