Metastases to bone marrow are discussed in Chapter 34, Section I.A in “Cytopenia.”

A. Pathogenesis. The bones most frequently involved with metastases are the femur, pelvis, spine, and ribs. Tumor cells may metastasize to vertebral bodies or the skull without entering the systemic circulation by seeding through Batson vertebral venous plexus (a valveless system of veins along the entire vertebral column that communicates with other venous systems, from the pelvis to the brain).

1. Mechanisms. Osteoclast-mediated destruction and direct tumor cell-mediated destruction are the two mechanisms by which skeletal metastases destroy bone. Stimulation or inhibition of osteoblastic activity also occurs. The relative balance of osteoclastic and osteoblastic activity determines whether a lesion is osteolytic or osteoblastic. Malignant cells secrete many factors known to both stimulate the proliferation and activity of osteoclasts and produce osteolysis, possibly indirectly through the osteoblasts. These factors include the following:

a. Transforming and fibroblastic growth factors; tumor necrosis factors

b. Prostaglandins; interleukin-1 (IL-1), IL-6, and IL-11

c. Parathyroid hormone-related protein

d. Bone morphogenic proteins

e. Matrix-degrading proteins, such as specific metalloproteinases

f. Receptor activator of nuclear factor kappa B ligand (RANKL), the essential osteoclast differentiation factor (discussed in Chapter 22, Section II.D.3.a)

g. Chemokines and chemokine receptors

h. Osteoblast inhibitory proteins: Dickkopf-1 and secreted frizzled protein 2

2. Frequency. A relatively small number of different malignancies account for most tumors that spread to bone.

a. Tumors that commonly metastasize to bone. Carcinomas of unknown primary site, lung, breast, kidney, prostate, and thyroid; plasmacytoma; melanoma; and occasionally Ewing sarcoma

b. Tumors that rarely metastasize to bone. Ovarian carcinoma and most soft tissue sarcomas

c. Certain carcinomas have a predilection for metastasizing to particular skeletal sites. For example, skeletal metastases to the hands are unusual, but about 50% of these metastases arise from a lung primary. Renal cell carcinomas often metastasize to the bones of the shoulder girdle.

3. Types of bone metastases and their occurrence in various tumors are shown in Table 33.1.

a. Osteolytic lesions are characterized by specific radiolucent areas: myeloma and commonly in renal cell and breast carcinomas.

b. Osteoblastic lesions are characterized by radiopaque areas: commonly in prostate cancer.

c. Mixed lesions: commonly in breast carcinoma and most tumors

B. Natural history. Bone metastases are usually confined within the bony substance and generally do not cross joint spaces. They lead to pain, pathologic fracture, neurologic compromise, and progressive immobility. Crippling bone disease can make bedridden patients susceptible to decubitus ulcers, hypercalcemia, and infections.

1. Cervical spine metastases compressing the cord may result in myelopathy and weakness of the muscles of respiration, resulting in paralysis, pneumonia, and possibly death. Thoracic spine metastases compressing the cord can result in paraplegia.

2. Dense osteoblastic metastases (e.g., with prostate cancer) or extensive involvement of bone marrow spaces can result in refractory pancytopenia. Pathologic fracture is less likely in the osteoblastic variant of metastatic prostate cancer.

C. Prognosis. The expected survival of patients with skeletal metastasis varies. Patients with lung cancer may only survive a few months. The median survival of patients with breast cancer and only skeletal metastases, however, is 2 years. The median survival time of patients with stage IV renal cancer is 11 months, but 20% to 30% of those with a solitary metastasis survive 5 years after the lesion is surgically resected. About 20% of patients with skeletal metastases from prostate cancer survive 5 years.

a. Dull, aching, or boring pain that is worse at night than with physical activity is characteristic of pain from bone metastases. This pain pattern also occurs with malignant invasion of retroperitoneal structures without bony involvement. As disease progresses, weight-bearing pain becomes more prominent. These characteristics are directly opposite to the typical pain of degenerative diseases, in which pain related to activity is present earlier and worse than pain at rest.

