Metastatic Bone Disease 

Updated: Jan 11, 2018
Author: Howard A Chansky, MD; Chief Editor: Harris Gellman, MD 

Overview

Practice Essentials

Metastatic bone disease occurs when cancer spreads from a primary organ site to bone. The spine is the most common location of metastatic disease. See the image below.

Lateral radiograph shows sclerotic metastasis of t Lateral radiograph shows sclerotic metastasis of the L2 vertebra in a 54-year-old man with prostatic carcinoma.

Diagnosis

Pain is an important symptom of musculoskeletal metastases, but it is nonspecific. The pain pattern can be helpful if, in addition to being activity related, it is present at rest and at night, especially in patients older than 50 years. However, this pain pattern can be present in patients with osteomyelitis and Paget disease, and in these instances, it is also nonspecific.

Testing

Laboratory tests that can be used to aid in the diagnosis of metastatic bone disease include the following:

  • Serum alkaline phosphatase: Indirect reflection of bone destruction
  • Serum protein electrophoresis
  • Urinalysis, urine protein electrophoresis
  • N-telopeptide of type II collagen: Marker of bone resorption but not widely used

Imaging studies

The following radiologic studies may be used to evaluate metastatic bone disease:

  • Radiography: For the basic assessment of the extent of a tumor and the degree of cortical erosion; can also be used for skeletal survey in patients with multiple myeloma
  • Computed tomography scanning: Most sensitive imaging modality to detect bone destruction, providing the best assessment of the extent of cortical destruction
  • Magnetic resonance imaging: Most sensitive study for the assessment of the anatomic (intramedullary and extraosseous) extent of a lesion
  • Bone scanning: Very sensitive study for the detection of occult lesions and the assessment of the biologic activity of lesions
  • Angiography: Depicts devascularization of vascular metastases; may also be used to assess pain palliation in patients with nonresectable metastases

Procedures

Biopsies should be obtained from any soft-tissue mass or, if no soft-tissue mass is present, from the most accessible bone in a mechanically safe area (eg, metaphysis vs diaphysis, acetabulum vs subtrochanteric femur).

In selected patients with metastatic disease of the spine, the following diagnostic procedures may be performed:

  • Percutaneous core needle biopsy
  • Open biopsy

See Workup for more detail.

Management

The life span of patients with metastatic bone disease is limited; thus, the goal of management needs to be centered on returning as much function as possible as rapidly as possible. Patients with metastatic bone disease are generally treated with surgery or radiation therapy.

Radiation therapy

Radiation therapy remains a primary therapeutic modality for the treatment of spinal metastasis, because nearly 95% of patients who are ambulatory at the start of radiation therapy remain so. Consequently, the possibility of regaining cord function once it is lost as a result of spinal metastasis is dismal. Therefore, such loss needs to be avoided by early diagnosis, treatment, and, if indicated, surgical intervention.

Surgery

The goals of surgical intervention for spinal surgery in patients with metastatic bone disease includes decreasing or eliminating pain, decompressing neural elements to protect cord function, and mechanically stabilizing the spine.[1, 2] Anterior or posterolateral decompression, combined with anteroposterior reconstruction, may be used in the following:

  • Diagnostic spinal surgery
  • Cervical spinal surgery
  • Thoracic and lumbar spinal surgery

Vertebroplasty, in which polymethylmethacrylate is percutaneously introduced, may be a minimally invasive treatment alternative for patients with one- or two-level vertebral body compression fractures.[3]

For the management of long bone metastatic disease accompanied by an impending or completed fracture, open internal fixation is usually the preferred method of treatment. Stabilization with a locked intramedullary device followed by radiation therapy to the entire bone as soon as the surgical wounds have healed is preferred.[4]

Devices and/or procedures used in the surgical fixation of long bones include the following:

  • Standard or cemented stems
  • Dynamic hip screws or plates
  • Intramedullary fixation devices
  • Total hip arthroplasty

Pharmacotherapy

Medications used in the treatment of metastatic bone disease include the following:

  • Monoclonal antibody antineoplastic agents (eg, denosumab)
  • Calcium metabolism modifiers/bisphosphonates (eg, pamidronate, zoledronate, and ibandronate)

See Treatment and Medication for more detail.

Background

The orthopedic surgeon has two major tasks to perform when treating patients who develop bone metastases.[1] The first task is to biopsy a bony lesion of unknown origin, which may be found during evaluation/staging studies or as a result of a patient's symptoms. (See Workup.)

The orthopedic surgeon's second task is to manage the stabilization of impending or already completed pathologic fractures of bones in a critical area, such as an upper or lower extremity, the pelvis, or the spine. In one study of patients with breast carcinoma, 19% of the patients developed a pathologic fracture or hypercalcemia as the first sign that the carcinoma had spread to bone. Moreover, 10% of the patients suffered spinal cord compression, and 9% of them experienced bone marrow failure. (See Prognosis and Treatment.)

In patients with bone metastases, it is important to develop strategies that emphasize maintenance of function, including ambulation, for the remainder of these patients’ lives and to intervene when possible before a fracture occurs. The morbidity and mortality rates associated with metastatic bone disease are greater when intervention is delayed. (See Prognosis and Treatment.)

