Bone Metastases
Summary of Key Points
Causes
• Tumor cells are attracted to particular niches in bone and may remain dormant for prolonged periods, as controlled by microenvironmental cues.
• Osteolytic damage is mediated largely by stimulation of osteoclasts via tumor-derived cytokines; intermediary cells, including immune cells and osteoblasts, are involved.
Diagnosis
• Differential diagnosis includes osteoporosis, degenerative disease, and Paget disease.
• The isotope bone scan is a sensitive test to detect the presence of skeletal pathology but gives little information about its nature.
• Structural information on skeletal damage from metastatic bone disease is best obtained by skeletal radiography supplemented with computerized tomography and magnetic resonance imaging.
• Positron emission tomography provides functional information that may aid in diagnosis.
Evaluation of the Patient
• An assessment of the patient’s symptoms and activity status is essential.
• Skeletal radiography assesses response to treatment, but the information is delayed and the method is insensitive.
• Early indications of response of bone metastases to treatment can be obtained by monitoring biochemical markers of bone metabolism.
• Isotopic bone scanning is not useful in monitoring response to treatment.
Treatment
• Antitumor treatments such as external beam radiotherapy, endocrine therapy, cytotoxic chemotherapy, targeted biological agents, and radioisotope therapy have a role in the multidisciplinary palliative treatment of metastatic bone disease.
• The bisphosphonates and the receptor activator of nuclear factor κ ligand inhibitor denosumab are inhibitors of osteoclast activity and have become important agents for the treatment of metastatic bone disease because they relieve symptoms, allow bone healing, and delay complications.
Complications
• Complications include pain, impaired mobility, pathological fracture, spinal cord compression, cranial nerve palsies, nerve root lesions, hypercalcemia, and suppression of bone marrow function.
• The treatment of choice for hypercalcemia is bisphosphonates in combination with intravenous rehydration.
• Orthopedic surgery has an important role in the treatment and prophylaxis of pathological fractures and spinal decompression and stabilization to relieve spinal cord compression or instability.
1. What proportion of the skeleton is undergoing remodeling at any one time?
2. Which cell type is responsible for resorbing bone associated with lytic bone lesions?
3. How do breast cancer cells cause lytic bone lesions?
A By stimulating osteoclast activity
B By inhibiting osteoblast activity
C By producing proteolytic enzymes
D By stimulating osteoclast activity and inhibiting osteoblast activity
4. Why is bone a favored site of metastasis in advanced breast and prostate cancer?
A Anatomic and blood flow reasons
B Bone is rich in essential tumor growth factors
C Tumor cells express particular ligands that facilitate binding to bone
5. Assessment of response in bone should not be assessed by the following imaging techniques.
6. Bone-targeted treatments in the setting of metastatic disease have been convincingly shown to have which effect on disease outcomes?
7. Adjuvant bisphosphonates in patients with early identification of cancer have been shown consistently to improve disease-free survival in which group of patients?
A All patients with node-positive breast cancer
B Postmenopausal women with early breast cancer
C Women with intact ovarian function and early breast cancer
1. Answer: B. Twenty percent of the skeleton is under remodeling at any point in time in order to maintain skeletal health and repair microdamage.
2. Answer: C. The osteoclast, originating from the granulocyte/macrophage lineage, is the only cell type capable of resorbing bone because of its highly specialized characteristics.
3. Answer: D. Tumor cells release a number of factors that affect the bone microenvironment. Breast cancer cells stimulate osteoclastic bone resorption and inhibit bone formation by osteoblasts, resulting in extensive bone destruction and the appearance of lytic bone lesions.
4. Answer: D. Although they are not completely understood, all of these factors contribute to the preferential colonization of bone by breast and prostate cancer cells.
5. Answer: A. Serial changes in bone scan appearances can be difficult to interpret. The flare response to successful treatment cannot be reliably distinguished from changes associated with progression.
6. Answer: C. Bisphosphonates and denosumab reduce skeletal morbidity by 30% to 50% across all solid tumors and myeloma. They also reduce pain and improve quality of life. Nonetheless, other than in retrospective subgroups, no improvement in overall survival or time to progression has been demonstrated.
7. Answer: A. Adjuvant trials of bisphosphonates show consistent benefit in women with early breast cancer who have either passed through menopause or undergone ovarian suppression therapy. No convincing benefits are seen in unselected populations. Only denosumab has been shown to influence development of bone metastases in castrate-resistant prostate cancer and rising prostate-specific antigen.
8. Answer: D. Osteonecrosis of the jaw is associated with use of both bisphosphonates and denosumab. Early reports suggested incidence rates of 10% to 15%, but carefully conducted prospective studies suggest the incidence is much lower at around 1% per year with 4 weekly treatments of intravenous bisphosphonates or subcutaneous denosumab. The incidence is even lower in patients receiving reduced-intensity treatment to prevent bone loss, with rates of <0.1% per year.