b. Bone pain intensified by activity is often the first symptom of imminent fracture. On the other hand, pathologic fractures, particularly in non-weight-bearing bones, can also be painless. Patients often report falling down, but it is often not clear whether the fracture was the cause or the effect of the fall.

c. Spinal instability secondary to bone loss can cause excruciating pain, which is mechanical in origin. The patient is comfortable only when lying absolutely still.

d. C-7 to T-1 vertebral pain is usually referred to the interscapular region; radiography of both cervical and thoracic spines is essential in these patients.

e. T-12 to L-1 vertebral pain is usually referred to the iliac crest or sacroiliac joint.

f. Sacral pain is usually referred to the buttocks, perineum, and posterior thighs. The pain typically is exacerbated by sitting or lying down and relieved by standing.

2. Serum alkaline phosphatase levels are usually elevated in patients with bone metastases. Elevations appear to reflect an osteoblastic (or healing) response to tumor destruction. In pure osteolytic tumors, such as plasma cell myeloma, the serum alkaline phosphatase level is normal.

a. Nonneoplastic causes of increased bone alkaline phosphatase include primary hyperparathyroidism, thyrotoxicosis, acromegaly, renal disease, Paget disease, osteomalacia, and healing fractures.

b. Physiologic increases occur in the pediatric age group (before bony epiphyseal closure) and pregnancy (placental source).

3. Radionuclide bone scan, using ^99mTc-methylene bisphosphonate, is the most effective screening test for skeletal metastases. The scan often detects metastases several months before radiologic changes are evident. Radionuclide bone scans reflect osteoblastic activity; thus, purely osteolytic lesions with a preponderance of osteoclastic activity, such as in patients with myeloma, may not be apparent on a bone scan.

a. Specificity. Patients with a known cancer and bone pain have positive bone scans in 60% to 70% of cases; patients without bone pain have positive scans in 10% to 15% of cases. Multiple “hot spots” are more specific than one or two.

(1) Retroperitoneal tumors often cause a bony response, characterized by diffuse isotope uptake over the anterior aspect of the spine.

(2) Patients with metastases from breast or prostate cancer, when clinically responding to endocrine therapy, may develop new abnormal areas on scans because of bone healing and increased osteoblastic activity.

(3) Multiple myeloma, a predominantly osteolytic process except in the presence of pathologic fracture, is the most frequent cause of falsenegative bone scans. These patients often have negative bone scans except in areas with fractures.

(4) Decreased uptake of radioisotope is seen in irradiated bone that never did contain metastases and thus cannot be interpreted as a sign of absence of metastases or of reduced tumor burden.

(1) Bone healing after fracture

(2) Radiation osteitis

(3) Arthritis and spondylitis

(4) Osteomyelitis

(5) Osteonecrosis

(6) Regional osteoporosis

(7) Paget disease of bone

(8) Hyperostosis frontalis interna

(9) Osteopetrosis (Albers-Schönberg disease)

(10) Osteogenesis imperfecta

4. Plain radiographs remain essential for the diagnosis and characterization of bone metastases. Metastatic lesions must involve 30% to 50% of bone matrix to be visualized on plain radiographs. Diffuse osteoporosis may be the only radiologic abnormality in some patients with extensive bony involvement (e.g., multiple myeloma). Skeletal infections with pyogenic bacteria are frequently associated with sclerotic reactions; chronic granulomatous infections, however, may result in purely osteolytic lesions. Other causes of osteoblastic reactions are shown in Table 33.1.

a. Indications. Radiographs should be obtained and compared with previous films of the involved areas in patients with bone pain, abnormalities on physical examination suggestive of fracture, or asymptomatic abnormalities in bone scans.