In females, the breasts and lungs are the most common primary disease sites; approximately 80% of cancers that spread to bone arise in these locations.[5, 6, 7, 8, 9] In males, cancers of the prostate and lungs make up 80% of the carcinomas that metastasize to bone.[10] The remaining 20% of primary disease sites in patients of both sexes are the kidney, gut, and thyroid, as well as sites of unknown origin. (See Pathophysiology and Etiology)

Pathophysiology and Etiology

Previously, the two main theories of how tumor cells metastasize and grow in bones were Paget's fertile soil hypothesis and Ewing's circulation theory. However, a substantial amount of work has more clearly defined the metastatic process to bone. Bone metastases occur in a predictable distribution. In order of frequency, the most common locations include the following:

  • Pelvis
  • Ribs
  • Proximal limb girdles

The red marrow theory, combined with knowledge about the cytokine stimulation of metastases, provides an excellent explanation of how this distribution occurs.

Metastases distal to the knee and elbow are extremely uncommon, but approximately 50% of these acral metastases are secondary to primary lung tumors. Carcinomas, such as those of the breast and prostate, rarely exhibit such a distinct pattern.

Metastasis and bone destruction

In 1995, Mundy and Yoneda described the cellular events necessary for the success of the metastatic process, including the attachment of tumor cells to the basement membrane, the production of proteolytic enzymes by tumor cells (such as metalloproteinases, which are enzymes that disrupt basement membranes), and the migration of tumor cells through the basement membranes into surrounding tissue, especially the arteriolar network.[11]

Cells from the primary site must, through the process of neovascularization or through migration to the nearest blood vessel, attach to the basement membrane of the vessel wall and produce proteolytic enzymes that disrupt the basement membrane.

The cells then migrate through the basement membrane and float away in the bloodstream to a distant site. The process through which these tumor cells are attracted to a specific site in the body is not completely clear, though type I collagen, a byproduct of bone resorption, has been shown to be a chemotactic factor that attracts tumor cells to bone.

If they survive the journey to the distant site, the tumor cells attach to the basement membrane of the vessel wall using proteolytic enzymes (integrins/cadherins). After disrupting the receptor site basement membrane, they migrate into the substance of the distal host tissue. Producing chemotactic factors, as well as RANK ligand (a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts), these cells stimulate osteoclast activity, causing bone resorption and leading to the formation of pockets or holes in the bone in which the tumor cells grow.

Another important substance that stimulates bone resorption is parathyroid hormone ̶ related peptide (PTHrP). This substance is expressed by breast carcinoma cells, as well as by oat cell tumors of the lung, and is a potent stimulant of osteoclasts. Guise et al reported elevated PTHrP levels in the bone marrow plasma (as compared with serum plasma levels) in rats with tumors.[12]

An interesting concept, reported by Mundy and Yoneda, is that myeloma cells are especially adapted to producing bone destruction through direct stimulation of osteoclasts.[11] During the resorption process, the osteoclasts release interleukin (IL)-6, which is a major regulatory factor in the growth of myeloma cells. Additional myeloma cells further stimulate increased osteoclastic production in a continuous feedback mechanism. This enhances survival of the tumor cells and further destruction of the bone.[11]

Epidemiology

United States statistics

Approximately 1.2 million patients present with cancer each year in the United States. Of these, approximately 600,000 persons have metastases to bone. In contrast, 2,700 patients per year develop primary bone sarcoma.

Age-related demographics

The age range of patients with sarcoma is different from that of individuals with carcinoma of bone; most metastatic bone lesions occur in adults older than 50 years, while most sarcomas occur in adolescents or young adults (<30 years). Therefore, a bone-occupying mass in an adult is much more likely to be a focus of metastatic carcinoma than to be a primary sarcoma of bone. However, in a patient with a bone lesion with no documentation of metastatic disease, caution is warranted to ensure the correct diagnosis.

Prognosis

In general, once skeletal metastases are present, patient survival is dramatically shortened. For example, the 5-year overall survival rate for people with prostate cancer is 93%, but once skeletal metastases are present, the average survival time is only 29 months. However, patients are surviving and remaining active for longer periods as treatment protocols improve. These factors make the orthopedic surgeon's task in prophylactic or reconstructive surgery more challenging.[13]

In addition, perioperative complications occur more frequently among patients with skeletal metastases; the perioperative mortality rate in this population is approximately 8%, and the perioperative infection rate is approximately 4% (although the infection rate is higher at previously irradiated sites).

Most patients with metastatic bone disease survive for 6-48 months. In general, patients with breast and prostate carcinoma live longer than those with lung carcinoma.[14, 15] Patients with renal cell or thyroid carcinoma have a variable life expectancy.

Kirkinis et al studied 462 patients presenting with metastatic bone disease to the extremities or pelvis who underwent orthopedic treatment.[16] Overall surival rates were 45% at 1 year, 29% at 2 years, and 13% at 5 years. Preoperative hemoglobin was found to be an independent predictor of better survival; lung histotype, age, pathologic fracture, and previous combined therapy were negative predictors of survival.

 

Presentation

History and Physical Examination

Although pain is an important symptom of musculoskeletal metastases, it is nonspecific. The pain pattern can be helpful if, in addition to being activity-related, it is present at rest and at night, especially in patients older than 50 years. However, this pain pattern can be present in patients with osteomyelitis and Paget disease, and in these instances, it is also nonspecific.

