Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section F – Local Effects of Cancer and Its Metastasis

Chapter 57 – Bone Metastases

Robert E. Coleman,Ingunn Holen

SUMMARY OF KEY POINTS

Incidence

  

   

A major cause of (often prolonged) morbidity in cancer

  

   

Especially prevalent in breast and prostatic cancer

Causes

  

   

Osteolytic damage is mediated largely by stimulation of osteoclasts via tumor-derived cytokines; intermediary cells, including immune cells and osteoblasts, are involved.

  

   

The vertebral-venous system of vessels is a significant anatomic pathway for metastatic spread to the skeleton.

Diagnosis

  

   

Differential diagnosis includes osteoporosis, degenerative disease, and Paget's disease.

  

   

The isotope bone scan is a sensitive test to detect the presence of skeletal pathology but gives little information about its nature.

  

   

Structural information on skeletal damage from metastatic bone disease is best obtained by skeletal radiography supplemented by computerized tomography or magnetic resonance imaging.

Evaluation of the Patient

  

   

An assessment of patients’ symptoms and activity status is essential.

  

   

Skeletal radiography assesses response to treatment, but the information is delayed and the method insensitive.

  

   

Early indications of response of bone metastases to treatment can be obtained by monitoring biochemical markers, including the bone isoenzyme of alkaline phosphatase, osteocalcin, and pyridinium cross-linking amino acids.

  

   

Isotopic bone scanning is not useful in monitoring response to treatment.

Treatment

  

   

Antitumor treatments, such as radiation therapy, endocrine therapy, cytotoxic chemotherapy, targeted biologic agents, and radioisotope therapy have a role in the multidisciplinary palliative treatment of metastatic bone disease.

  

   

The bisphosphonates are inhibitors of osteoclast activity and have become important agents for the treatment of metastatic bone disease, because they relieve symptoms, allow bone healing, and delay complications.

Complications

  

   

Complications include pain, impaired mobility, pathologic fracture, spinal cord compression, cranial nerve palsies, nerve root lesions, hypercalcemia, and suppression of bone marrow function.

  

   

Bisphosphonates in combination with intravenous rehydration constitute the treatment of choice for hypercalcemia.

  

   

Orthopedic surgery has an important role in the treatment and prophylaxis of pathologic fractures and spinal decompression and stabilization in the relief of spinal cord compression.

INCIDENCE

Primary Tumors Leading to Bone Metastases

Primary bone cancer occurs predominantly among children and adolescents and is rare. By contrast, secondary bone cancer—particularly from carcinomas of the breast, lung, prostate, kidney, and thyroid—is common. The incidence of bone metastases from different primary sites recorded in postmortem studies is summarized in Table 57-1 . Although the variability in these metastatic patterns is probably related to molecular and cellular biologic characteristics of both the tumor cells and those of the tissues to which they metastasize, other factors, such as vascular pathways and blood flow, are also important.[1]


Table 57-1   -- Incidence of Skeletal Metastases from Autopsy Studies

 

 

INCIDENCE (%) OF BONE METASTASES

Primary Tumor

No. of Studies

Median

Range

Breast

5

73

47–85

Prostate

6

68

33–85

Thyroid

4

42

28–60

Kidney

3

35

33–40

Bronchus

4

36

30–55

Esophagus

3

6

5–7

Gastrointestinal tract

4

5

3–11

Rectum

3

11

8–13

Modified from Coleman RE: Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006;12(Suppl): 6243–6249.

 

 

 

Given the high prevalence of carcinomas of the breast, bronchus, and prostate, these cancers probably account for more than 80% of cases of metastatic bone disease. The distribution of bone metastases is predominantly to the axial skeleton—particularly the spine, pelvis, and ribs—rather than to the appendicular skeleton, although lesions in the humeri and femora are also common.

