Cancer-Related Bone Pain

Edgar Ross

Lalitha Sundararaman

Mary Alice Vijjeswarapu

Epidemiology Review

Bone pain due to cancer is caused by primary bone tumors and those malignant diseases that commonly metastasize to the bones. Bone is the third most common site of metastasis after lung and liver.¹ Metastatic bone pain most commonly results from cancers of the breast, prostate, and lung.² Other malignancies involving bone are renal cell carcinoma, thyroid cancer, lymphoma, and multiple myeloma.³ The longer these malignancies persist, the higher the probability of finding bone metastases. Current therapies have increased survival time of patients suffering from many of these malignancies. This has resulted in an increasing prevalence of metastatic bone disease. Li et al.⁴ estimated that 279,679 (95% confidence interval: 274,579 to 284,780) US adults alive on December 31, 2008, had evidence of metastatic bone disease in the previous 5 years (Table 46.1). Breast, prostate, and lung cancers accounted for 68% of these cases.

Prostate cancer is very likely to metastasize to bone rather than other organs. Because patients are living longer than other patients with metastatic diseases, prostate cancer patients are at increased risk of having prolonged periods of pain secondary to bony invasion.⁵

Vertebral involvement is the most common site of bony metastases. The incidence ranges from 30% to 70%.⁶ Most patients with metastatic disease of the vertebrae experience back pain.⁷

Bony metastases compromise both the bone’s integrity and strength. In the vertebrae, this leads to the increased risk of a pathologic fracture, found most commonly in the elderly. Compression fractures affect between 8% and 30% of cancer patients with vertebral body involvement.⁸^,⁹ In many cases, the fracture occurs without an initial traumatic event suggesting that vertebral load is an independent factor in the etiology of a pathologic fracture.¹⁰ Other factors that can lead to pathologic fractures include iatrogenic causes such as steroids, malnutrition-induced osteoporosis, bone mineral loss as a result of inactivity, and destruction of bone secondary to radiation therapy.¹¹

Complications from vertebral fracture include a redistribution of load across affected vertebral bodies creating the increased risk of fractures at adjacent levels, increased risk of embolic phenomena as a result of inactivity and pain, kyphosis-induced restriction of vital capacity,¹² predisposition to atelectasis, and early satiety-induced anorexia.¹³ Because of this, bony metastases contribute significantly morbidity and decreased life span.³^,¹⁴

TABLE 46.1 Estimated Number of Prevalent Cases of Metastatic Bone Disease in the National Commercially Insured Population Aged 18-64 Years, The National Fee-for-Service Medicare Population Aged ≥65 Years, and the US Adult Population on December 31, 2008, All Cancers and by Specific Cancer Types

Cancer Type	Commercially Insured, Ages 18-64 years (n = 120,694,145)	Fee-for-Service Medicare, Ages ≥65 years (n = 25,950,760)	US adult population^a (n = 230,118,000)
All cancers	60,411 (59,134-61,689)	128,540 (125,485-131,595)	279,679 (274,579-284,780)
Female breast	25,754 (24,911-26,596)	35,960 (34,341-37,579)	90,904 (88,095-93,714)
Prostate	4,969 (4,609-5,329)	37,240 (35,593-38,887)	62,841 (60,253-65,429)
Lung	7,879 (7,421-8,337)	15,900 (14,823-16,977)	35,222 (33,415-37,030)
Other	21,809 (21,046-22,573)	39,440 (37,745-41,135)	90,712 (87,843-93,580)
NOTES: Data presented as estimated number of patients with metastatic bone disease (95% confidence interval).
^aUS Census 2008.
From Li S, Peng Y, Weinhandl ED, et al. Estimated number of prevalent cases of metastatic bone disease in the US adult population. Clin Epidemiol 2012;4(1):87-93. Reproduced with permission of Dove Medical Press in the format Republish in a book via Copyright Clearance Center.