There are two main scenarios in which an orthopedic surgeon will be consulted to help evaluate a patient with a suspicious bony defect, as follows:

  • In the first instance, the surgeon is asked to help evaluate a patient who has experienced a pathologic fracture or who has a known primary carcinoma as well as a bony defect
  • In the second, more worrisome instance, the surgeon is consulted in the evaluation of a patient whose bony defect was serendipitously found during the radiologic evaluation of another condition

In the above instances, the orthopedist must perform the following three functions:

  • Determine the cause of the bony defect
  • Predict the probability of fracture [17]
  • Prophylactically fix a pathologic or impending fracture

These functions are discussed further in Workup.

 

DDx

Diagnostic Considerations

In addition to the conditions listed in the differential diagnosis, problems to be considered include the following:

Differential Diagnoses

 

Workup

Approach Considerations

Determining cause of bony defect

In a limited number of patients, bony defects are found serendipitously during radiographic evaluation of the affected part for other reasons. In these instances, the orthopedist is asked to determine if the discovered bony defect is a benign event requiring no further management or one that needs further investigation. The following are examples of defects that may be found:

  • A stippled, calcific, benign-appearing enchondroma found in the proximal humerus during an evaluation of a patient for a rotator cuff tear
  • Bony physiologic changes in the intertrochanteric area of the proximal femur, which may be found on plain anteroposterior (AP) pelvic radiographs during evaluation of the pelvis for other reasons
  • An area of fibrous dysplasia, which may be observed on radiographs that have been taken of a patient involved in some traumatic event

It is often difficult to determine whether a bony defect found during a bone survey for metastatic disease is the result of that disease or of some other condition. For instance, a benign bone island, an area of osteopoikilosis or fibrous dysplasia, can produce a similar radiographic appearance. A bone biopsy is often required to determine the actual diagnosis of such a defect. If the patient has already been diagnosed as having a primary tumor, the management of the recently discovered bony defect is relatively uncomplicated.

When the diagnosis of the bony defect must be proved for therapeutic reasons, biopsy is appropriate. For example, the radiotherapist or oncologist may need confirmation that the recently discovered bony defect is the same as the primary tumor or that the bony site results from another condition. Bone biopsies can be accomplished in a number of ways, but for the diagnosis of bony metastases, the most appropriate and least invasive method is needle biopsy.

Predicting probability of fracture

If the biopsy confirms that the bony defect has been caused by metastatic disease, the orthopedist must then decide if the defect fits the criteria for an impending fracture. The definition of an impending fracture is the presence of a bony defect that is likely to result in a pathologic fracture with physiologic loading (eg, activities of daily living). In this case, the orthopedist should determine the probability of fracture by examining plain radiographic findings and by conducting an interview with the patient.

Quantitating the risk of fracture on the basis of plain radiography alone is highly subjective. The broad guidelines in the literature are based on small numbers of patients and therefore are of limited value; using them can result in errors of judgment more than 50% of the time.

According to a report by Hipp et al, useful criteria are as follows[18] :

  • Defect geometry affecting load-bearing capacity
  • Histologic cell causing the defect - Blastic, lytic, or mixed
  • Anatomic site - Femoral neck vs greater trochanter

For instance, according to the study, the factor of risk for fracture of a normal proximal femur is approximately 0.4. The thinnest part of a cortical wall is the critical factor for predicting loss of strength. Central lesions with a 50% symmetrical loss of bone produce a 60% loss of bending strength. In patients who have eccentric bone loss, a 50% bone mass reduction results in a 90% reduction of bending strength. Therefore, a lesion located in areas that increase the risk factors to the bone must be considered.

Length of a bony lesion has been reported as critical only in torsional loads. The load-bearing capacity of bone apparently depends on the following:

  • Location of the defect with respect to the applied load
  • Type of applied load
  • Amount of bone loss
  • Condition of the remaining bone

The anatomic location of a bony lesion also is important. As the literature has shown, a drill hole that has been placed inappropriately in the lateral femoral shaft (at or below the level of the lesser trochanter) for fixation of a nonneoplastic femoral neck fracture results in a high risk of bone fracture with weight bearing through the lateral femoral cortical drill hold defect. Therefore, a similarly sized metastatic lesion in this area can be expected to create a similarly high fracture risk.

Laboratory Studies

Laboratory tests that can be used in the diagnosis of metastatic bone disease include the following:

  • Serum alkaline phosphatase - Indirect reflection of bone destruction because it is a reflection of osteoblastic response; may not be elevated in purely lytic tumors, such as plasma cell myelomas; nonspecific because it can also be elevated in Paget disease, benign insufficiency fractures, endocrine disease, and others
  • Serum protein electrophoresis (SPEP)
  • Urinalysis, urine protein electrophoresis (UPEP)
  • N-telopeptide (NTx) of type II collagen - Marker of bone resorption, but not widely used

Radiography

Radiography can be used for the basic assessment of the extent of a tumor and the degree of cortical erosion. It can also be used for a skeletal survey in patients with multiple myeloma. (See the images below.)

