AAOS Comprehensive Orthopaedic Review

Section 4 - Orthopaedic Oncology and Systemic Disease

Chapter 43. Metastatic Bone Disease

I. Evaluation/Diagnosis

A. Overview


1. Demographics


a. Metastatic bone disease occurs in patients older than 40 years.


b. Most common reason for destructive bone lesion in adults


c. More than 1.4 million cases of cancer per year in the United States; bone metastasis develops in about 50% of patients


d. Bone is the third most common site of metastasis (after lung and liver).


e. Most common primary cancer sites that metastasize to bone are breast, prostate, lung, kidney, and thyroid.


2. Genetics/etiology


a. Two main hypotheses


i. 1889: Paget's "seed and soil" hypothesis (ability of tumor cells to survive and grow in addition to the compatible end-organ environment)


ii. 1928: Ewing's circulation theory


(a) Tumors colonize particular organs because of the routes of blood flow from the primary site.


(b) Organs are passive receptacles.


(c) Batson plexus—Valveless plexus of veins around the spine allows tumor cells to travel to the vertebral bodies, pelvis, ribs, skull, and proximal limb girdle (eg, prostate metastases).


b. Mediators of bone destruction include tumor necrosis factors; transforming growth factors (TGFs); 1,25 dihydroxyvitamin D3; and parathyroid hormone-related protein (PTHrP).


B. Clinical presentation (

Table 1)


1. History


a. Progressive pain that occurs at rest and with weight bearing


b. Constitutional symptoms (weight loss, fatigue, loss of appetite)


c. Personal or family history of cancer


d. History of symptoms related to possible primary sites (hematuria, shortness of breath, hot/cold intolerance)


e. Primary tumors may metastasize quickly or take 10 to 15 years or longer (breast, renal, prostate).


2. Physical examination findings


a. Occasional swelling, limp, decreased joint range of motion, neurologic deficits (10% to 20%) at metastatic bone sites


b. Possible breast, prostate, thyroid, or abdominal mass


c. Stool guaiac


d. Regional adenopathy


3. Laboratory studies


a. Complete blood cell count (anemia suggests myeloma)


[Table 1. Workup of Patients Older Than 40 Years With a Destructive Bone Lesion*]


Figure 1. Osteolytic and osteoblastic metastases. A, Lung cancer metastases are generally purely osteolytic, as demonstrated in this radiograph. Note the lesion in the left proximal femur that is destroying the lateral cortex. B, Prostate cancer metastases are osteoblastic as noted throughout the pelvis, spine, and proximal femurs in this radiograph.]

b. Serum protein electrophoresis/urine protein electrophoresis (abnormal in myeloma)


c. Thyroid function tests (may be abnormal in thyroid cancer)


d. Urinalysis (microscopic hematuria in renal cancer)


e. Basic chemistry panel: calcium, phosphorus, alkaline phosphatase, lactate dehydrogenase (LDH)


f. Specific tumor markers: prostate-specific antigen (PSA) (prostate); carcinoembryonic antigen (CEA) (colon, pancreas); cancer antigen 125 (CA 125) (ovarian)


4. Common scenarios


a. Known cancer patient with multiple bone lesions—Does not necessarily require confirmatory biopsy.


b. Known cancer patient with bone pain and normal radiographs—May be symptomatic from chemotherapy/bisphosphonates or may require bone scan or MRI to define an early destructive lesion.


c. Patient without history of cancer with a destructive bone lesion—Must differentiate between metastatic disease and primary malignant bone tumor.


C. Radiographic appearance/workup


1. Appearance


a. Osteolytic (most occurrences): lung, thyroid, kidney, gastrointestinal (Figure 1, A)


b. Osteoblastic: prostate, bladder (Figure 1, B)


c. Mixed osteolytic/osteoblastic: breast


d. Most common locations include spine (40%), pelvis, proximal long bones, and ribs.


e. The thoracic spine is the most common vertebral location of metastasis.


f. Metastatic carcinoma to the spine spares the intervertebral disk.


g. Lesions distal to the elbow/knee are most commonly from the lung as a primary site.


h. Pathologic fracture is a common presentation (25%).


i. An avulsion of the lesser trochanter implies a pathologic process in the femoral neck with impending fracture.


