Metastatic Tumors of Bone

Metastatic Tumors of Bone

Eugene S. Jang, MD, MS

Lee Jae Morse, MD

Andrew S. Fang, MD, FAAOS

Dr. Jang or an immediate family member serves as a board member, owner, officer, or committee member of Accreditation Council for Graduate Medical Education. Neither of the following authors nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter: Dr. Morse and Dr. Fang.


The word metastasis, derived from the ancient Greek methistanai (to change the setting), was first used in 1829 to describe the process by which malignancies migrate to other organs. Bone metastases from carcinoma and hematologic malignancies together are responsible for most destructive bone lesions in adults older than 40 years. As advances in systemic cancer treatment strategies continue to improve survival, the prevalence of patients with metastatic tumors of bone will steadily increase. Pain from disseminated cancers is by far the most common oncologic presentation encountered in orthopaedics. Surgeons of all subspecialties and practice settings must therefore be familiar with the pathophysiology of bone metastases, as well as the fundamentals of the workup and initial treatment of these patients.

Etiologies for Metastatic Tumors of Bone


The most common etiologies for a destructive bone lesion in adults older than 40 years include metastatic carcinoma, multiple myeloma, and lymphoma. Cancer is diagnosed in more than 1.7 million people in the United States every year; approximately 50% of these individuals will have bony metastases at some point in their disease course.1 Additionally, metastatic disease is a substantial driver of the overall economic burden of cancer, accounting for 17% of the total yearly costs for cancer care in the United States.2 Because of ongoing improvements in systemic therapy, patients are surviving longer with metastatic disease, and the probability of encountering these patients continues to rise. Of all the locations to which carcinomas tend to metastasize, bone is the third most common, after the lung and liver.3 Breast and prostate cancer are the most frequent cause of metastatic bone disease, together comprising approximately 80% of all cases,4 followed by lung, kidney, and thyroid.

Anatomy and Biomechanics

Skeletal metastases most often occur in the axial skeleton (spine, pelvis, and ribs) and proximal limb girdle (proximal femur and proximal humerus).4 Certain subtypes of cancer exhibit predilections for specific locations, such as the proximal humerus for renal cell carcinoma (Figure 1) and distal phalanges for lung cancer. The location, size, number, and destructiveness of metastatic lesions all affect the biomechanical properties of bone, which in turn determine the risk of pathologic fracture. Biomechanical studies have identified that lytic lesions in the inferomedial femoral neck and the posteromedial proximal femur near the lesser trochanter pose the highest fracture risk.5 Several CT-based scoring systems have
been described to apply these biomechanical and anatomic principles in predicting risk of pathologic fracture.6 Proceeding with prophylactic fixation in cases of impending fracture is associated with improved quality of life and survival benefit when compared with patients with completed fractures.

Pathophysiology of Metastasis of Bone

General Biologic Principles

Metastasis is a complex multistep process leading to a subset of the malignant cells that develop the ability to evade host defenses, cross the basement membrane, and intravasate into blood vessels. Once circulating tumor cells appear in the bloodstream, they can disseminate to distant sites. Only a small subset of these circulating cells will produce the necessary proteins (integrins, cadherins, and matrix metalloproteinases) to adhere to the vascular endothelium and extravasate into end organs. The tumor cells will then use growth factors (such as transforming growth factor beta, insulinlike growth factor, fibroblast growth factor, and bone morphogenetic protein) to proliferate, thus forming a metastatic focus. Tumor cells do not directly destroy bone; they will instead express cytokines that stimulate osteoblasts to secrete nuclear factor kappa-B ligand (RANKL), which signals osteoclast precursors to intensify osteoclastogenesis and tips the balance of bone homeostasis toward increased bone destruction. The RANKL pathway is central to the pathophysiology of metastatic bone disease, which also makes it a critical target for pharmacologic treatment. Both diphosphonates (which directly inhibit osteoclasts) and denosumab (an anti-RANKL monoclonal antibody) have been found to delay time to skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, or need for radiation therapy/surgery.7,8,9 These drugs should thus be considered as part of the treatment plan for any metastatic bone disease.