Lateral view of the femur of a 70-year-old man wit Lateral view of the femur of a 70-year-old man with metastatic prostate carcinoma, the most common cause of osteoblastic metastases in men.
Radiograph of a patient with severe rest- and acti Radiograph of a patient with severe rest- and activity-related pain at the time of presentation.
Pathologic fracture. Radiograph shows a displaced Pathologic fracture. Radiograph shows a displaced fracture through an osteolytic lesion in the distal femur of a 53-year-old woman with lung carcinoma.
Radiograph shows osteolytic metastasis in the dist Radiograph shows osteolytic metastasis in the distal femur of a 51-year-old woman with breast carcinoma.

Computed Tomography

Computed tomography (CT) is the most sensitive imaging modality for detecting bone destruction, providing the best assessment of the extent of cortical destruction. However, it is not always indicated if radiography and the clinical picture are informative and the surgical plan is clear.[19]  (See the images below.)

Axial computed tomography scan shows 2 rounded, mi Axial computed tomography scan shows 2 rounded, mixed osteolytic-sclerotic lesions in the thoracic vertebral body of a 44-year-old woman with lung carcinoma.
Axial computed tomography scan shows a destructive Axial computed tomography scan shows a destructive osteolytic lesion in the left acetabulum of a woman with vulval carcinoma. Soft-tissue extension into the pelvic cavity is present.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is the most sensitive study for assessing the anatomic (intramedullary and extraosseous) extent of a lesion. (See the images below.)

Sagittal spin-echo T2-weighted magnetic resonance Sagittal spin-echo T2-weighted magnetic resonance image shows hypointense lesions in the T10 and L3 vertebrae in a 66-year-old man with lung carcinoma. The tumor involves the T10 pedicle. See also the next image.
Sagittal short-tau inversion recovery magnetic res Sagittal short-tau inversion recovery magnetic resonance (MRI) from a 66-year-old man with lung carcinoma. This MRI shows hyperintense lesions in the T10 and L3 vertebrae, with T10 pedicular involvement.
Sagittal short-tau inversion recovery (STIR) magne Sagittal short-tau inversion recovery (STIR) magnetic resonance image (MRI) in a 68-year-old man with thyroid carcinoma. This MRI shows severe compression of the L1 vertebra with retropulsion. Affected T11-L2 vertebrae show signal hyperintensity, posterior vertebral body marginal bulging, and spinal canal narrowing. See also the next image.
Sagittal gadolinium-enhanced spin-echo T1-weighted Sagittal gadolinium-enhanced spin-echo T1-weighted magnetic resonance image from a 68-year-old man with thyroid carcinoma. This image shows heterogeneous enhancement of the T11-L2 vertebrae, with prominent epidural component enhancement and spinal canal compromise. See also the next image.
Axial spin-echo T1-weighted magnetic resonance ima Axial spin-echo T1-weighted magnetic resonance image (MRI) in a 68-year-old man with thyroid carcinoma. This MRI shows tumor extension from the L1 vertebral body and left pedicle into the left psoas muscle and epidural space, with resultant spinal cord compression. See also the next image.
Axial gadolinium-enhanced spin-echo T1-weighted ma Axial gadolinium-enhanced spin-echo T1-weighted magnetic resonance image from a 68-year-old man with thyroid carcinoma. This image shows heterogeneous enhancement of the soft tissue component of the L1 vertebral metastatic tumor.

Bone Scanning

Technetium-99m (99mTc) bone scanning is a very sensitive study for the detection of occult lesions and the assessment of the biologic activity of lesions. However, it is not useful by itself for multiple myeloma. This modality is part of the workup for an unknown primary site to identify other lesions and to determine which lesion will be easiest to biopsy.

99mTc bone scanning also provides an indirect measure of destruction, because it reflects the activity of osteoblasts. In addition, it can be used to demonstrate increased activity, because a lesion consolidates in response to radiotherapy. (See the image below.)

Typical scintigraphic pattern of bone metastases i Typical scintigraphic pattern of bone metastases in a 60-year-old man with nasopharyngeal carcinoma. This posterior technetium-99m bone scintiscan shows multiple randomly distributed focal lesions scattered throughout the skeleton, particularly the spine, ribs, and pelvis.

Angiography

Angiography has essentially has been supplanted by MRI. It is still useful, however, for the preoperative embolization of vascular lesions, such as renal cell carcinomas, thyroid metastases, and (occasionally) myelomas.

Biopsy

Any isolated (solitary) presumed metastasis should be treated as a resectable primary tumor until there is proof to the contrary.

A biopsy should be obtained from any soft-tissue mass that is present. If no soft-tissue mass is present, a biopsy should be obtained from the most accessible bone; preferably, the biopsy should be performed in a mechanically safe area (eg, metaphysis vs diaphysis, acetabulum vs subtrochanteric femur).

 

Treatment

Approach Considerations

Most patients with metastatic bone disease should be cared for in conjunction with a medical oncologist and the use of radiation oncology. Because the lifespan of patients with metastatic bone disease is limited, the goal of management must center on returning as much function as possible as rapidly as possible.

For an isolated lesion, proceed with therapy on the assumption that it is a primary tumor (sarcoma) until there is proof to the contrary. This helps to avoid complications, such as the placement of an intramedullary nail through a primary sarcoma of the proximal femur. In general, skeletal sarcomas have a bimodal distribution, with a peak in childhood and adolescence and a smaller peak in the elderly population (the same population in which metastatic disease is common).