PATHOPHYSIOLOGY

Over the past 10 years, animal models for bone tumor growth, bone remodeling, and bone pain have demonstrated a correlation with many features found in human bony metastatic pain. Mouse studies using murine sarcoma cells injected into the intramedullary space of the femur demonstrate mechanical as well as movement-related pain behaviors. These behaviors¹⁵ increase with time and with increasing tumor-induced bone destruction offering a model that appears to replicate the human experience of how metastatic bone cancer contributes to bone pain. In normal mice, a nonnoxious stimulus to the femur does not elicit the synthesis of any tissue factors, whereas in mice with bone cancer, a nonnoxious stimulus elicits the synthesis of substance P, which binds to the neurokinin-1 receptor expressed in the spinal cord. Likewise, c-fos is not expressed at the level of the spinal cord in normal mice, but this protein is found in a population of mice with bony tumors.¹⁶

Both osteolytic and osteoblastic changes in bone occur in some tumor types such as lung, breast, and renal tumors. A predominance of osteolysis is found in multiple myeloma and sarcomas, leading to increased destruction of bone with time. The predominant lesion in men with bone metastases from prostate cancer is osteoblastic which leads to increased numbers of irregular bone trabeculae weakening bone.¹⁷

In the prostate model, colonies of malignant prostate tissue exist along the length of the intramedullary canal divided by newly formed bone.¹⁸ In the sarcoma model, there is no new bone formation, only destruction, which is greatest at the proximal and distal head with little to no destruction at the midshaft of the bone. The prostate model also demonstrates the formation of new bone along the length of the long bone involving diaphysis and proximal and distal endpoints with an increase of osteoclasts throughout the length of the intramedullary canal. These cells stimulate osteolytic remodeling inducing an inflammatory reaction mediated by macrophages. It is suspected that this macrophage-induced inflammatory activity may be the basis for neuropathic type of pain found in malignancies of the bone.¹⁹

Multiple studies have demonstrated that the periosteum is richly innervated by both sympathetic and sensory nerve fibers.²⁰^,²¹ The periosteum receives the greatest amount of afferent sensory fibers per unit area in bone. In addition, the periosteum, bone marrow, and mineralized bone are also innervated by both sensory and sympathetic fibers.

Osteolytic animal models demonstrate microscopic fragmentation and disruption of the bony matrix secondary to tumor growth. In the osteoblastic model, there is evidence of destructive injury as well as an increase in the density of sensory fibers compared to normal bone. An increase in specific transcription factors has also been demonstrated, including activating transcription factor-3 (ATF-3). Expression of ATF-3 is usually detectable in peripheral nerve injury models. It is also expressed in the nucleus of sensory neurons damaged by osteolytic tumor cells. However, this transcription factor is not detectable in normal sensory neuron nuclei or in sensory neurons affected by peripheral inflammation. Animal models with increased ATF-3 demonstrate an increase in movement-related pain behavior. Gabapentin improved pain-related behavior in this model²² but did not change tumor growth, bone destruction, or changes in peripheral sensory fibers that were impacted by tumor infiltration. These changes suggest that pain experienced secondary to tumor infiltration is neuropathic.²³

Osteolytic metastases in breast cancer secrete parathyroid hormone-related peptide (PTHrP) which, in turn, binds to the parathyroid hormone-related peptide receptor (PTHR1) on marrow stromal cells, resulting in the production of receptor activator of nuclear factor-κB ligand (RANKL). RANKL stimulates osteoclast differentiation which then demineralizes bone, leading to increased levels of insulin-like growth factor 1 (IGF-1) and TGF-β from bony matrix, supporting neoplastic proliferation increased PTHrP supporting growth of metastatic disease. This is exploited in the advent of the new antibody to RANKL denosumab that is used to combat bony metastatic proliferation and complications caused by it.²⁴

