What Are the Approaches to Pain in Skeletal Bone Disease?

Introduction and Scope of the Problem

Bone disease is a common occurrence in patients with malignancies and a common site for metastatic spread with advanced breast, lung, prostate, thyroid, and renal cancers as well as multiple myeloma. The incidence of bone metastasis in breast and prostate cancers is as high as 65% to 75%, and up to 90% to 100% in multiple myeloma. Bone metastases portend a significant risk for future complications and associated morbidity, causing pain, pathologic fractures, and spinal cord compression, as well as metabolic derangements such as hypercalcemia of malignancy. Additionally, early bone loss and increased risk for skeletal-related events may result from medications such as antihormonal treatments, long-term heparin anticoagulants, proton-pump inhibitors, and cumulative glucocorticoid exposure (e.g., as an antineoplastic, antiemetic, or adjuvant pain medication). Medical conditions less often encountered in palliative medicine, such as endocrinopathies, malabsorption syndromes, rheumatoid arthritis, cystic fibrosis, severe liver disease, posttransplantation states, and long-term immobility, may also cause decreased bone density. A detailed list of malignancy and nonmalignancy-associated conditions is presented in Table 8.1 .

Table 8.1

Causes of Malignancy- and Nonmalignancy-Associated Skeletal Bone Disease

Diseases or Disorders	Medications
Alcohol abuse disorder	Antacids
Bone metastases from solid tumors	Antidepressants
Cushing syndrome	Antiglycemics
Diabetes mellitus type I	Antihormonal agents
Hemochromatosis	Chemotherapy
HIV	Contraceptives
Hyperparathyroidism	Glucocorticoids
Hyperthyroidism	Heparins
Hypogonadism	Immunosuppressants
Inflammatory bowel disease
Leukemia or myelodysplastic syndromes
Multiple myeloma
Pathologic fractures
Renal insufficiency
Rheumatoid arthritis
Severe liver disease
Solid organ transplant

Pain may be a presenting symptom in up to 80% of patients with bone metastases and often requires a multimodal approach for evaluation and treatment. Uncontrolled incident pain may limit mobility and activity, ultimately leading to deconditioning, decreased functional status, and poor quality of life. This highlights the importance of preventing skeletal-related events and the use of bone-directed agents as adjuvant pain options in nonfracture bone pain. According to the WHO guidelines for pharmacological management of cancer pain, initiation of analgesia should be based on severity of pain, with mild to moderate pain being managed with NSAIDs or acetaminophen, along with opioids for more moderate to severe pain. Opioids are the most commonly used analgesic for pain due to metastatic bone disease, with both long-acting and short-acting opioids being recommended along with dose titration to achieve adequate response. Bone-targeted therapies such as bisphosphonates and denosumab, other adjuvant treatments such as steroids, and radiotherapy, including external beam radiation and radioisotopes (see Chapter 9 ), can be utilized as part of a bone pain treatment plan. Standardized management that addresses bone-related pain and prevention of skeletal-related events is essential to prevent complications, suffering, and premature death due to decreased functional status. Although several modalities are available for treating bone pain, this chapter will focus primarily on bone-directed medications for pain and prevention of skeletal-related events from metastatic cancer.

Relevant Pathophysiology

Bone Metabolism and Metastases

Bone metabolism in healthy adults is based on a dynamic homeostasis between bone production involving osteoblasts and bone resorption involving osteoclasts. Regulatory factors including receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) secreted by osteoblasts play an important role in bone metabolism along with growth and differentiation of osteoblasts by platelet-derived growth factor, fibroblast growth factor, and transforming growth factor-β. Osteoclasts resorb bone by secreting enzymes that break down the bone matrix, dissolving bone minerals through activation of osteoclast precursors using RANKL, which binds to its transmembrane receptor RANK (receptor activator of nuclear factor kappa B). Bone metabolism can be disrupted by metastatic cancer cells that take advantage of the normal physiology of bone marrow. Due to bone marrow being an abundant source of growth factors, bone metastases have a favorable microenvironment for growth. Production of a large range of cytokines and growth factors further increases osteoblast production of RANKL that leads to activation of osteoclasts and disruption in bone formation and resorption. Through this mechanism, a positive feedback loop or “vicious cycle” is created in which osteolysis perpetuates indefinitely until osteoclast activity is inhibited. Radiographically, bone metastases are identified based on the type of lesion, with osteoblastic lesions often identified with prostate cancer and multiple myeloma. Additionally, osteolytic lesions are seen in patients with metastatic breast, lung, thyroid, and stomach cancers and in those with multiple myeloma. Bone-targeted therapies play a role in preventing skeletal-related events from these lesions and treating pain associated with them.

Mechanism of Action of Bone-Targeted Therapies

Bisphosphonates are one type of bone-targeted therapy available today. Bisphosphonates generally work in several ways: absorbing calcium phosphate to provide physicochemical protection, suppressing the normal functioning of mature osteoclasts, and preventing osteoclast precursors from maturing. The two classes of bisphosphonates are nonnitrogenous (e.g., etidronate, clodronate) and nitrogenous (pamidronate, zoledronate [zoledronic acid]). Bone resorption is the primary process implicated in pain from bone metastases and decreased bone integrity, making osteoclasts the key therapeutic target for skeletal metastases. Non-nitrogenous bisphosphonates are ingested and metabolized by osteoclasts, which leads to osteoclast apoptosis and death. Nitrogenous bisphosphonates bind and block the enzyme farnesyl diphosphate synthase in the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase pathway, affecting osteoclastogenesis, cell survival, and cytoskeletal integrity.

Another type of bone-targeted therapy is a monoclonal antibody called denosumab. Denosumab received FDA approval in the United States in 2010 for use in postmenopausal females with osteoporosis at high risk for fractures. Since then, it has been approved for many uses, including prevention of skeletal-related events in patients with bone metastases from solid tumors. Denosumab is a fully human monoclonal antibody that has a high specificity and affinity to RANKL and inhibits its function, regulating turnover of healthy bone. Binding to RANKL inhibits its action and the osteoclast maturation process, slowing bone resorption. The key difference between the two types of bone-directed therapies is the location in which they are active, with bisphosphonates primarily acting within the bone matrix with its strong affinity for bone, and denosumab acting in the extracellular space, not directly associating with bone tissue. Lastly, bisphosphonates have a variable treatment time based on type, with an overall slower onset and longer duration of action. In contrast, denosumab has a rapid onset of action and shorter duration of effect, and is fully reversible when stopped.

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