Osteoclastic bone resorption can be modified by bisphosphonates; these substances are presently being used in the management of metastatic breast carcinoma and multiple myeloma.[1, 20] Future research and modification of RANK ligand (RANKL) is expected to produce additional substances that can further arrest or retard bone destruction by metastatic disease.

Image-guided percutaneous cryoablation is a lasting, safe, and effective treatment for the alleviation of painful metastatic tumors involving bone. In a study of 61 adult patients with one or two painful bone metastases (Brief Pain Inventory score ≥4 in a 24-hour period) who had refused or who had had ineffective conventional treatment, pain scores decreased significantly at 1, 4, 8, and 24 weeks following percutaneous image-guided cryoablation.[21] Of the 61 patients treated with this procedure, only one had a major complication (osteomyelitis at the ablation site).

Other intriguing research is being conducted in the area of angiogenesis inhibition. At present, such efforts are being directed at patients with gastrointestinal (GI) tumors. There is a need for additional research in the areas of combined large-vessel embolization and microscopic angiogenesis inhibition.

Patients with myeloma, leukemia, or metastatic carcinoma may have anemia, thrombocytopenia, and leukopenia secondary to chronic disease and marrow replacement. If liver disease, metastatic or otherwise, is present, then a coagulopathy may be present as well.

Perioperative resuscitation with appropriate factors and cellular elements is essential. With predisposition for thrombosis, provide prophylaxis against deep vein thrombosis (DVT) and pulmonary embolism (PE).

Treat patients with hydration and bisphosphonates or denosumab.[20, 22] Hypercalcemia is common in these individuals.

When a bony site displays radiographic and clinical evidence of an impending or already completed pathologic fracture, surgical stabilization is indicated. Most current literature supports the prophylactic fixation of impending fractures. Waiting for an impending fracture to occur increases morbidity and mortality and affects the patient's ability to regain function in as short a time as possible.

Spinal Radiation Therapy

Radiation therapy remains a primary therapeutic modality for the treatment of spinal metastasis. Nearly 95% of patients who are ambulatory at the start of radiation therapy remain so. Patients who start with limited ambulatory neurologic function have a 60% chance of improvement after radiation therapy. In those persons who have lost sphincter function, the chance of regaining it is no greater than 40%.

The point is that the odds of regaining cord function once it is lost as a result of spinal metastasis are dismal. Every effort must be made to prevent such loss through early diagnosis, nonoperative treatment, and, if indicated, surgical intervention.

The efficacy of radiation therapy is dependent on the radiosensitivity of the tumor. The presence of bone in the spinal canal or of a circumferential epidural tumor limits the success of management with radiation therapy alone. Patients with these conditions and cord compromise have been shown to experience improved outcomes with radical tumor resection and internal fixation/stabilization.

Pharmacologic Therapy

In a multicenter, randomized trial involving 1404 patients with at least one breast cancer metastasis to bone and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, treatment with intravenous (IV) zoledronic acid for 96 weeks was superior to treatment with oral ibandronic acid for preventing skeletal events in patients with bone metastases.[23]

In the primary per-protocol analysis, the annual rate of skeletal-related events (SREs) per person-year was 0.499 in the ibandronic acid group and 0.435 in the zoledronic acid group.[23] In the intention-to-treat analysis, the SRE rate per person-year was 0.507 in the ibandronic acid group and 0.425 in the zoledronic acid group. Both drugs had acceptable side-effect profiles, and the researchers concluded that the more convenient oral drug may still be considered for patients who have a strong preference or who have difficulties with IV infusions.

Denosumab, a human monoclonal antibody targeting and binding to RANKL, has been employed for prevention of SREs in metastatic breast cancer and is approved by the US Food and Drug Administration (FDA) for aromatase inhibitor–induced bone loss.[24]  A review by Irelli et al noted that bisphosphonates and denosumab have generally similar toxicity profiles, though pyrexia, bone pain, arthralgia, renal failure, and hypercalcemia are more common with bisphosphonates and hypocalcemia and toothache are more common with denosumab.[25]

In January 2018, denosumab was approved by the FDA for prevention of SREs in patients with multiple myeloma. It was originally indicated for SREs in patients with solid tumors. Osteoclast-activating factors, such as RANKL, are implicated in an increased risk for SREs with multiple myeloma.

In a phase 3 trial comparing denosumab with zoledronic acid in 1718 patients with bone metastases, denosumab was noninferior and showed an advantage in significantly reducing the risk for renal adverse events.[22] A post-hoc analysis at 15 months was also conducted because many of the SREs (60%) occurred early, within 3 months, which led the authors to speculate that the data reflected events occurring before the treatment had enough time to take effect.

Results did show superiority of denosumab (n = 450) over zoledronic acid (n = 459) in terms of the endpoint of time to the first SRE.[22] With regard to median progression-free survival (PFGS), a difference of more than 10 months was observed between the denosumab group (46.09 months) and the zoledronic acid group (35.38 months). No difference in overall survival was noted between the treatment groups.

