Skeletal complications in cancer patients with bone metastases

Abstract

As a result of significant improvements in current therapies, the life expectancy of cancer patients with bone metastases has dramatically improved. Unfortunately, these patients often experience skeletal complications that significantly impair their quality of life. The major skeletal complications associated with bone metastases include: cancer-induced bone pain, hypercalcemia, pathological bone fractures, metastatic epidural spinal cord compression and cancer cachexia. Once cancer cells invade the bone, they perturb the normal physiology of the marrow microenvironment, resulting in bone destruction, which is believed to be a direct cause of skeletal complications. However, full understanding of the mechanisms responsible for these complications remains unknown. In the present review, we discuss the complications associated with bone metastases along with matched conventional therapeutic strategies. A better understanding of this topic is crucial, as targeting skeletal complications can improve both the morbidity and mortality of patients suffering from bone metastases.

Keywords: bone metastasis; cancer-induced bone pain; hypercalcemia; metastatic epidural spinal cord compression; pathological bone fractures; skeletal complications.

Figure 1. The mechanisms whereby disseminated tumor cells are directly involved in the development of skeletal complications associated with bone metastasis

Growing evidence suggests that once in the marrow, DTCs create a favorable microenvironment for their own metastatic progression by interfering with the normal functions of bone marrow. Indeed, DTCs disturb bone remodeling by altering the balance between osteoclastogenesis and osteoblastogenesis. Osteolytic tumor cells stimulate osteoclastic activities by expressing PTHrP or IL-6, and/or by inducing RANKL secretion by osteoblasts. Osteoclastogenesis mediated by DTCs plays a crucial role in the development of serious complications involved with bone metastasis, including bone pain, hypercalcemia, and malignant fracture. In addition, ET-1 expressed by DTCs develops osteoblastic metastatic lesions in the bone and is related to cancer-induced bone pain. At the same time, DTCs engage with sensory neurons in the marrow directly through NGF, COX-2, and Ang II signaling pathways, resulting in cancer-induced bone pain. These pain transmitters may also affect metastatic growth. Therefore, targeting bone remodeling and blocking the cancer/nerve interactions may be a successful therapeutic strategy for eradicating bone metastatic disease and improving patient quality of life. DTC: disseminated tumor cell; OB: osteoblast; OC: osteoclast; PTHrP: parathyroid hormone-related protein; IL-6: interleukin-6; RANK: receptor activator of nuclear factor κB ligand; RANKL: receptor activator of nuclear factor κB ligand; ET-1: endothelin-1; NGF: nerve growth factor; COX-2: cycloxygenase-2; Ang II: angiotensin II.