Osteoclastic-induced changes in pH also play a role in bone pain. Tumor cell growth can exceed its vascular supply leading to tumor cell death and further decrease in tissue pH and more pain. Additionally, as tumors grow, associated inflammatory cells which may comprise as much as 80% of the tumor mass reduce local pH. This localized decrease of pH in the bony matrix will lead to an increased absorption of bone as manifested by osteoclastic activity.²⁵ The administration of a transient receptor potential vanilloid (TRPV) antagonist within the mouse model correlates with a decrease in pain behaviors in all stages of tumor growth, suggesting a new potential therapeutic target to reduce cancer-related bone pain.²⁵ Tumor cells also produce formaldehyde through a demethylation process by serine hydroxymethyltransferase and lysine-specific histone demethylase 1. When the cancer cells migrate into the bone marrow, formaldehyde leads to upregulation of the transient receptor potential vanilloid subfamily member 1 (TRPV1) in the peripheral nerve fibers. IGF-1 produced by osteoblasts also increases TRPV1 receptors that contribute to neuropathic pain associated with cancer spread.

Osteoprotegerin (OPG) is a secreted soluble receptor, which is a tumor necrosis factor receptor (TNFR). This receptor prevents the activation of osteoclasts via a binding-sequestering of the OPG ligand. This has been shown to decrease the amount of pain-related behavior in the mouse sarcoma model. The monoclonal antibody (AMG-162) can inhibit bone destruction by reducing osteoclast function leading to a reduction in inflammatory-mediated changes in the dorsal root ganglion (DRG) which has been correlated with bony metastatic pain.²⁶

Inflammatory cells associated with tumor stroma secrete a variety of compounds that sensitize or excite afferent neurons. Compounds include prostaglandins, tumor necrosis factor-α, endothelins, interleukin-1 and interleukin-6, epidermal growth factor, transforming growth factor-β, and platelet-derived growth factor. Receptors for these factors are directly expressed by afferent neurons. All may play a role in bone pain suggesting new targets. In clinical practice, only prostaglandin and agents targeting endothelin have been used to control metastatic bone pain. Prostaglandins play a role in both sensitization and excitation of nociceptors via direct binding to the prostanoid receptor.²⁶

Nerve growth factor (NGF) is a neurotrophic factor expressed in tissue following nerve injury by both the nerves injured as well as surrounding tissues. Upregulation of NGF is thought to be a component in the hyperalgesia following nerve injury. Anti-NGF therapy could be effective in the control of pain related to bone cancer.²⁷ In the osteolytic sarcoma mouse model, anti-NGF antibody demonstrated effectiveness in attenuation of pain behaviors and was found to be more effective than acute administration of 10 and 30 mg/kg doses of morphine sulfate.²⁸

EVALUATION OF THE PATIENT WITH BONE CANCER

The two most important imaging modalities in the evaluation of malignancy of the bone are plain radiography and radioisotope bone scans.

Radiography

Radiographic studies should be ordered first in the evaluation of patients with complaints of bone pain in the context of malignancy. Radiographic patterns fall into osteolytic, osteoblastic, or mixed presentation. Osteoblastic lesions appear opaque and sclerotic. Osteolytic lesions appear more radiolucent compared to surrounding bone. Risk of fracture is greatest if more than 50% of long bone is involved.⁷^,²⁹

Bone Scan

Radioisotope bone scans are very good at identification of multifocal lesions.³⁰ Radioisotopes accumulate in areas of new bone growth and are diminished in areas of metastasis secondary to decreased blood flow to the area. Cancers such as melanoma and multiple myeloma may have false negatives when reviewed on bone scan secondary due to their lack of reactive bone activity.

Computed Tomography

Computed tomography (CT) offers improved spatial resolution in the evaluation of cortical bone destruction.³¹ CT is beneficial in evaluation of the three-dimensional characteristics of diseased bone identified by plain radiographs and isotope scans. CT scan evaluations are optimal to study the pelvic and shoulder girdles and spinal lesions. Additionally, CT-guided needle biopsies can be used to identify cell types.

