The following module was designed to supplement medical students’ learning in the clinic. Please take the time to read through each module by clicking the headings below. This module discusses the diagnosis and management of bone pain secondary to cancer.
Bone metastasis is a complication of cancer spreading from other sites of the body and bone is one of the most common sites of distant metastases. It causes significant morbidity and reduced quality of life with pain being the most common symptom (1). The most likely cancers to spread to the bones are breast, prostate, lung, kidney, thyroid, multiple myeloma, and lymphoma (2). In fact, 50-70% of those with advanced breast and prostate cancer will have bone involvement (3).
Bone metastases most often distribute to the areas of red marrow such as the axial skeleton (skull, vertebrae, ribs, sternum), pelvis and proximal femurs (1,2). Bone pain attributed to metastases is the principal source of cancer-related pain and can severely impact quality of life (3).
Based on radiographic findings, bone metastases are divided into sclerotic/osteoblastic, osteolytic, or mixed lesions (4). These lesions cause complications known as skeletal-related events: bone pain, hypercalcemia, pathological fractures, and spinal cord compression (5). The exact mechanism by which bone metastases cause bone pain is poorly understood, but what is known is that malignant cells have a negative impact on the natural cycle of bone resorption and formation. Bone integrity is normally maintained by a balance of osteoclast activity (breaking down bone) and osteoblast activity (building new bone) (3). When this process is disrupted by malignant cancer cell invasion, it leads to bone destruction, instability and fractures (5).
The invasion of tumour cells into bone only plays a minor role in bone destruction. More importantly, there are factors that the cancer cells secrete that are involved in activating osteoclast activity and in stimulating the host immune system to release more activation factors. It is the up-regulation of osteoclast activity that ultimately results in bone breakdown in osteolytic lesions.
In osteoblastic lesions, typically from prostate cancer metastases, tumour cells have been shown to secrete osteoblast growth factors (TGF-beta and platelet-derived growth factor) which inhibit osteoclast activity and results in the loss of ability for normal bone remodelling (4). While the predominant mechanism of osteoblastic lesions is not bone breakdown, there is still disruption of normal regulation, resulting in formation of weak, irregular bone.
Adding to this, bone-derived growth factors and cytokines released from resorbing bone can attract and facilitate further cancer cell growth and proliferation (4). This “seed-and-soil hypothesis” describes the mechanism of bone metastasis (6).
Bone pain is the most common type of cancer-associated pain and its presentation can vary greatly between individuals. It can wax and wane, or be unwavering, and is oftentimes worse at night. The quality of pain can be quite variable, ranging from dull and aching to sharp and intense, or have neurogenic features due to highly innervated periosteum, all of which can complicate management (4). The cause of the pain is due to bone destruction, bone instability and subsequent fractures.
When a patient presents with bone pain from bony metastases, there are several important investigations to acquire in order to diagnose and to prevent other complications and morbidity associated with untreated bone metastases. Important labs include complete blood count, serum calcium and alkaline phosphatase to name a few, and the clinical context will determine what imaging is appropriate. Some examples of imaging that may be ordered are x-ray, bone scan, CT, MRI and PET scan (7).
Treatment of bone pain has two components, the first one being treating the underlying cause, the cancer itself, with systemic therapies such as chemotherapy, hormone therapy, targeted therapy or immunotherapy, and/or radiation therapy. Occasionally surgical management is needed to stabilize bones or repair fractures. The second part is treating the symptomatic bone pain which involves localized and/or systemic therapy.
Radiation therapy is the treatment of choice for localized bone pain when there are limited lesions that can be individually targeted. Radiation may be delivered in a single treatment or given over a longer period (e.g. 5 days).
Radiation can be highly effective for pain control. Bone fixation by orthopaedic surgery or bone cement is another form of localized treatment. Bones at risk of fracture or bones that are already fractured can be surgically stabilized to improve pain and mobility.
Systemic therapies include systemic radiation, anti-resorptive drugs (e.g. bisphosphonates and denosumab) and pain medication such as opioid analgesics, NSAIDs and acetaminophen.
Systemic radiation therapy can be an effective treatment for diffuse or multifocal bone pain, relieving pain for several months (7). This method delivers radiation to the cancer cells through IV administered radioactive drugs that are taken up by cancer cells by way of their rapid turnover. It is most effective when the metastatic lesions are osteoblastic, but is often used for treatment of both lytic and blastic lesions (7).
Anti-resorptive medications are the preferred systemic therapy for diffuse bone pain because they address the symptoms as well as the malignant cells. In addition to their anti-resorptive effects on osteoclasts, bisphosphonates have been shown to cause osteoclast apoptosis and may have direct apoptotic effects on tumour cells (4). In both breast cancer and multiple myeloma, bisphosphonates reduced skeletal-related events (radiotherapy for bone pain or impending fracture, pathological fracture, hypercalcemia of malignancy, spinal cord compression, and need for orthopaedic surgery) (4). Denosumab, a monoclonal antibody, is another agent that may be used that has shown to reduce skeletal-related events and a mortality benefit in multiple myeloma (4). The most serious, but rare side effect from these agents is medication-related osteonecrosis of the jaw (MRONJ). The risk is <2% in the first year of treatment, and rises to 4.6% per year by year 3 and beyond (8). Risk factors for developing MRONJ include longer duration of therapy, higher dose, higher potency agents, and concurrent dental surgery, so it is recommended to complete any dental work before initiating therapy.
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