Dynamics of Bone Cell Interactions and Differential Responses to PTH and Antibody-Based Therapies

Abstract

We propose a mathematical model describing the dynamics of osteoblasts and osteoclasts in bone remodeling. The goal of this work is to develop an integrated modeling framework for bone remodeling and bone cell signaling dynamics that could be used to explore qualitatively combination treatments for osteoporosis in humans. The model has been calibrated using 57 checks from the literature. Specific global optimization methods based on qualitative objectives have been developed to perform the model calibration. We also added pharmacokinetics representations of three drugs to the model, which are teriparatide (PTH(1-34)), denosumab (a RANKL antibody) and romosozumab (a sclerostin antibody), achieving excellent goodness-of-fit of human clinical data. The model reproduces the paradoxical effects of PTH on the bone mass, where continuous administration of PTH results in bone loss but intermittent administration of PTH leads to bone gain, thus proposing an explanation of this phenomenon. We used the model to simulate different categories of osteoporosis. The main attributes of each disease are qualitatively well captured by the model, for example changes in bone turnover in the disease states. We explored dosing regimens for each disease based on the combination of denosumab and romosozumab, identifying adequate ratios and doses of both drugs for subpopulations of patients in function of categories of osteoporosis and the degree of severity of the disease.

Keywords: Bone remodeling; Combination therapies; Denosumab (anti-RANKL antibody); Intermittent PTH; Mathematical modeling; Osteoporosis; Pharmacokinetics of monoclonal antibodies; Romosozumab (anti-sclerostin antibody); Wnt pathway.