Disease-Specific Mechanisms

Breast cancer, the most common cause of metastatic bone disease in women, can present with either lytic or blastic bone lesions. The molecular pathways connecting RANKL to bone destruction are a well-described mechanism in bone metastases. Breast cancer cells respond to transforming growth factor beta, a naturally occurring cytokine involved in bone turnover, by secreting parathyroid hormone-related protein. Parathyroid hormone-related protein from breast cancer cells serves as a potent activator of the RANKL pathway, which results in increased osteoclastic activity. The resulting bony destruction results in the release of more transforming growth factor beta from bone cells, and this so-called vicious cycle of bone destruction repeats (Figure 2).

Prostate cancer is the most common cause of metastatic bone disease in men, but pathologic fractures from prostate cancer are relatively rare because of the classically osteoblastic nature of these metastases. On a
molecular level, the tendency for prostate cancer metastases to be osteoblastic in nature can be explained by the expression of endothelin-1 by prostate cancer cells, which directly stimulates osteoblasts to produce bone.

Lung cancer metastases tend to be osteolytic, with parathyroid hormone-related protein influencing the RANK/RANKL pathway in a manner similar to breast cancer. Metastatic lung carcinoma has a unique predilection for acral metastases (affecting skeletal sites distal to the elbow and knee), which is uncommon in other metastatic carcinomas.

Renal cell carcinoma is notable for its unique surgical implications. Kidney cancers tend to overexpress growth factors related to angiogenesis and the coagulation cascade: epidermal growth factor receptor, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor.10 These angiogenic growth factors may explain the propensity for metastases of renal cell carcinoma to be highly vascularized with the potential for substantial blood loss during surgery. As a result, patients with renal cell carcinomas may benefit from embolization before surgical resection or stabilization, especially in locations such as the pelvis.11 Another unique consideration is that for solitary renal metastases, surgical resection is associated with improved survival when compared with curettage.12 Moreover, variable response of this tumor to radiation and curettage can lead to continued progression of disease and eventual failure of fixation.

Thyroid cancers are typically localized, but metastasis significantly lessens the likelihood of long-term survival. Follicular thyroid carcinoma, the subtype most associated with metastasis to bone, is characterized by overexpression of fibroblast growth factor and vascular endothelial growth factor and thus tends to bleed during surgical intervention.

Plasma cell malignancies (solitary plasmacytoma if a single lesion or multiple myeloma if multiple sites) commonly occur in red marrow-rich bones and present
with lytic lesions causing pain, anemia, and renal insufficiency. Similar to breast cancer and lung cancer, plasma cell tumors create a RANKL-mediated cycle of bone destruction and have a propensity for hemorrhage because of vascular endothelial growth factor expression. Primary and secondary lymphomas of bone have variable survival depending on pathologic subtype, but are usually treatable. Both RANKL and vascular endothelial growth factor play a role in the mechanism of bony destruction in lymphoma.

Although the presentation and underlying biology of these diseases can vary widely, the evaluation of the patient presenting with multiple bony lesions concerning for metastatic disease has been standardized over time. The diagnostic algorithm, which includes history and physical examination, plain radiographs of the affected bone, CT of the chest/abdomen/pelvis, laboratory studies, whole-body bone scan, and biopsy of the most accessible tumor, has been shown to yield the correct diagnosis and primary tumor location in 85% of patients13 (Figure 3).

Evaluation of the Patient With Suspected Bony Metastasis

History and Physical Examination

Evaluating the patient with suspected skeletal metastasis begins with a detailed history and physical examination. Patients often present with progressive pain associated with weight bearing, which should raise concern for an impending pathologic fracture. Understanding the factors that elicit or exacerbate the pain is critical; for example, persistent pain at rest may directly result from the tumor itself, whereas pain related specifically to weight-bearing activity suggests mechanical weakness of the bone caused by the tumor. A detailed personal and family cancer history is helpful, keeping in mind that patients with a previously localized cancer may be in remission for decades before metastasis occurs (particularly those with breast, renal, or prostate cancer). Asking about other symptoms of primary cancers that commonly metastasize to bone (eg, breast mass, frequent urination related to enlarged prostate, fatigue, or unintentional weight loss), as well as history of smoking, environmental exposures, or other risk factors for cancer, may also be helpful. On examination, patients may have an antalgic gait, guarding of the affected limb, or discomfort with range of motion. Straight leg raise against gravity is a useful test of the integrity of the peritrochanteric region; this maneuver places more than twice a patient’s body weight across the hip joint, and the absence of pain with this maneuver is relatively reassuring against an impending pathologic fracture.14