Spinal Surgery

The spine is the most common location of metastatic disease. The timing of treatment is critical in persons with spinal metastases because patients with spinal disease have a life expectancy of 6 months to more than 2 years, depending on the primary tumor type.[13]

In deciding between surgical and nonsurgical management of spinal disease, it is necessary to take the following into account:

  • The patient's overall condition
  • The patient's chance for improvement with presently available treatment options
  • The patient's personal wishes

In general, patients with at least 6-12 weeks of life expectancy may be surgical candidates, depending on the location of the lesion in the spine and the impending neurologic consequences of disease progression at that level.

A study comparing surgery with radiotherapy as a treatment option for patients with spinal metastases determined that motor impairment was the main reason for surgery.[26] The investigators also found that better identification of patients with little remaining survival time is needed to avoid the time-consuming treatments of major surgery and long-term radiotherapy in these individuals.

The study reviewed medical records from 903 patients in Norway who were admitted for radiotherapy or surgery for spinal metastasis during an 18-month period between 2007 and 2008.[26] Fifty-eight patients were treated with surgery, and 845 were treated with radiotherapy. Eleven of the patients in the surgical group and 244 of the patients in the radiotherapy group died within 2 months after the start of treatment.

Spinal surgery in this setting may be performed for diagnostic or therapeutic purposes.

Diagnostic

Diagnostic management is usually performed with core needle biopsies up to the level of D8 and with open biopsies or minimally invasive costotransversectomies above the level of D8.

Obtaining a biopsy is not necessary in all patients with metastatic disease of the spine. In patients with myeloma, core needle biopsy (CNB) of the iliac crest is part of the staging process and is appropriate for diagnosis, which means that biopsy of a defect in a vertebral body is not required.

Percutaneous CNBs have successful positive results in 65% of destructive (lytic) lesions of vertebrae metastases but in only 20-25% of blastic ones. Open biopsy has a yield success rate of 85% regardless of the lesion type. Always remember to obtain a culture and Gram stain on all specimens, because infection is a great imitator of disease in bone, especially in the spine.

Percutaneous needle biopsy of C2 can be performed through a transoral approach. In the author's experience, biopsy of C1 and C3 can also be accomplished through this approach, but the procedure is much more difficult than it is for C2. This procedure must be performed under fluoroscopic control at all times. When the transoral approach is taken, a broad-spectrum antibiotic covering multiple organism types should be administered during the perioperative period to prevent secondary infections.

An open biopsy of the thoracic spine above T8 is best performed through a costotransversectomy. When the biopsy is performed with a needle, control via fluoroscopy or computed tomography (CT) is advisable. Biopsy specimens can be safely obtained from lesions below T8 with a core needle, such as the Craig, by using the Ottolenghi technique.

Therapeutic

Therapeutic spinal surgery is performed to manage pain, decompress neural elements, and restore mechanical stability to the spine. In rare incidents of radioresistant tumors, such as those occurring in thyroid and renal cell carcinoma, surgical resection and intercalary stabilization may serve as the only effective treatment modality.[27] However, tumor embolization for such metastases has been reported to offer improved longevity in patients with these specific tumors.

Treatment objectives

The objectives of therapeutic surgery for spinal metastases include decreasing or eliminating pain, decompressing neural elements to protect cord function, and mechanically stabilizing the spine.[1, 2] The most important of these criteria is decompression of neural elements, because the loss of neural function is almost always an unrecoverable catastrophe, especially in anterior cord injury.

Anterior or posterolateral decompression, combined with anteroposterior (AP) reconstruction, allows treatment of a wide variety of patient problems. When such techniques are used, 75-100% of patients experience improved pain outcomes; some neurologic improvement occurs in 50-75% of patients. More important, 95% of patients without preoperative neural deficits maintain their function after these procedures. Once neurologic function is lost, fewer than 40% of patients regain it.

Prognostic indicators

As with long-bone fractures, prognostic indicators can be used in evaluating patients with spinal metastases, helping to predict which patients may progress to vertebral collapse, spinal cord compression, and neurologic dysfunction. Although not ideal, these indicators are very helpful.

The four-column concept, which is based on radiographic criteria and includes the concept of laterality, provides one set of prognostic indicators. Tumor destruction of fewer than three columns suggests stability of the spine; a spine in which three or four columns have been destroyed is considered unstable and in need of stabilization. Tumor biology and location also are helpful indicators.

Indications for therapeutic surgery

Primary surgical intervention is appropriate when adjuvant therapy alone will fail to produce long-lasting success. Patients with radioresistant tumors, mechanical instability from bone destruction, bone in the spinal canal, or circumferential epidural tumors fit the indications for primary surgical treatment.

Therapeutic surgical procedures are also necessary when the progression of neurologic symptoms occurs despite the administration of the primary method of nonoperative treatment (ie, radiotherapy or chemotherapy). In addition, therapeutic surgery is needed when fracture, instability, or tumor progression, with impending or actual spinal cord compression, is present.

Surgery of cervical spine

In the cervical spine, pain and instability are the most common indications of disease. Neurologic deficits are relatively uncommon in the upper cervical spine because of the larger canal diameter, occurring in only 15% of cases of upper spinal disease metastases. In the lower cervical spine, 25-35% of lesions produce spinal cord compression.

