Dynamic modeling of bone remodeling, osteolytic metastasis and PK/PD therapy: introducing variable order derivatives as a simplification technique

Abstract

Bone is constantly being renewed: in the adult skeleton, bone resorption and formation are in a tightly coupled balance, allowing for a constant bone density to be maintained. Yet this micro-environment provides the necessary conditions for the growth and proliferation of tumor cells, and thus bone is a common site for the development of metastases, mainly from primary breast and prostate cancer. Mathematical and computational models with differential equations can replicate this bone remodeling process. These models have been extended to include the effects of disruptive tumor pathologies in the bone dynamics, as metastases contribute to the decoupling between bone resorption and formation and to the self-perpetuating tumor growth cycle. Such models may also contemplate the counteraction effects of currently used therapies, and, in the case of treatments with drugs, their pharmocokinetics and pharmacodynamics. We present a thorough overview of biochemical models for bone remodeling, in the presence of a tumour together with anti-cancer and anti-resorptive therapy, formulated as systems of first-order differential equations, or simplified using variable order derivatives. The latter models, of which some are new to this paper, result in equations with fewer parameters, and allow accounting for anomalous diffusion processes. In this way, more compact and parsimonious models, that promptly highlight tumorous bone interactions, are achieved, providing an effective framework to counteract the loss of bone integrity on the affected areas.

Keywords: Bone metastasis; Bone remodeling; Fractional calculus; Osteolytic metastases; Variable order derivatives.