Bone metastases (BM) are a common complication of cancer, whose management often requires a multidisciplinary approach. Despite the recent therapeutic advances, patients with BM may still experience skeletal-related events and symptomatic skeletal events, with detrimental impact on quality of life and survival. A deeper knowledge of the mechanisms underlying the onset of lytic and sclerotic BM has been acquired in the last decades, leading to the development of bone-targeting agents (BTA), mainly represented by anti-resorptive drugs and bone-seeking radiopharmaceuticals. Recent pre-clinical and clinical studies have showed promising effects of novel agents, whose safety and efficacy need to be confirmed by prospective clinical trials. Among BTA, adjuvant bisphosphonates have also been shown to reduce the risk of BM in selected breast cancer patients, but failed to reduce the incidence of BM from lung and prostate cancer. Moreover, adjuvant denosumab did not improve BM free survival in patients with breast cancer, suggesting the need for further investigation to clarify BTA role in early-stage malignancies. The aim of this review is to describe BM pathogenesis and current treatment options in different clinical settings, as well as to explore the mechanism of action of novel potential therapeutic agents for which further investigation is needed.
Keywords: ActRIIA, activin-A type IIA receptor; BC, breast cancer; BM, bone metastases; BMD, bone mineral density; BMPs, bone morphogenetic proteins; BMSC, bone marrow stromal cells; BPs, bisphosphonates; BTA, bone targeting agents; BTM, bone turnover markers; Bone metastases; Bone targeting agents; CCR, chemokine-receptor; CRPC, castration-resistant PC; CXCL-12, C–X–C motif chemokine-ligand-12; CXCR-4, chemokine-receptor-4; DFS, disease-free survival; DKK1, dickkopf1; EBC, early BC; ECM, extracellular matrix; ET-1, endothelin-1; FDA, food and drug administration; FGF, fibroblast growth factor; GAS6, growth-arrest specific-6; GFs, growth factors; GnRH, gonadotropin-releasing hormone; HER-2, human epidermal growth factor receptor 2; HR, hormone receptor; IL, interleukin; LC, lung cancer; MAPK, mitogen-activated protein kinase; MCSF, macrophage colony-stimulating factor; MCSFR, MCSF receptor; MIP-1α, macrophage inflammatory protein-1 alpha; MM, multiple myeloma; MPC, malignant plasma cells; N-BPs, nitrogen-containing BPs; NF-κB, nuclear factor-κB; ONJ, osteonecrosis of the jaw; OS, overall survival; Osteotropic tumors; PC, prostate cancer; PDGF, platelet-derived growth factor; PFS, progression-free survival; PIs, proteasome inhibitors; PSA, prostate specific antigen; PTH, parathyroid hormone; PTH-rP, PTH related protein; QoL, quality of life; RANK-L, receptor activator of NF-κB ligand; RT, radiation therapy; SREs, skeletal-related events; SSEs, symptomatic skeletal events; Skeletal related events; TGF-β, transforming growth factor β; TK, tyrosine kinase; TKIs, TK inhibitors; TNF, tumornecrosis factor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; mTOR, mammalian target of rapamycin; non-N-BPs, non-nitrogen containing BPs; v-ATPase, vacuolar-type H+ ATPase.