In addition to the direct effects of primary tumors in bone, bone complications in cancer patients occur from metastasis to bone and through the effects of cancer-related treatments and conditions. Bone is a very common metastatic site for many cancers, including myeloma, melanoma, and breast, prostate, thyroid, lung, bladder, and kidney cancers. Metastatic bone lesions can be osteolytic (bone destruction resulting from increased bone resorption and reduced formation), osteoblastic (increased bone formation), or both. Metastases to bone are associated with severe morbidity, including severe pain, impaired mobility, symptomatic hypercalcemia, pathologic fracture, and spinal cord compression, and can result in paralysis or death. Similarly, significant morbidity and adverse impact on quality of life are associated with cancer treatment-induced bone loss (CTIBL). Negative effects on bone can be caused by cytotoxic chemotherapy, hormonal therapies, androgen deprivation therapy, radiation therapy, glucocorticoid use, gonadal suppression/ablation, immobilization, and deficient nutrition (eg, vitamin D and calcium deficiencies). Preventing and treating bone complications in cancer patients are critical components in optimal care.
Drs. Murthy, Morrow, and Theriault review the processes involved in bone biology and bone remodeling to highlight the importance of the RANK ligand pathway in normal bone remodeling and cancer-related bone complications. Normal bone remodeling is a process that balances bone resorption by osteoclasts and bone formation by osteoblasts; critical molecular mediators in this process include RANK ligand, a stimulator of bone resorption, and osteoprotegerin (OPG), an inhibitor of bone resorption. In metastatic disease, RANK ligand appears to be central to a ‘vicious cycle’ of bone destruction and tumor growth, in which feedback between tumor cells and the bone microenvironment promotes release of growth factors from bone, promoting tumor growth and causing release of tumor factors that further promote bone destruction. A role of RANK ligand in CTIBL is indicated by the effect of estrogen in downregulating the RANK ligand-induced differentiation of osteoclasts. RANK ligand is also implicated in bone destruction in multiple myeloma (MM); myeloma cells express RANK ligand, upregulate RANK ligand expression in marrow cells, and downregulate OPG expression.
Drs. Chlebowski and Tagawa discuss bone loss, fracture risk assessment, and strategies to prevent bone complications in breast cancer and prostate cancer patients. Patients with breast cancer are at risk of loss of bone mineral density (BMD) related to hormone ablative therapy, including endocrine therapies, and chemotherapy-related premature menopause, as well as postmenopausal bone loss. Similarly, risk of bone loss is posed by hormone ablative therapy including gonadotropin-releasing hormone analogs and orchiectomy in men with prostate cancer. Strategies for preventing or treating bone loss include weight-bearing and muscle-strengthening exercise, smoking cessation, and reduced alcohol consumption among life-style measures, use of calcium and vitamin D supplements, and pharmacologic intervention with oral or intravenous bisphosphonates, SERMs, or calcitonin. Guidelines for management of bone loss in women with breast cancer include recommendations for exercise, vitamin D and calcium supplementation, and bisphosphonate therapy for those with BMD in the osteoporotic range. Guidelines for men with prostate cancer are still evolving, although data support BMD measurement in every newly diagnosed patient and consideration of pharmacologic therapy for patients with osteoporosis.
Drs. Rove and Crawford discuss the mechanisms and types of metastasis to bone from solid organ tumors and the risk factors and burdens of skeletal-related events (SREs)--eg, radiation, surgery, fracture, and spinal cord compression--in patients with bone metastases. Metastasis to bone is a frequent event in visceral cancers; for example, bone metastasis is observed in more than half of patients with advanced breast or prostate cancer and a third or more of patients with non-small cell-lung cancer. There is preferential metastasis to the axial skeleton, with vertebrae, pelvis, proximal ends of long bones, and the skull being targeted. The resulting skeletal complications can increase mortality and dramatically impoverish quality of life through loss of mobility, independence, and social functioning. The authors note that a 1-year study showed that half of patients with prostate cancer and bone metastases experienced at least one SRE, with a mean cost of $12,469, with the cost increasing to $26,384 for patients with more than one SRE. Identifying and mitigating contributing causes of SREs, timely diagnosis of bone metastasis, and use of appropriate interventions (eg, hormone therapies, bisphosphonates, monoclonal antibodies, external beam radiation and radiopharmaceuticals, and surgery) could all contribute to reducing the burden associated with SREs. Use of biomarkers may ultimately allow early identification of patients at greatest risk for SREs and timely implementation of prevention strategies.
Bone disease in MM results from both increased bone resorption and reduced bone formation. As reviewed by Dr. Drake, nearly all patients with MM have skeletal complications, with these complications having an enormous impact on quality of life and survival. Fracture or severe bone pain is often the event that results in diagnosis of MM, with MM patients having a 16-fold increased risk for fracture in the year preceding diagnosis. Approximately 90% of MM patients eventually have osteolytic lesions, approximately 60% of patients have bone pain at the time of diagnosis, and approximately 60% have fracture during the course of disease; the presence of fracture is associated with an approximately 20% increased risk of death. Efforts to treat bone disease in this setting are crucial to improve quality of life and reduce risk of future complications. Intravenous bisphosphonates currently are the cornerstone of treatment, with radiation therapy, orthopedic and neurosurgical intervention, and kyphoplasty and vertoplasty all constituting important components of therapy for bone disease in these patients.
Numerous factors are involved in risk of bone complications associated with bony metastases and CTIBL. Numerous screening and imaging modalities are used to evaluate patients for risk and identify existing complications, with approaches varying according to type of primary cancer, other contributing risk factors, type of cancer treatment, and patient characteristics. Practitioners must be extremely vigilant for bone morbidity in cancer patients and must strive to reduce its burden on quality of life and survival. Numerous treatments are available for bone complications, with options again varying depending on disease and patient characteristics. The task of preventing and treating bone complications in cancer is thus a complex one, in which expert guidance is needed.
Financial Disclosure: Dr. Gradishar has served as an advisor or consultant for Abraxis BioScience, Bristol-Myers Squibb, and sanofi-aventis. This article was conceived of and fully funded by Amgen, and Amgen provided background direction for the article.