b. Routine complete skeletal surveys are not indicated except in patients with plasma cell myeloma, which may be associated with painless osteolytic lesions in crucial bone sites, such as the femora or cervical spine.

c. Vertebral involvement from metastatic cancer is manifested by loss of the pedicles or lateral spinous processes and vertebral collapse with sparing of the intervertebral space. Infections that involve the intervertebral disk space destroy it. Some chronic infections (e.g., tuberculosis or bru cellosis), however, may involve the vertebrae and not the intervertebral spaces, result in vertebral collapse, and thereby mimic malignancy.

d. Postirradiation osteitis produces irregular, diffuse (rather than localized) osteolytic or mixed lesions confined to the radiation portal.

5. Positron Emission Tomography (PET) using ¹⁸F-deoxyglucose has become a standard tool in treatment planning for many cancers. PET scans cannot provide as detailed anatomic information as standard radionuclide bone scans, but this limitation can be overcome by performing a combined PET/CT scan. PET scans have greater specificity for detecting skeletal metastases, but radionuclide bone scans retain improved sensitivity and are much less expensive than PET scans. Thus, while useful information about skeletal metastases can be obtained from PET scans used to follow the course of a primary tumor, their use to diagnose skeletal metastases remains experimental.

6. CT scans are useful to diagnose early metastases of bone, particularly the spine, when hot spots are detected on the radionuclide scan but corresponding plain radiographs are normal. CT scans elucidate cortical erosion, subtle fractures, and matrix calcification or ossification. In addition, they are useful to evaluate epidural compression, the extent of metastases (e.g., in the femur), and areas difficult to image by conventional radiographs (e.g., costovertebral junction, sternum, and sacrum).

7. MRI scanning is best at delineating the extraosseous extension of a soft tissue mass through the bone cortex (e.g., epidural compression). This technique is also ideal for demonstrating the intraosseous extension of tumor into the cancellous bone. MRI may also be used to reveal subtle insufficiency or pathologic fractures about the hip and pelvis or to evaluate specific sites associated with pain.

8. Biopsy. If a fracture has already occurred, care must be taken to sample the tumorous area adequately rather than the healing area of fibrous tissue and osteoid formation. Specific expertise in bone histopathology must be available. If only a single bone is involved, the biopsy must be approached as if the lesion were resectable for cure. Potentially curable lesions include a solitary renal cell metastasis and sarcoma.

a. Indications. If other sites associated with a lower risk for morbidity are not available, bone biopsy for the differential diagnosis of cancer is indicated in patients with the following conditions:

(1) An isolated bone lesion that the radiologist interprets as being compatible with a primary bone tumor

(2) An osteolytic bone lesion in a crucial area (e.g., cervical spine or femoral neck) and no history of cancer

(3) A history of a cancer that metastasizes to bone, localized bone pain, normal radiographs of the area, equivocal bone scan and alkaline phosphatase results, and no evidence of disease elsewhere

(4) Isolated bone pain in a region that was previously irradiated and radiographic findings that are not typical of postirradiation osteitis

b. Contraindications. Bone biopsy should not be done in asymptomatic patients known to have cancer but with isolated, osteolytic lesions in noncrucial areas that are suspected to be benign lesions or metastatic disease. Biopsy in these patients often results in chronic pain at the biopsy site. If a cancer is discovered, it is a metastasis for which treatment could have awaited the development of symptomatic disease.

E. Medical management is necessary in patients with multiple painful metastatic sites.

1. Chemotherapy and endocrine therapy are useful for treating metastatic tumors known to respond to these modalities. Chemotherapy doses may need to be attenuated because of compromised marrow function from neoplastic invasion or irradiation.