18F-FDG-PET-CT

The visualization of glucose metabolism by positron-emission tomography with 18F-fluorodeoxyglucose, coupled with a simultaneously obtained CT (18F-FDG-PET-CT), is now a standard diagnostic technique in oncology. In patients with highly metabolically active cancers such as lung cancer or malignant melanoma, PET-CT with FDG has replaced other techniques for the detection of bone metastases. In highly active tumors, bony metastases can be detected with high sensitivity and specificity.³²

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) provides better contrast resolution in defining soft tissue and marrow involvement. Also, it can define vascular relationships without contrast enhancement.³¹ MRI is very beneficial in the evaluation of tumor infiltration of muscle and bone marrow, spinal cord compression, and lesions which are otherwise insufficiently imaged by the previously listed approaches.

TREATMENT

The site and distribution of bone metastases and the skeletal sequelae, such as pathologic fracture and spinal cord compression, can impact the patient’s prognosis. The focus of treatment should be directed at tumor regression, relief of cancer-related symptoms, and preservation of functional capacity. In some cases, metastatic disease is so advanced that it is resistant to both chemotherapy and radiotherapy. When metastatic involvement cannot be completely treated, the best way forward is to focus on symptom management. Impaired neurologic function, pathologic fractures, and debilitating pain are the most important reasons for aggressive treatment. Palliation may employ radiotherapy, radiopharmaceuticals, chemotherapy, hormone therapy, bisphosphonates, calcitonin, analgesics (opioids and antiinflammatory drugs), adjuvant analgesics (e.g., corticosteroids), and surgery.³³ Details for these interventions are found elsewhere.

Analgesic medications provide pain relief during therapy with more definitive modalities (e.g., surgical fixation, radiation therapy) as well as when malignant bone pain is resistant to other modalities of treatment. Conventional administration of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) may not produce adequate analgesia because of the incidental and intermittent nature of pain a patient might experience. These medications also have dose-limiting side effects. NSAID use is often limited by the risks of gastrointestinal (GI) bleeding and inhibition of platelet function, especially in patients with low platelet counts and taking steroids. In these latter patients, a cyclooxygenase-2 (COX-2) inhibitor may be preferred (see the following section). Patients can have renal and cardiovascular complications with both selective and nonselective NSAIDs. These patients are also prone to having comorbidities that may place them at increased risk of complications, particularly patients undergoing cancer chemotherapy and with advanced disease. Targeted pharmacotherapeutic and interventional approaches can be used to improve these risk-benefit ratios. The remainder of this chapter focuses on those therapies that have been studied specifically for the treatment of cancer-related bone pain to supplement material presented elsewhere in this text.

CYCLOOXYGENASE-2-SPECIFIC INHIBITORS

COX-2-specific inhibitors (coxibs) have demonstrated efficacy in the treatment of chronic and acute pain comparable to traditional (nonselective) NSAIDs without the severity of GI complication during short-term use or platelet inhibition effects.³⁴ The superior safety profile of coxibs in conjunction with similar efficacy of conventional NSAIDs supports their use in analgesic regimens for bone cancer. Many tumors express the COX-2 isoenzyme, which is involved in the synthesis of prostaglandins.³⁵ In the murine sarcoma model, acute administration of a selective COX-2 inhibitor attenuated both ongoing and movementevoked bone cancer pain, whereas chronic inhibition of COX-2 significantly reduced ongoing and movement-evoked pain behaviors and reduced tumor burden, osteoclastogenesis, and bone destruction by >50%. COX-2 is expressed in 40% of human invasive breast cancers, and bone is the primary site of metastasis in cases of breast cancer.³⁶^,³⁷ COX-2 inhibition also inhibited bone metastasis in both a prevention and treatment regimen. This suggests COX-2 produced in breast cancer cells are significant in supporting progression of osteolytic bone metastases in patients with breast cancer, and that COX-2 inhibition may halt this process. Furthermore, COX-2 inhibition may benefit iatrogenically caused tumor progression.³⁸ COX-2 inhibitors, such as celecoxib, have also been shown to increase apoptosis and decreased progression of osteosarcoma cell lines.³⁹

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