Metastatic bone disease: Pathogenesis and therapeutic options: Up-date on bone metastasis management

Abstract

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.

Fig. 1

The vicious circle of lytic BM in solid malignancies. The onset of lytic BM from solid tumors (e.g. BC) is due to the establishment of a self-propagating vicious circle, based on the cross-talk between cancer cells and the bone microenvironment. Tumor cells secrete pro-osteoclastogenic cytokines that, either directly or indirectly (via osteoblasts), stimulate osteoclast differentiation and activity. This leads to an enhanced bone resorption, and consequent release of matrix-embedded growth factors (e.g. TGF-β, PDGF and insulin-like growth factor) which in turn promote cancer cell proliferation.

Fig. 2

Mechanisms of sclerotic BM formation: major hypotheses. The mechanisms leading to the onset of sclerotic BM have not been completely elucidated. Tumor cells secrete a number of growth factors (e.g. TGF-β, BMP, FGF and Wnt) which enhance the differentiation of mesenchymal progenitors into osteoblasts (red). In PC, tumor-derived ET-1 and PSA are capable of inhibiting bone resorption, shifting the balance of bone turnover towards osteogenesis (green). More recently, BMP-4 has emerged as a novel factor promoting osteogenesis, through the induction of endothelial cell conversion to osteoblasts (blue). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Mechanisms of BM onset in MM. In MM, reciprocal interactions between MPC and bone-residing cells lead both to suppressed osteogenesis and increased bone resorption. MPC interfere with osteoblast differentiation (green) through the secretion of sclerostin and DKK1, and the inhibition of the transcription factor Runx-2 in osteoblast precursors. In addition, MPC promote the apoptosis of osteocytes (red), whose number and viability are reduced in MM patients, compared to healthy controls. Finally, the cross-talk between tumor cells and bone microenvironment induces the release of pro-osteoclastogenic factors, including RANK-L, IL-6, Activin A, MCSF and MIP-1α, with a consequent increase of osteoclast maturation and activity (blue). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Mechanisms of action of common and potential therapeutic agents for BM management. The image shows the mechanisms of action of common BTA, such as denosumab and BPs, as well as potentially novel therapeutic options which warrant further investigation. On one hand, denosumab interacts with RANK-L, thus interfering with its binding to RANK on osteoclasts (OC); on the other hand, BPs directly act on the latter, compromising their survival and/or bone-resorbing activity. Moreover, BPs have been shown to exert a direct anti-tumor activity (in vitro and in vivo), and to stimulate an anti-cancer immune response. Other agents (e.g. Src-inhibitors, mTOR inhibitors) inhibit fundamental signaling pathways in OC, while mTOR inhibitors also exert an anti-cancer effect. Inhibitors of cathepsin-K, a lysosomal enzyme involved in bone matrix degradation, have also been developed, although routine use is limited by their toxicity. Due to their ability to interfere with osteoblast (OB) differentiation and activity, both sclerostin and DKK-1 are under investigation as therapeutic targets for BM management.