2. Bisphosphonates. Pyrophosphonates are natural compounds that are potent inhibitors of osteoclast-mediated bone resorption and contain two phosphonate groups bound to a common oxygen. Bisphosphonates (such as pamidronate or clodronate) are analogs of the endogenous pyrophosphonate with a carbon replacing the oxygen atom. The wide variety of alternative carbon substitutions results in marked differences in antiresorptive properties and side effects. Bisphosphonates have become the standard treatment for tumorinduced hypercalcemia (see Chapter 27, Section I), have been successfully used in the treatment of conditions characterized by increased osteoclast-mediated bone resorption (such as Paget disease of bone or osteoporosis), and are a valuable form of therapy for bone metastases.

These drugs are poorly absorbed and often poorly tolerated when administered orally. They are highly concentrated in bone and become biologically inactive once the drug becomes a part of bone that is not remodeling. As a result, continued administration of bisphosphonates is required to achieve the desired lasting inhibition of bone resorption.

a. Intravenous bisphosphonates. Zoledronic acid (Zometa, 4 mg IV over 15 minutes) or pamidronate (Aredia, 90 mg IV over 2 hours) every 3 to 4 weeks as a supplement to antitumor therapy substantially reduces morbidity and subsequent skeletal events for patients with myeloma and metastatic bone disease. Although both pamidronate and zoledronic acid have shown efficacy for patients with osteolytic bone disease caused by breast cancer or myeloma, only zoledronic acid has reduced skeletal events among patients with other cancers, regardless of whether the disease results from osteolytic, osteoblastic, or mixed metastatic bone lesions. Pain is improved in about half of the patients given pamidronate even without anticancer treatments. Oral clodronate is also helpful but is less effective than the intravenous forms.

It has become increasingly recognized that many different cancer treatments may induce bone loss and increase the risk of fracture. Glucocorticosteroids lead to enhanced loss of bone and induce fractures. Gonadal ablation with drugs such as GnRH agonists or aromatase inhibitors also has been shown to increase bone loss and heighten the risk of fracture. Several studies have shown the ability of IV bisphosphonates administered less frequently to prevent bone loss and actually increase bone density and, in some cases, reduce fracture risk among cancer patients receiving therapies that induce bone loss. However, more studies are needed to establish the long-term safety and efficacy of this approach for this at-risk cancer population.

Bisphosphonates may also have an antitumor effect. Some randomized trials have shown a reduction in both skeletal and visceral metastases in patients with myeloma or breast cancer. Recent studies show an overall survival advantage among previously untreated myeloma patients receiving zoledronic acid compared to oral clodronate.

b. Adverse effects of bisphosphonates. It is important to recognize that these agents occasionally are associated with side effects, including renal dysfunction and osteonecrosis of the jaw (ONJ).

(1) Renal dysfunction. The type of renal lesion is different between the two bisphosphonates. Pamidronate more often will cause a glomerular lesion initially associated with proteinuria, which may be at nephrotic syndrome levels. By contrast, zoledronic acid more often causes tubular dysfunction and thus is not often associated with albuminuria. Most reports of renal insufficiency during bisphosphonate therapy have involved patients with multiple myeloma.

The nephrotoxicity is both dose- and infusion time dependent. After the bisphosphonate is temporarily discontinued and renal function returns to baseline, the drug may be cautiously reinstituted using longer infusion times (e.g., 30 to 60 minutes for zoledronic acid).

(2) Hypocalcemia. Most patients receiving high-potency bisphosphonates do not become hypocalcemic because of compensatory mechanisms, most importantly, increased secretion of parathyroid hormone. Hypomagnesemia and/or reduced creatinine clearance frequently are simultaneous factors. Thus, serum creatinine, magnesium, calcium, and phosphate should be monitored during bisphosphonate therapy.

(3) Osteonecrosis of the jaw (ONJ) is defined as the presence of exposed bone in the maxillofacial region that does not heal within 8 weeks of treatment. IV bisphosphonates are associated with an increased risk of ONJ (3% to 8% of patients). The concomitant use of angiogenesis inhibitors (e.g., bevacizumab, sunitinib) may be additive risk factors for the development of ONJ in patients receiving bisphosphonates.