2. Workup (Table 1)


a. Plain radiographs—Images in two planes and of the entire bone should be obtained (consider referred pain).


b. Differential diagnosis of lytic bone lesion in patient older than 40 years includes metastatic disease, multiple myeloma, lymphoma, and, less likely, primary bone tumors, Paget sarcoma, and hyperparathyroidism (

Table 2).


c. Bone scan


i. Detects osteoblastic activity (may be negative in myeloma, metastatic renal cancer)


ii. Identifies multiple lesions, which are common in metastatic disease (

Figure 2, A)


d. CT scan of chest, abdomen, pelvis to identify primary lesion


e. Staging evaluation of lytic bone lesion will identify primary site in 85% of patients (Table 1).


[Table 2. Differential Diagnosis of Destructive Bone Lesion in Patient Older Than 40 Years*]

f. Bone marrow biopsy when considering myeloma as a diagnosis


g. MRI scan of the primary lesion is generally not necessary unless defining disease in the spine (Figure 2, B).


h. Difficult to differentiate osteoporosis from metastatic disease with a single vertebral compression fracture; tumor is suggested by soft-tissue mass and pedicle destruction.


D. Biopsy/pathology


1. A biopsy of a destructive bone lesion must be performed unless the diagnosis is certain.


2. Placing an intramedullary device in a 65-year-old patient with lytic lesions in the femur without appropriate workup is dangerous (could be a dedifferentiated chondrosarcoma).


3. An open incisional biopsy or closed needle biopsy (fine needle aspiration/core) can be performed for diagnosis.


4. Histologic appearance is islands of epithelial cells with glandular or squamous differentiation (

Figure 3, A and B).


5. The carcinoma cells have tight junctions and reside within a fibrous stroma.


6. Thyroid (follicular): follicles filled with colloid material (Figure 3, C)


7. Renal cancer often has a clear appearance to the cytoplasm within the epithelial cells (Figure 3, D); in some cases, it may be poorly differentiated and may have a sarcomatoid pattern.


8. Epithelial cells are keratin-positive.


9. Special immunohistochemistry stains can sometimes determine the primary site of disease.


[Figure 2. Metastases seen on a total body bone scan and MRI. A, This total body bone scan shows increased uptake in the sacroiliac region but also identifies metastases in the anterior pelvis, ribs, and shoulder girdle. B, MRI is not used routinely to evaluate extremity bone metastases, but it is helpful in defining vertebral lesions, as in this thoracic spine.]

a. Thyroid transcription factor-1: lung, thyroid


b. Estrogen receptor/progesterone receptor: breast


c. PSA: prostate

II. Pathophysiology/Molecular Mechanisms

A. Metastatic cascade


1. Primary tumor cells proliferate and stimulate angiogenesis.


2. Tumor cells cross the basement membrane into capillaries and must avoid host defenses.


3. Tumor cells disseminate to distant sites.


4. Cells arrest in distant capillary bed, adhere to vascular endothelium, and extravasate into end-organ environment (integrins, cadherins, matrix metalloproteinases).


5. Tumor cells interact with local host cells and growth factors (TGF-β, insulin-like growth factor, fibroblast growth factor, bone morphogenetic protein).


6. Tumor cells proliferate to become a site of metastasis.


B. RANKL/osteoprotegerin


1. Tumor cells do not destroy bone; cytokines from the tumor stimulate osteoclasts or osteoblasts to destroy or generate new bone, respectively.


[Figure 3. Histologic examples of bone metastasis from the most common primary lesions. A, Prostate—note the new bone formation by the osteoblasts that are stimulated by factors secreted by the tumor cells. B, Lung—note the clumps of epithelial cells characterized by tight cell-cell junctions. C, Thyroid (follicular)—the epithelial cells are forming follicles surrounding a central colloid substance. D, Renal—the epithelial tumor cells are characterized by clear cytoplasm.]

2. Osteoblasts/stromal cells secrete receptor activator of nuclear factor κ B ligand (RANKL).


3. Osteoclasts have receptors for RANKL (RANK).


4. Increased secretion of RANKL by osteoblasts causes an increase in osteoclast precursors, which eventually results in increased bone destruction.


