The skeleton is the third most common site of metastatic disease after lung and liver. Bone metastasis is more prevalent than primary bone tumors. Solid tumors more frequently metastasize to the bone.
Eighty percent of bone metastases originate from prostate, breast, and lung cancer. Other common primary malignancies that metastasize to the bone include the bladder, kidneys, thyroid, lymphomas, and sarcomas.
Bone metastases affect survival rates ranging from 6 to 7 months in lung cancer to several years in the breast (19 to 25 months) or prostate cancer (12 to 53 months). Metastases may present with a single bone lesion, oligometastatic disease, multiple bone metastases, or visceral plus bone metastases. A study by Hernandez et al. estimated the cumulative incidence of bone metastases in the United States as 2.9% at 30 days, 4.8% at one year, 5.6% at two years, 6.9% at five years, and 8.4% at ten years. Prostate cancer posed the highest risk for bone metastases (18% to 29%) followed by lung, renal, or breast cancer.
Bone metastases occur mostly through the hematogenous spread. However local invasion from soft tissue tumors is also possible. Hematogenous spread through the venous system is the predominant process of spinal metastasis. This is because lung and breast cancers metastasize preferably in the thoracic region due to the venous drainage of the breast through the azygos vein as it communicates with the plexus of Batson in the thoracic region. Prostate cancer usually metastasizes to the lumbar-sacral spine and pelvis because it drains through the pelvic plexus in the lumbar region.
A pivotal occurrence in the pathogenesis of bone metastases involves the cellular interaction between the receptors on the tumor cells (e.g., CXCR4, RANKL) and the stromal cells of the bone marrow and bone matrix. These interactions subsequently lead to the release of growth factors, cytokines (IL-6, IL-8) and angiogenic factors (VEGF) leading to tumor growth and osteoclast activation and resultant osteolysis. The predilection for bone as a site of metastases is dependent on specific tumor characteristics, and the receptive bone microenvironment termed the seed and soil hypothesis.
Secondary bony involvement can be largely classified as osteoblastic (prostate cancer) and osteolytic (breast, lung).
Histopathology of bone metastases is only employed for diagnostic purposes in patients of primary unknown cancers or in the presence of multiple cancers.
The vertebra is the most common site affected, followed by the femur, pelvis, ribs, sternum, proximal humerus, and skull. Bone metastases may be asymptomatic or manifest in a variety of ways termed skeletal-related events (SRE) as a result of the destruction of normal bone architecture. The following further describes SRE:
It is pertinent to identify bone metastasis early, both for staging and prognostication as well as the implementation of prophylactic and treatment strategies which may lead to decreased morbidity and mortality.
Bone metastases can be characterized as osteolytic, sclerotic, or mixed on imaging studies.
X-rays or plain radiograph is the initial imaging of choice in patients presenting with bone pain. Plain films are used to assess abnormal radionuclide uptake or to detect pathological fractures.
Plain radiography best detects osteolytic lesions, but they may not be apparent until they are greater than 1 to 2 centimeters and with loss of 50% of the bone mineral content at the site of disease. Osteolytic lesions are seen as thinning of trabeculae and ill-defined margins on radiographs, while sclerotic lesions appear nodular and well circumscribed as a result of thickened trabeculae. Plain films tend to be insensitive, especially in detecting bone metastases and with asymptomatic and subtle lesions. Progression of disease and response to therapy can be monitored with plain films and further correlation with other modalities. Sclerosis or new bone formation in osteolytic metastatic lesions is demonstrated by the sclerotic rim of reactive bone, which starts at the periphery and eventually involves the center with continued healing. Purely sclerotic lesions are more difficult to assess. Major disadvantages of plain radiographs include poor sensitivity.
Computed tomography (CT) is more sensitive (74%) than plain radiographs. It is useful in the evaluation of cortical and trabecular bone as well as in the assessment of osteolytic and sclerotic lesion. CT scan is advantageous as it can determine staging and treatment response of other organs in addition to bone and objectively assess reactive sclerosis by calculating the change in Hounsfield units. Ribs are better evaluated with CT due to the high cortex to marrow ratio.
In the detection of bone metastasis, MRI demonstrates a sensitivity of 95% and specificity 90%. MRI is also more advantageous than a bone scan as it can detect marrow involvement before the development of osteoblastic lesions. It can be used with women who are pregnant and used to detect spinal cord compression. Bone metastases manifest as low T1 signal and high intensity on the T2 weighted sequence. Whole-body MRI requires 40 to 45 minutes to perform and involves short-tau inversion recovery (STIR) and/or T1-weighted sequences.
Nuclear medicine scans also are used to detect bone metastases using osteotropic radioisotopes; these include skeletal scintigraphy, SPECT, and PET scan.
