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

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.

Figure 1

(a) The PK model describes circulating sclerostin mAb concentrations that drive changes in circulating total sclerostin protein (SCLER) in the PD model. C represents drug concentration; At is the peripheral compartment; sc = subcutaneous; iv = intravenous; Vc, Vp, CL, Kin, Kout, Vmax, Km are model parameters defined in Table 1. (b) Parameter estimates for the PK model were generated by fitting the model to romosozumab data, and parameter estimates for the PD model were generated by fitting the model to blosozumab data.

Figure 2

Schematic of the bone-remodeling systems model. Intersection points of sclerostin signaling effects within the model are identified with numbers corresponding to description in the text. New model compartments are indicated with white text and shading and corresponding equation numbers.

Figure 3

Simulated P1NP (a), CTx (b), lumbar spine BMD (c), and total hip BMD (d) (blue line) overlaying data from a clinical trial with blosozumab (red points). This qualification dataset was not used in constructing the model (n = 29, 31, 30, 30 for arms PBO, 180 mg Q2W, 180 mg Q4W, and 270 mg Q2W, respectively).

Figure 4

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.