5. Osteoprotegerin (OPG) is a decoy receptor that binds to RANKL and inhibits an increase in osteoclasts.


C. Vicious cycle in breast cancer


1. TGF-β is stored in the bone and released during normal bone turnover.


2. TGF-β stimulates metastatic breast cancer cells to secrete PTHrP.


3. PTHrP from cancer cells stimulates osteoblasts to secrete RANKL.


4. RANKL from osteoblasts stimulates osteoclast precursors and increases osteoclasts.


5. Osteoclasts destroy bone and release TGF-β, so the cycle of destruction repeats.


D. Other disease-specific factors


1. Breast cancer cells also secrete osteoclastic stimulants (interleukin [IL]-6, IL-8).


2. Prostate cancer—Endothelin-1 stimulates osteoblasts to produce bone.


3. Overexpression of epidermal growth factor receptor is common in renal cell carcinoma.


E. Fracture healing in pathologic bone


1. Likelihood of pathologic fracture healing: multiple myeloma > renal carcinoma > breast carcinoma > lung carcinoma (ie, pathologic fracture healing is most likely in patients with myeloma and least likely in patients with metastatic lung cancer)


2. Most important factor in determining healing potential is the length of patient survival.


F. Other physiologic disruptions


1. Calcium metabolism—Hypercalcemia is present in 10% to 15% of cases.


a. Common with lung, breast cancer metastasis


b. Does not correlate with number of bone metastases


c. Early symptoms: polyuria/polydipsia, anorexia, weakness, easy fatigability


d. Late symptoms: irritability, depression, coma, profound weakness, nausea/vomiting, pruritus, vision abnormalities


e. Treatment requires hydration and possibly intravenous bisphosphonate therapy.


2. Hematopoiesis—Normocytic/normochromic anemia is common with breast, prostate, lung, and thyroid cancer metastasis.


3. Thromboembolic disease


a. Patients with malignancy have increased thrombotic risk.


b. Require prophylaxis, especially after lower extremity/pelvic surgery


4. Pain control/bowel abnormalities


a. Use narcotics for pain control.


b. Requires laxatives/stool softener to avoid severe constipation

III. Biomechanics

A. Stress riser in bone occurs whenever there is cortical destruction.


B. Defects


1. Open section defect—When the length of a longitudinal defect in a bone exceeds 75% of diameter, there is a 90% reduction in torsional strength.


2. 50% cortical defect (centered) = 60% bending strength reduction.


3. 50% cortical defect (eccentric) = >90% bending strength reduction.

IV. Impending Fractures/Prophylactic Fixation

A. Indications for fixation


1. Snell/Beals criteria


a. 2.5-cm lytic bone lesion


b. 50% cortical involvement


c. Pain persisting after radiation


d. Peritrochanteric lesion


2. Mirels scoring system (

Table 3)


a. Four factors are scored: radiographic appearance, size (proportion of bone diameter occupied by the lesion), site, and pain.


b. Prophylactic fixation is recommended for a score ≥9 (33% fracture risk).


3. Spinal lesions—impending fracture/collapse






Risk of fracture/collapse exists when 50% to 60% of the vertebral body is involved (without other abnormalities).



Risk of fracture/collapse exists when only 20% to 30% of the vertebral body is involved if there is also costovertebral joint involvement.





Risk of fracture/collapse exists when 35% to 40% of the vertebral body is involved (without other abnormalities).


[Table 3. Mirels Scoring System for Prediction of Pathologic Fracture in Patients With Metastatic Bone Lesions]



Risk of fracture/collapse exists when 25% of vertebral body is involved if there is also pedicle/posterior element involvement.


B. Other factors to consider


1. Scoring systems are not exact and cannot predict all human factors.


2. Histology of primary lesion


3. Expected lifespan, comorbid conditions, and activity level


4. Most surgical decisions can be based on plain radiographs.


5. Prophylactic fixation compared with fixation of actual pathologic fracture


a. Decreased perioperative morbidity/pain


b. Shorter operating room time


c. Faster recovery/shorter hospital stay


d. Ability to coordinate care with medical oncology

V. Nonsurgical Treatment

A. Indications


1. Nondisplaced fractures


2. Non-weight-bearing bones (

Figure 4)


3. Poor medical health/shortened lifespan


B. Observation/pain management/bracing


1. Observation or activity modifications are used for patients with very small lesions or advanced disease.


2. Functional bracing can be used in the upper and lower extremities and spine.


3. Pain management is important in all symptomatic patients.


a. Opioids: fentanyl, oxycodone, hydrocodone


b. Nonopioids: nonsteroidal anti-inflammatory drugs, trycyclic antidepressants, muscle relaxants, steroids


c. A bowel program is necessary to prevent severe constipation.