Appropriate treatment depends on the degree of involvement. In the C1 and C2 bodies, lateral mass involvement is the critical factor because of the primary role these structures play in the overall stability of this area. Patients with destruction of the lateral mass of C1 do not obtain pain relief from radiation therapy alone, because of rotatory instability. They require posterior stabilization from the occiput to C2, with postoperative radiation therapy.

Patients with C2 body involvement and minimally displaced fractures or with diffuse involvement of the entire body can be treated with radiation therapy and immobilization in a cervical orthosis until fracture stability and bony restitution have occurred.

With gross destruction of the body of C2 and instability, surgery may be indicated as dictated by the patient's condition and neurologic status. The patient may require posterior fusion or a combined anterior and posterior approach. Patients who are not surgical candidates need to be treated with realignment and immobilization with a halo vest and with radiation therapy. Patients with posterior C2 involvement require radiation therapy and an orthosis for pain control. If the spinous processes of C2 are lost, cervical kyphosis can ensue.

Anterior decompression and reconstruction with autologous or allograft bone are effective means of achieving decompression and stabilization with one- or two-level anterior metastatic disease from C3 to C7. Additional posterior stabilization is usually necessary for disease that has more than two levels of involvement.

Surgery of thoracic and lumbar spine

In the thoracic and lumbar spine, metastatic disease occurs most frequently in the vertebral body. Therefore, anterior decompression and stabilization are the most effective means of decompressing the spinal canal. Such surgery allows correction of the deformity caused by the tumor and direct stabilization of the involved portion of the vertebral body.

Depending on the level and extent of the lesion, the surgical approach ranges from an anterior thoracotomy to a thoracoabdominal or retroperitoneal approach. One level of involvement or two contiguous levels can be approached, decompressed, and stabilized. More than two levels of involvement necessitate the addition of posterior segmental stabilization to provide adequate mechanical stability.

The posterior approach (with no anterior stabilization) should be reserved for diffuse disease over many levels or for isolated posterior disease alone. Fixation of two levels above and two levels below the involved areas, using segmental instrumentation, is necessary for proper stabilization. AP decompression and stabilization are required for circumferential disease or after the decompression of multiple levels.

Vertebroplasty

The percutaneous introduction of polymethylmethacrylate (vertebroplasty) may be a minimally invasive treatment alternative for patients with one- or two-level vertebral body compression fractures.[3] Originally described for the management of osteoporotic compression fractures, the procedure has risks, which include (particularly) the development of neurologic complications. It is being introduced into the orthopedic community as an additional tool to help in the management of patients with the aforementioned compression fractures.

Surgical risks

Surgical intervention has risks because patients with metastatic disease have poor nutritional status, low platelet counts, and low total white blood cell (WBC) counts. These constitutional deficits, combined with radiation therapy, place patients at high risk for wound infections and other complications, including excessive blood loss (with certain tumors, such as myelomas, as well as renal cell and papillary thyroid carcinomas), myocardial infarction, DVT, and pneumonia.

The incidence of such complications ranges from 10% to 15%, depending on the patient's underlying condition.

Surgical Fixation of Long Bones

Open internal fixation of long bones is usually the preferred method of treatment for the management of metastatic long-bone disease accompanied by an impending or completed fracture. Stabilization with a locked intramedullary device followed by radiation therapy to the entire bone as soon as the surgical wounds have healed is preferred.[4]

Some locations deserve special consideration. Replacement arthroplasty, unipolar or bipolar, is most appropriate for pathologic fractures of the femoral and humeral head or neck. This is also the preferred management technique for distal femoral or proximal tibial condylar defects. Although the proximal femur and humerus are frequent sites of metastases, it has been found that metastases are less frequent at the distal femoral and proximal tibial locations. The last two sites are usually associated with melanoma, myeloma, or lymphoma.

When discovered, defects of almost any size in the ulna and radius, though rare, must be fixed, because the ulna and radius are subject to constant torsional loads secondary to the pronation/supination actions of the forearm. Dysfunction of the forearm for the patient with a pathologic fracture of one of these bones is poorly tolerated. If possible, a firmly fixed device is needed to protect these small bones from further stress.

The use of radiation therapy after healing of the surgical wound is critical and can result in the healing of pathologic fractures, especially in the case of lesions related to breast cancer.[28]

Standard or cemented stems

Standard or cemented stems, including calcar replacements, are appropriate in the proximal femur. Standard cemented stems are also appropriate in the proximal humerus. Presently, off-the-shelf femoral and humeral devices are available in long, straight or bowed stems. The longest stem possible should be used in these situations to stabilize any actual or potential additional lesions distal to the proximal site.

Good clinical results, rapid return to function, and almost no wear complications are observed because of the shortened lifespan (ie, 4-48 months) of patients with metastatic bone disease.

The use of long cemented stems does carry an increased risk that during the procedure cardiac arrest will occur secondary to pressurization of the cement, and appropriate measures must be taken to minimize such an event during the placement of the stem.[29] Such measures include distal venting of the canal with drill holes, meticulous canal preparation, avoidance of hyperpressurization, and the staging of bilateral procedures, as well as the provision of adequate hydration and blood pressure support to the patient during this part of the process.

