title: Dynamic modeling of bone metastasis, microenvironment and therapy: Integrating parathyroid hormone (PTH) effect, anti-resorptive and anti-cancer therapy.
abstract: Bone is a common site for the development of metastasis, as its microenvironment provides the necessary conditions for the growth and proliferation of cancer cells. Several mathematical models to describe the bone remodeling process and how osteoclasts and osteoblasts coupled action ensures bone homeostasis have been proposed and further extended to include the effect of cancer cells. The model proposed here includes the influence of the parathyroid hormone (PTH) as capable of triggering and regulating the bone remodeling cycle. It also considers the secretion of PTH-related protein (PTHrP) by cancer cells, which stimulates the production of receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts that activates osteoclasts, increasing bone resorption and the subsequent release of growth factors entrapped in the bone matrix, which induce tumor growth, giving rise to a self-perpetuating cycle known as the vicious cycle of bone metastases. The model additionally describes how the presence of metastases contributes to the decoupling between bone resorption and formation. Moreover, the effects of anti-cancer and anti-resorptive treatments, through chemotherapy and the administration of bisphosphonates or denosumab, are also included, along with their corresponding pharmacokinetics (PK) and pharmacodynamics (PD). The simulated models, available at http://sels.tecnico.ulisboa.pt/software/, are able to describe bone remodeling cycles, the growth of bone metastases and how treatment can effectively reduce tumor burden on bone and prevent loss of bone strength.
authors.affiliation: IDMEC, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal. Electronic address: rui.coelho@tecnico.ulisboa.pt.
authors.forename: Rui Moura
authors.initials: RM
authors.lastname: Coelho
authors.affiliation: INESC-ID, Instituto Superior Técnico, Universidade de Lisboa, Rua Alves Redol, 9, 1000-029 Lisboa, Portugal. Electronic address: jlml@inesc-id.pt.
authors.forename: João Miranda
authors.initials: JM
authors.lastname: Lemos
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal. Electronic address: ialho@medicina.ulisboa.pt.
authors.forename: Irina
authors.initials: I
authors.lastname: Alho
authors.affiliation: IDMEC, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal. Electronic address: duarte.valerio@tecnico.ulisboa.pt.
authors.forename: Duarte
authors.initials: D
authors.lastname: Valério
authors.affiliation: Hospital de Santa Maria, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal. Electronic address: ajrsferreira@gmail.com.
authors.forename: Arlindo R
authors.initials: AR
authors.lastname: Ferreira
authors.affiliation: Hospital de Santa Maria, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal. Electronic address: luiscosta.oncology@gmail.com.
authors.forename: Luís
authors.initials: L
authors.lastname: Costa
authors.affiliation: IDMEC, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal. Electronic address: susanavinga@tecnico.ulisboa.pt.
authors.forename: Susana
authors.initials: S
authors.lastname: Vinga
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D000069448:Denosumab / Q000627:therapeutic use*; D004164:Diphosphonates / Q000627:therapeutic use*; D006801:Humans; D008954:Models, Biological; D009362:Neoplasm Metastasis; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010281:Parathyroid Hormone / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D004164:Diphosphonates; D010281:Parathyroid Hormone; D000069448:Denosumab
keywords: Bone metastasis; Bone remodeling; Systems biomedicine