Radiographs including the entire affected bone should be taken in two orthogonal planes. Metastases from lung, thyroid, renal, and gastrointestinal malignancies, as well most hematopoietic malignancies, tend to be radiolucent on radiographs, indicating an osteolytic process. Prostate and bladder cancers classically have a calcified matrix, which appears radiopaque, indicating an osteoblastic process, whereas breast cancers often have a mixed osteolytic and osteoblastic appearance (Figure 4). CT of the chest, abdomen, and pelvis is indicated in the workup for an unknown primary because the most common primary cancers with a propensity for bone are primarily within the chest (lung, breast), retroperitoneum (renal), and pelvis (prostate).13

Technetium-99m phosphate bone scintigraphy is recommended in the evaluation of an adult patient presenting with a destructive bone lesion. Whole-body bone scans are used to perform a global assessment of metastatic burden by detecting osteoblastic activity throughout the skeleton. This can be helpful in distinguishing a solitary lesion from a widely metastatic process, particularly when evaluating a lesion of unknown etiology or staging a new diagnosis. In diseases without a significant osteoblastic component to the pathophysiology, or those in which false-negative rates with bone
scan may be significant (eg, multiple myeloma, renal cell carcinoma), bone scans may be less useful.15 In general, however, bone scans are a relatively inexpensive and effective way to detect other bone lesions that may necessitate weight-bearing precautions, intervention for impending pathologic fracture, alterations to patient positioning in the operating room, or special considerations for anesthesiologists (ie, cervical spine disease necessitating modified intubation techniques).

Although not part of the standard workup for an unknown primary tumor, whole-body positron emission tomography combined with CT has gained more traction recently, with the idea that it can simultaneously assess for bone metastases and search for the primary tumor with a single study. However, recent studies suggest that although positron emission tomography/CT may be useful in assessing overall metastatic burden, it does not outperform standard evaluation for identification of the primary cancer in patients with a skeletal metastasis of unknown primary.16

Laboratory Studies

Laboratory studies can often assist with narrowing the differential diagnosis. A complete blood count screens for anemia and unusual distributions of cell populations, which can be seen in hematologic malignancies. A complete metabolic panel will determine the levels of serum calcium, alkaline phosphatase, and lactate dehydrogenase, which are helpful in assessing for hypercalcemia (a potentially serious sequelae of metastatic disease) and can also be of prognostic value.17 Erythrocyte sedimentation rate and C-reactive protein are sensitive tests to rule out osteomyelitis, another etiology of a destructive bone lesion in an adult. Finally, serum and urine protein electrophoresis together are a highly sensitive and specific combination of tests for the detection of multiple myeloma. Serum protein electrophoresis (which detects the heavy chain monoclonal proteins produced by myeloma) is simple to obtain and detects approximately 80% of myelomas, whereas urine protein electrophoresis provides additional sensitivity (10% to 15% of myelomas produce only light chains, which can only be detected in urine), and biopsy is often obtained for definitive confirmation of the diagnosis.18

In addition to the aforementioned laboratory tests, some centers may add thyroid-stimulating hormone and free thyroxine levels to evaluate for thyroid cancer, as well as a urinalysis for the detection of microscopic
hematuria associated with renal cell cancer. There are also novel laboratory tests in development with the goal to detect the onset and progression of metastatic carcinoma to bone.19


Any solitary bone lesion should be assessed with a biopsy unless the radiographic findings are pathognomonic. A common error is to assume that a bone lesion in a patient previously treated for localized carcinoma represents metastatic disease and treat it as such without a tissue diagnosis. In these scenarios, there is a 15% probability that the lesion is a malignancy unrelated to the original carcinoma.20 Treating a bone lesion in a patient as a presumed metastasis without performing an appropriate workup can lead to catastrophic results. Reaming a bone and placing an intramedullary device contaminates the length of the bone as well as the surrounding soft tissues, with a theoretical risk of spreading of the tumor cells systemically. To avoid this risk, an open biopsy or needle biopsy (core biopsy) of the lesion should be performed before surgical stabilization. If this is performed in the operating room under the same anesthetic, the surgeon must be prepared to wait for results of a frozen section and abort the case if the findings are inconclusive or suggest a primary bone malignancy.

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May 1, 2023 | Posted by in ORTHOPEDIC | Comments Off on Metastatic Tumors of Bone
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