Advances in
Bone Cancer Treatment:
Preventing Metastasis and Bone Loss
Introduction
Bone metastasis is a common complication in patients with advanced malignancies, occurring in more than 400,000 individuals in the United States each year. It is a significant cause of morbidity in these patients, resulting in decreased mobility and quality of life. As shown in Table 1, bone is a frequent site of metastasis, and is seen in most patients with metastatic prostate, breast, and thyroid cancers, and melanoma.
As the population ages, both the number of patients with cancer and the number at risk for bone metastasis are expected to increase, challenging medical professionals and our approaches to treatment. Recent advances in our understanding of the process of bone metastasis and trials of therapies to treat and prevent metastasis are improving our ability to more effectively treat bone cancer, bone loss, and their complications. Current research on the pathophysiology of bone and its relationship to metastasis and bone loss, and the potential role of bone-targeted agents in cancer treatment and prevention are discussed. Patients need our help to navigate the complex information becoming available. Both physicians and other caregivers need to be able to counsel patients on the effects of current and new therapies and their potential benefits and risks.
Assessment and Treatment
Bone metastases disrupt bone cell function, resulting in the production of a range of biomarkers that can be used as surrogate measures to evaluate the effects of bone-targeted treatments. Additionally, bone markers provide useful prognostic information, enabling the identification of patients at particularly high risk of skeletal complications and/or death. In the clinic, functional imaging offers the promise of more accurate disease assessment than is possible with conventional anatomical imaging techniques. In animal model systems, the ability to view the behavior of single cells is likely to transform our understanding of the underlying biological processes in bone.
Today, bisphosphonates are the mainstay for long-term treatment of bone metastases and skeletal-related events (SREs) associated with solid tumors and multiple myeloma. Zoledronic acid, the most potent bisphosphonate currently available, has been shown in several large phase III trials to delay the onset and decrease the proportion of patients experiencing an SRE. Despite the demonstrated benefits of bisphosphonate therapy, newer therapies are needed. Several novel agents are being investigated to treat or prevent metastasis and bone loss. The most clinically advanced of these is denosumab, a monoclonal antibody that binds and neutralizes RANKL, a key mediator of bone destruction. Denosumab is being studied in several phase III trials in metastatic bone disease and across a range of conditions, including osteoporosis, treatment-induced bone loss, bone metastases, multiple myeloma, and rheumatoid arthritis. Other agents in earlier development focus on inhibiting cathepsin K, c-Src, TGF-β signaling, DKK1, and other pathways involved in bone growth and resorption.
Preventing Bone Loss Associated with Cancer Therapies
Bone loss is a frequent complication of aromatase inhibitor therapy in breast cancer, androgen deprivation therapy in prostate cancer, and early menopause induced by chemotherapy in young women with cancer. This bone loss, which typically is more severe and more rapid than that seen in the context of normal aging, results in significantly increased fracture risk.
Bisphosphonates have been shown to be effective in preventing cancer therapy-induced bone loss, and ongoing trials are evaluating the optimal agents and regimens for treatment of breast and prostate cancer.
New Focus on Preventing Bone Metastasis
Ongoing trials in breast and prostate cancer are evaluating whether adjuvant therapy with bisphosphonates can prevent bone metastasis and improve survival. Results from several ongoing trials of bisphosphonates for metastasis prevention, including AZURE, NSABP B-34, SWOG S0307, and ZEUS, are eagerly awaited and should expand our knowledge of the potential of this class of agents in the adjuvant setting.
New Insights into Biology of Bone, Metastasis, and Cancer
Our appreciation of the interactions between cancer cells, the bone microenvironment, and hematopoietic stem cells is increasing rapidly. However, there remains much that we do not understand. Tumor characteristics that lead to a biological preference for metastasis to bone are being investigated. We need to understand the role of tumor stem cells in metastasis, as well as the mechanisms by which tumor cells both adapt to the bone microenvironment and are able to remain dormant for years before metastases become clinically apparent.
This CME activity provides an overview of current approaches to treating metastastic bone cancer. The results from major recent trials of bone metastasis prevention are summarized, as well as the use of bone-targeted therapies in preventing and treating bone loss associated with cancer therapies. Current research on the pathophysiology of bone and its relationship to metastasis and bone loss is discussed, as is the potential role of bone-targeted agents in cancer treatment and prevention. The purpose of this activity is to provide up-to-date, evidence-based information for use in the clinic, including highlights of rapid developments in the field and new treatments and management strategies that are likely to emerge over the next 1-2 years.