Dynamic hip screws or plates

In the author's opinion, it is not appropriate to use a dynamic hip screw or plate for fixation of pathologic proximal femoral fractures, because of the increased risk from already existing defects and the potential for additional metastatic defects in the femur distal to the initial lesion. Although successful use of such constructs for surgical management of intertrochanteric femoral fractures has been reported, the frequently deficient medial femoral cortex wall defects, combined with the inability to address any bony disease distal to these constructs, make them a relatively poor choice.

Intramedullary fixation devices

The use of intramedullary fixation devices, such as third-generation cephalomedullary implants in the femur and other designs, is the preferred method of fixation for fractures of the tibia and humerus. The use of cement is still helpful in the filling of large defects in the bone, but present-day locking devices are well suited for stabilization of these bones.

Total hip arthroplasty

The issue of concurrent lateral acetabular metastases with proximal femoral disease is worth mentioning. Microscopic disease of the bone has been found around the acetabulum in 83% of patients during replacement arthroplasty for pathologic femoral neck fractures. On the basis of these data, some authors have recommended routine total hip arthroplasty (THA) for management of this event.

However, this microscopic disease has not been clearly shown to cause clinical failures after femoral side–only replacements, and the goal of this type of surgery, which is to return patients to as much function as possible, is not realized with THA. Additionally, because radiation therapy is used postoperatively to manage such microscopic foci, it is questionable whether THA affords any benefit over the use of unipolar devices.

Continuing to use hemiarthroplasty is probably appropriate for proximal femoral disease management, unless clear evidence of structural compromise is present on preoperative evaluation of these patients.

In the event of a THA, the use of a cemented socket is highly recommended because postoperative irradiation and the primary disease process limit any advantage that might be gained from employing a porous ingrowth device. Larger lesions may require the use of acetabular cages and/or the use of Harrington-type reconstruction with Kirschner wires (K-wires) and cement.[14] With more extensive disease, a saddle prosthesis or resection arthroplasty may be needed.[30]

Diet

A nutritional deficiency may retard wound healing and the potential for rehabilitation.

Activity

Activity restrictions are dependent on the location of the lesion, the mechanical integrity of the remaining bone, and the surgical construct. At the first sign of pain in a lower extremity, the patient with a presumed pathologic lesion should be placed on crutches or a walker.

One advantage of prosthetic replacement over internal fixation is the potential for immediate weightbearing and the restoration of preoperative activity levels.[30]  This is especially important for patients with limited life expectancy.

Most patients with metastatic bone disease benefit from outpatient physical therapy. For severely debilitated patients, pain palliation may be the primary goal of surgery; the potential for functional recovery is limited.[31, 2, 32, 33, 34]

Long-Term Monitoring

Pain relief is probably the best guide to the regression of a lesion. Monitoring the response of skeletal metastases to radiation therapy or medical therapy (eg, chemotherapy or bisphosphonates) is difficult. This is because increased bone deposition from an osteoblastic metastasis (such as that from prostate or breast carcinoma) can, on a bone scan or, often, a radiograph, have an appearance similar to that of deposition from posttreatment consolidation. Metastatic prostate carcinoma is the most common cause of osteoblastic metastases in men.

 

Medication

Medication Summary

Although patients are generally treated with surgery or radiation therapy, bisphosphonates are playing an increasingly important role in the treatment and prevention of metabolic bone disease. In the future, the modification of RANK ligands is expected to produce additional substances that can further arrest or retard bone destruction by metastatic disease.[1, 20]

Calcium Metabolism Modifiers

Class Summary

Bisphosphonates can be given either orally or intravenously. The intravenous rout is preferred by many oncologists as it is given monthly as a short infusion and does not have the gastrointestinal adverse effects of the oral bisphosphonates. These agents are analogues of inorganic pyrophosphate and act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals. They prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability. The newer bisphosphonates are not completely free of the risk of causing a mineralization defect, but their safe therapeutic window is much wider.

Pamidronate (Aredia)

Pamidronate's main action is to inhibit the resorption of bone. The drug is adsorbed onto calcium pyrophosphate crystals and may block the dissolution of these crystals, also known as hydroxyapatite, which are an important mineral component of bone. There is also evidence that pamidronate directly inhibits osteoclasts. No food, indomethacin, or calcium should be ingested within 2 hours before and 2 hours after pamidronate administration. It is administered intravenously.

Zoledronate (Zometa)

Zoledronate inhibits bone resorption. It inhibits osteoclastic activity and induces osteoclastic apoptosis. The drug is adsorbed onto calcium pyrophosphate crystals and may block the dissolution of these crystals, also known as hydroxyapatite, which are an important mineral component of bone. No food, indomethacin, or calcium should be ingested within 2 hours before and 2 hours after zoledronate administration. It is administered intravenously.

Monoclonal Antibodies

Class Summary

Denosumab binds to RANK ligand, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption.

Denosumab (Prolia, Xgeva)

Denosumab is a monoclonal antibody that specifically targets RANK ligand, an essential regulator of osteoclasts. Note that two brands exist; they are not interchangeable, and the doses are different. Xgeva is indicated for the prevention of skeleton-related events (SREs) in patients with multiple myeloma or in patients with cancer metastases from solid tumors. SREs include bone fractures from cancer and bone pain requiring radiation. Prolia is indicated in women with breast cancer who have aromatase inhibitor–induced bone loss. Prolia is also indicated for men with prostate cancer who have androgen deprivation–induced bone loss.