C. Medical


1. Chemotherapy/hormonal treatment (prostate, breast metastasis)


2. Bisphosphonates


a. Inhibit osteoclast activity by inducing apoptosis


[Figure 4. Radiograph of the left humerus of a 59-year-old woman with metastatic thyroid cancer that caused a pathologic fracture. She was not a safe surgical candidate and was therefore treated nonsurgically. Note the callus formation about the fracture site.]

b. Inhibit protein prenylation and act on the mevalonate pathway


c. Significant decrease in skeletal events (breast, prostate, lung)


d. Reduced pain


e. Used in virtually all cases of metastatic bone disease: 4 mg zoledronic acid administered intravenously every month


f. Complication: small incidence of osteonecrosis of the jaw


D. Radiation


1. External beam radiation


a. Indications: pain, impending fracture, neurologic symptoms


b. Dose: usually 30 Gy in 10 fractions to bone lesion


c. Pain relief in 70% of patients


d. Postoperatively, the entire implant should be irradiated after 2 weeks to decrease fixation failure and improve local control.



Figure 5. AP (A) and lateral (B) radiographs of the spine of a woman with metastatic lung cancer to the thoracic vertebra, causing painful collapse. The patient was treated with vertebroplasty, with marked pain relief.]

e. Should be used for patients with radiosensitive tumors of the spine who have pain or tumor progression without instability or myelopathy


2. Radiopharmaceuticals


a. Samarium Sm-153 or strontium chloride 89


b. Delivery of radiation to the entire skeleton (bone scan concept)


c. Palliation of pain—may delay progression of lesions


d. Use requires normal renal function and blood counts.


e. Iodine-131 is used to treat metastatic thyroid cancer.


E. Minimally invasive techniques


1. Radiofrequency ablation—Used for palliative pain control (commonly used in pelvis/acetabulum).


2. Kyphoplasty/vertebroplasty (Figure 5)


a. Pain relief in patients with vertebral compression fractures from metastasis


b. The risk of cement leakage in vertebroplasty (35% to 65%) is usually not clinically relevant.

VI. Surgical Treatment/Outcome

A. Overview


1. Goals of surgical treatment


a. Relieve pain


b. Improve function


c. Restore skeletal stability


2. Considerations prior to surgery


a. Patient selection (functional status, activity level, comorbidities)


b. Stability/durability of planned construct (withstand force of 6× body weight around hip)


c. Addressing all areas of weakened bone


d. Preoperative embolization for highly vascular lesions (renal, thyroid metastasis)


e. Extensive use of methylmethacrylate (cement) to improve stability of construct


f. Standard of care in patients with bone metastasis is cemented joint prostheses, not uncemented prostheses


B. Upper extremity


1. Overview



Figure 6. Radiographs of the upper extremity of a 67-year-old right-handed man with metastatic renal carcinoma that caused pain at rest and with activity. A, AP radiograph shows the osteolytic lesion in the right proximal humerus. B, Postoperative radiograph after placement of a locked right humeral intramedullary rod. This lesion was curetted and cemented during the surgery and received radiation after 2 weeks.]


Figure 7. Radiographs of the distal humerus of a 56-year-old woman with metastatic endometrial cancer. A, AP view demonstrates the permeative appearance of the lesion. The patient had persistent pain after radiation of the metastasis. B, Postoperative radiograph after curettage, cementation, and double plating of the lesion.]