Skeletal scintigraphy or bone scan is the most commonly used radionuclide imaging which uses 99mTc-MDP employed in the detection of skeletal metastases. Radioisotopic imaging methods depict bone metastatic lesions as areas of increased tracer uptake.
Bone scan provides the advantage of scanning the whole skeleton and has a high sensitivity (78%) therefore resulting in early diagnosis. When osteoblastic activity is prominent, the lesions are readily detected using radionuclide bone scanning. However, bone scans have a low specificity for differentiating between benign and malignant bone lesions and for the detection of predominantly osteolytic lesions. Bone scans can be used to monitor the progression of disease and response to treatment.
SPECT uses 99mTc-MDP radioisotopes uptake to detect bone lesions; however, images are acquired in cross-sectional rather than a planar fashion. SPECT has a higher specificity of 91% compared to skeletal scintigraphy.
PET is a nuclear medicine technique that uses the radiotracers 18F FDG or 18FNaF for the detection of skeletal metastases. 18F FDG PET scan identifies bone metastases based on a high glucose metabolism exhibited by neoplastic cells. PET has a better spatial resolution compared to skeletal scintigraphy. 18F NaF-PET is proven to be substantially more sensitive and specific than bone scan and SPECT for the detection of bone metastases.
Combining imaging techniques and modalities allows for improved visualization both anatomically and functionally, leading to increased diagnostic accuracy. One example of this is the 18F-Sodium fluoride (18F-NaF) PET/CT bone scanning which has a significantly greater sensitivity (100%) and specificity (97%). Other hybrid imaging techniques include SPECT/CT, PET/CT, and PET/MRI.
Blood tests can aid in supporting the diagnosis of bone metastases. Complete blood count and a comprehensive metabolic panel should be obtained routinely. CBC may reveal anemia, thrombocytopenia, or pancytopenia in late stages. Serum calcium and alkaline phosphatase may be elevated due to ongoing osteolysis. Bone turnover markers are still being studied as indicators of bone resorption. Tartrate-resistant acid phosphatase has been proven to elevated in patients with breast and prostate cancer with bone metastases.
Objective scoring models such as the Mirel classification system for long bones and assessment of spinal stability in addition to imaging criteria are used to determine the surgical necessity for impending pathological fractures.
The therapeutic approach to bone metastases should be a multidisciplinary approach targeted at preserving the quality of life, including pain control, minimizing SREs, and achieving local tumor control. It is pertinent to consider a multitude of factors including the extent of disease spread, performance status, impending fracture, and side effects when creating the initial approach for the treatment of bone metastases.
A major aspect of treating bone metastases is analgesia/pain control for the debilitating pain that occurs with bone metastases. Pain control can be initiated with NSAIDs and titrated up to or in conjunction with narcotics as needed for symptom relief. Glucocorticoids may also be useful for additional pain control.
Osteoclast inhibitors (bisphosphonates and denosumab) decrease morbidity and mortality associated with bone metastases as they reduce skeletal-related events and can be used for analgesia to some extent.
Local radiation for symptomatic bone metastases is a significant component of the palliative approach in providing analgesia. It is also used postoperatively to consolidate continued bone healing. External beam radiation is the standard approach for painful bone metastases and is beneficial in reducing pain by up to 50% to 80%. Several studies have proven that a single 8 Gy fraction compared to more prolonged or fractionated radiation is non-inferior; however, it may carry a higher need for pretreatment (20 % vs. 8%). Stereotactic body radiation therapy spares the normal tissue while delivering highly conformal radiation to the affected area. There are no clear guidelines on stereotactic body radiotherapy (SBRT) use however it may be indicated over external beam radiation therapy (EBRT) in specific instances of bone metastases specifically vertebral from certain radio-resistant neoplasms.
Bone-targeted radiopharmaceutical therapy (e.g., beta-emitting agents strontium-89, alpha-emitting radium-223) provides the specific advantage of treatment of diffuse pain associated with osteoblastic bone metastases. It is typically used in bowel movement associated with prostate and breast cancer or for analgesia in radiation therapy for refractory pain.
Systemic chemotherapy when amenable, aimed at the primary tumor can also provide analgesia by reduction of tumor size and control of tumor spread.
Surgery is indicated for impending or complete fracture, mechanical stability, and spinal cord compression. In cases where the spread of the primary cancer is limited to a single bone lesion, en bloc resection of the metastasis can be done by means of local tumor control.
Local ablation via radiofrequency ablation (RFA), cryoablation, and focused ultrasound (FUS) should be considered for patients with persistent pain following radiation therapy or patients with recurrent pain.
The differential diagnosis for bone metastases includes chondrosarcoma, primary malignant lymphoma of the bone, multiple myeloma, post-radiation sarcoma, and osteomyelitis.
A distinction between acute osteoporotic fractures versus metastatic fractures should be made on radiographic imaging. In osteoporosis, the cortical bone may be preserved; however, cortical bone destruction is typical with metastatic cancer.