Breast cancer, the most common malignancy in women of western Europe and North America and which, in the areas of its highest incidence, accounts for some 10% of all cancers, is the tumor most often associated with metastatic bone disease. Because of the long clinical course this disease potentially can follow even after metastases have developed, morbidity from bone deposits presents a major problem for health care systems. Approximately 70% of patients dying from breast cancer will have radiologic evidence of skeletal metastases before death, and bone is the first metastatic site in over 40% of those with distant relapse. Median survival after first relapse in bone is around 2 years, and significantly longer than is seen after first relapse in visceral sites such as the liver.[1] Although the management of metastatic visceral disease has improved in recent years, the prognosis following visceral relapse remains poor, whereas bone metastases can be a protracted problem over many years. Favorable factors for a longer survival after first relapse in bone are low histologic grade, positive estrogen receptor status, long postoperative disease-free interval, and lack of development of extraosseous disease.[2]

There is increased interest in personalized medicine whereby biologic factors are utilized to predict the probability or distribution of recurrence. The association between estrogen receptor expression and bone metastasis has been appreciated for 20 years.[1] However, more recently, other markers, especially the noncollagenous bone proteins, have been suggested as predictors of bone recurrence. These have included bone sialoprotein (BSP), which in addition to being apparently predictive of bone metastasis in breast cancer,[3] may be relevant in other tumors with a propensity to metastasize to bone.[4]Parathyroid-related peptide (PTHrP) is expressed by a very high proportion of breast cancers in bone,[5] and it was previously suggested that immunohistochemical determination of PTHrP expression by the primary tumor might be a useful predictive test. However, long-term follow-up of a large cohort of patients with PTHrP assessment of the primary tumor has indicated that this is not the case with PTHrP positivity associated with a better prognosis and a lower incidence of metastasis.[6]

Gene expression profiling has identified genetic signatures that are strongly associated with prognosis, [7] [8] possibly outperforming conventional panels of clinical and pathologic criteria. However, the risk of metastasis per se does not necessarily predict for metastasis to specific sites. Recently, a 69-gene signature was described that was specifically predictive of metastasis to bone as opposed to metastasis in other sites.[9] The set of genes expressed suggested involvement of the fibroblast growth factor receptor pathway in the process of metastasis to bone. Subsequently, a classifier of 31 genes was constructed that was able to predict all tumors relapsing in bone with a specificity of 50%. Much more work is required to confirm the utility of genetic profiling in clinical management, but this approach holds much promise.

The skeleton is by far the most common site of metastatic disease in prostatic cancer. Unlike breast cancer, in which radiologically the lesions frequently show a mix of osteoblastic and osteolytic appearances, osteosclerotic disease predominates in prostatic cancer. Nevertheless, computed tomography (CT) often identifies lytic areas within these ostensibly sclerotic lesions. Histologic and biochemical studies also have demonstrated increased bone resorption in metastatic prostatic cancer.[10] As in breast cancer, metastatic bone disease in prostatic cancer can follow a relatively long course. For example, patients of good performance status and bone-only disease affecting the axial skeleton have a median survival of about 53 months, compared with 30 months for those with additional visceral disease and only 12 months for poor-performance status patients with both bone and visceral disease.[11]

Several studies have attempted to correlate the extent of skeletal metastatic involvement with survival in patients with advanced prostate cancer. A system based on the number of lesions identified by bone scintigraphy was predictive for survival,[12] and a bone scan index to quantify the extent of skeletal involvement by tumor more accurately has been developed.[13] It is based on the known proportional weights of each of the 158 bones derived from the so-called “reference man,” a standardized skeleton in which postmortem-based individual bone weights were reported for the average adult. The bones were considered individually and assigned a numeric score representing the percentage involvement with tumor multiplied by the weight of the bone. In an analysis of outcomes according to the bone scan index in 191 patients with androgen-independent prostate cancer, patients with low, intermediate, or extensive skeletal involvement had median survivals of 18.3, 15.8, and 8.1 months, respectively.[13]

In lung cancer, the incidence of bone metastases identifiable at the time of primary diagnosis is highest in the small cell variety and lowest with squamous cell tumors, but at autopsy the incidence of bone metastases is similar for all four main histologic types of lung cancer (squamous cell, small cell, large cell anaplastic, and adenocarcinoma) at about 30%. Survival from primary diagnosis of lung cancer is poor, and fewer than 10% of patients are alive after 5 years. Once metastatic disease is evident, most patients die within a few months. Bone metastases from lung cancer are usually of the osteolytic type, but because of the poor survival prospects, morbidity from them is much less of a long-term health care problem than for either breast or prostatic cancers.