Figure 8. CT scan of the pelvis of a 47-year-old man with metastatic thyroid cancer defines a large, destructive lesion in the left sacroiliac region.]

a. Upper extremity metastases affect activities of daily living, use of external aids, bed-to-chair transfers.


b. Much less common (20%) than lower extremity metastases


2. Scapula/clavicle—usually nonsurgical treatment/radiation


3. Proximal humerus


a. Resection and proximal humeral replacement (megaprosthesis); excellent pain relief but poor shoulder function


b. Intramedullary locked device (closed versus open with curettage/cement) (Figure 6)


4. Humeral diaphysis


a. Intramedullary fixation: closed versus open with curettage/cement


b. Intercalary metal spacer: selected indications for extensive diaphyseal destruction or failed prior device


5. Distal humerus


a. Flexible nails should be supplemented with cement and extend the entire length of bone (insert at elbow).


b. Orthogonal plating—Combine with curettage/cement (Figure 7).


c. Resection and modular distal humeral prosthetic reconstruction


6. Distal to elbow—Individualize treatment with plates or intramedullary devices.


C. Lower extremity


1. Overview


a. Common location for bone metastasis



Figure 9. Imaging studies in patients with metastatic disease to the acetabulum. A, AP radiograph of the right pelvis in a 71-year-old man with metastatic renal cell carcinoma to the right acetabulum and ischium. The acetabular disease is not well defined on plain radiographs. B, CT scan of the right acetabulum defines the destruction of the posterior acetabulum, placing the patient at risk for a displaced fracture. Acetabular reconstruction would require a reinforced ring or cage device to prevent protrusion with disease progression. C, AP view of the pelvis in a 59-year-old woman with widely metastatic thyroid cancer and with multiple comorbidities shows destruction of the left acetabulum. Nonsurgical treatment with immobilization in a wheelchair or a Girdlestone procedure for pain relief would be reasonable options.]


Figure 10. Metastases to the femoral neck. A, AP radiograph of the left hip in a 70-year-old woman with metastatic breast cancer reveals a pathologic femoral neck fracture. No other lesions were noted throughout the femur. B, Radiograph obtained after a cemented bipolar hip reconstruction. Most patients with femoral neck disease do not require acetabular components. Internal fixation of a pathologic hip fracture is not indicated. C, Radiograph of a hip after implantation of a long-stemmed femoral component, which can be used to prevent pathologic fractures in the femoral diaphysis. Patients with long-stemmed prostheses have a higher risk of cardiopulmonary complications due to intraoperative/postoperative thromboembolic events.]

b. Surgical treatment if patient has ≥3 months to live


2. Pelvis (Figure 8)


a. Treat non-weight-bearing areas with radiation or minimally invasive techniques.


b. Resection or curettage in selected cases


3. Acetabulum (Figure 9, A and B)


a. Surgical treatment requires extensive preoperative planning (cross-sectional imaging, embolization for vascular lesions).


b. Extent of bone destruction delineates treatment options (standard total hip arthroplasty, acetabular mesh/cage, rebar reconstruction to transmit stresses from acetabulum to unaffected ilium/sacrum).


c. Girdlestone procedure is appropriate in patients with end-stage disease and severe pain (Figure 9, C).



Figure 11. Intertrochanteric lesions. A, Radiograph of the hip of a patient with metastatic thyroid cancer. A lesser trochanter avulsion or osteolytic lesion indicates a pathologic process in the older patient.B, The patient was treated prophylactically with a locked femoral reconstruction nail.]


Figure 12. Radiograph of the right femur of a 60-year-old woman demonstrates a pathologic fracture. A staging workup did not reveal a primary site of disease, but a biopsy of the femoral lesion showed carcinoma. The patient should be treated with a femoral reconstruction nail.]


Figure 13. Radiographs of the right femur of a 78-year-old woman with metastatic endometrial cancer. A, AP view reveals multiple osteolytic lesions. The lesion in the greater trochanter placed her at increased risk for pathologic fracture. Postoperative radiographs of the proximal (B) and distal (C) femur show stabilization of the entire femur with an intramedullary reconstruction nail.]

4. Femoral neck (Figure 10)


a. Pathologic fractures or impending fractures require prosthetic reconstruction.


b. Internal fixation with cement has an unacceptably high failure rate because of the likelihood of disease progression.


c. Usually a bipolar cup is satisfactory; a total hip arthroplasty should be performed only if the acetabulum is involved with metastatic disease or the patient has extensive degenerative joint disease.


5. Intertrochanteric (Figure 11)


a. The intramedullary reconstruction nail (open versus closed) protects the entire femur.


b. Calcar-replacement prosthesis for lesions with extensive bone destruction


c. Rare utilization of dynamic hip screw plate/screws/cement in patients with extremely short lifespan


6. Subtrochanteric


a. Intramedullary locked reconstruction nail


b. Resection and prosthetic replacement (megaprosthesis)


i. Patients with periarticular bone destruction that does not allow rigid fixation


ii. Displaced pathologic fracture through osteolytic lesion


iii. Radio-resistant lesion (large renal cell metastasis)


iv. Solitary lesion (some series indicate improved survival for resection of solitary metastasis from renal carcinoma)


v. Salvage of failed fixation devices (Figure 12)


7. Femoral diaphysis: intramedullary locked reconstruction nail (Figures 13 and



[Figure 14. Imaging of a 49-year-old man with metastatic renal cell carcinoma and painful progression of disease after placement of an intramedullary reconstruction nail in the right femur. A, Lateral radiograph demonstrates the loss of anterior cortex proximally. B, Prior to salvage of the impending hardware failure, embolization of the feeding vessels is performed. This should be done routinely for patients with metastatic renal carcinoma unless a tourniquet can be used for surgery. C, Radiograph obtained after the proximal femur was resected and the defect reconstructed with a cemented megaprosthesis using a bipolar acetabular component.]

8. Distal femur


a. Locking plate/screws/cement


b. Retrograde intramedullary device


c. Resection and distal femoral replacement


9. Distal to knee


a. Individualize treatment with prostheses, intramedullary devices, plates/screws/cement. (

Figure 15)


b. Avoid amputation if possible.


D. Spine


1. Risk factors for progressive neurologic deficit


a. Osteolytic lesions


b. Pedicle involvement


c. Posterior wall involvement


2. Indications for surgical treatment


a. Significant or progressive neurologic deficit


b. Intractable pain


c. Progression of deformity


3. Surgical options


a. Anterior vertebrectomy


b. Posterior decompression/instrumentation


c. Anterior/posterior combination approach (

Figure 16)


[Figure 15. Radiographs of the right knee of a 67-year-old woman with metastatic breast cancer to the tibia. A, Lateral radiograph demonstrates the destruction of the tibia with concomitant severe osteopenia. This extends throughout the length of the bone. B, Lateral radiograph obtained after 18 months reveals a locked intramedullary tibial rod in good position. With postoperative radiation, bisphosphonates, and hormonal treatment, the bone quality greatly improved.]

[Figure 16. Images of the spine of a 57-year-old woman with metastatic thyroid cancer. A, A CT sagittal reconstruction of the thoracolumbar spine demonstrates complete destruction and collapse of L1, with severe central canal obstruction at this level. Note also the extensive disease at L4 and S2. B, Axial CT image at L4 demonstrates the canal compromise at this level and the extent of the soft-tissue mass. AP (C) and lateral (D) radiographs obtained after L1 corpectomy, partial L4 corpectomy, and posterior thoracic-lumbar-pelvic fixation with pedicle screws, rods, and a transiliac bar. A distractible cage is shown at L1.]

Top Testing Facts

1. The most common primary sites that metastasize to bone are breast, prostate, lung, renal, and thyroid.


2. Careful history, physical examination, and radiographic staging will identify 85% of primary lesions; biopsy is needed when the primary lesion has not been identified.


3. The most common diagnosis of a lytic, destructive lesion in a patient older than age 40 years is bone metastasis.


4. The histology of metastatic bone disease is epithelial cells in a fibrous stroma.


5. Breast carcinoma cells secrete PTHrP, which signals osteoblasts to release RANKL, which causes osteoclast activation and bone resorption.


6. Osteolytic lesions have a greater likelihood of pathologic fracture than osteoblastic lesions.


7. Bisphosphonates cause osteoclast apoptosis by inhibiting protein prenylation and act via the mevalonate pathway.


8. External beam radiation is helpful for pain control and important in maintaining local control postoperatively.


9. Pathologic femoral neck lesions require prosthetic replacement, not for situ fixation.


10. Locked intramedullary fixation is used for diaphyseal impending or actual fractures (femoral rods must extend into the femoral neck).


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