CAUSES

Mechanisms of Metastases

The predominant distribution of bone metastases in the axial skeleton, in which most of the red bone marrow is situated, suggests that the slow blood flow at these sites could assist in the attachment of metastatic cells. Contrast this, for example, with the circulation in the kidneys, which accounts for a high proportion of cardiac output and in which metastatic disease is extremely rare. Furthermore, the high incidence of bone metastases in prostate and breast cancers, without corresponding lesions in the lungs, is assumed to in part reflect the circulation of tumor cells through the vertebral-venous plexus, which parallels, connects with, and provides bypasses for the portal, pulmonary, and caval system of veins and so provides a pathway for the spread of disease between distant organs.[14] However, these anatomic characteristics do not account adequately for metastatic patterns. It seems likely that molecular properties of both the malignant cells and those of the tissue in which metastases develop are of critical importance.

Pathogenesis

Bone Remodeling

Bone is a highly specialized connective tissue comprising an unmineralized (osteoid) matrix composed predominantly of type I collagen; and a mineralized component of hydroxyapatite crystals, which encloses the marrow space containing a variety of marrow-residing cells (osteoblasts, osteoclasts, bone marrow stromal cells, immune cells, stem cells, adipocytes, fibroblasts, endothelial cells), platelets, fat, and interstitial fluid. During childhood and adolescence, bone is constantly shaped and remodeled, with peak bone mass being reached in early adulthood. Bone turnover continues throughout life, with up to 20% of the skeleton undergoing remodeling at any time so as to replace damaged bone and maintain skeletal integrity. The total duration of a remodeling cycle in young adults is estimated to be around 200 days. This process is essential for providing bone strength and is responsive to mechanical stress.[15]

Bone resorption is mediated by the osteoclast, a multinucleated giant cell derived from granulocyte-macrophage precursors, whereas bone formation is carried out by osteoblasts, derived from mesenchymalfibroblast-like cells. In a healthy individual, bone resorption and bone formation are coupled and perfectly balanced in location, time, and amount. Bone remodeling is regulated by complex interactions between hormones, paracrine growth factors, and cytokines, and involves interactions between osteoclasts and osteoblasts as well as other cell types present in the bone microenvironment ( Fig. 57-1 ).

 
 

Figure 57-1  Schematic diagram illustrating the normal bone remodeling cycle. Osteoclasts attracted to a site of fatigued bone create an erosion cavity. Osteoblasts are attracted and synthesize the organic matrix, which will fill the resorption cavity. The new bone is then remineralized to complete the remodeling process.

 

 

The presence of tumor cells in metastatic bone disease leads to disruption of the fine-tuned balance between bone formation and bone resorption, either causing excess bone resorption (as associated with lytic bone lesions) or increased levels of bone formation (as in osteosclerotic bone lesions). In many cases there are mixed lesions, comprising both lytic and sclerotic features ( Fig. 57-2 ). In the late stages of cancer, tumor masses may also damage the skeleton by compression of vasculature and consequent ischemia.

 
 

Figure 57-2  Histologic section showing resorption lacunae on a bone trabeculum. Multinuclate osteoclasts (arrows) are resorbing bone in close association with mononuclear hematopoietic cells. The bar represents 20 mm.  (From Boyce BF: Normal bone remodeling and its disruption in metastatic bone disease. In: Rubens RD, Fogelman I [eds]: Bone Metastases—Diagnosis and Treatment. London, Springer Verlag, 1991, p 14.)

 

 

 

Tumor Cell–Bone Cell Interactions

Malignant cells secrete factors that stimulate osteoclastic activity both directly and indirectly, as reviewed by Mundy[16] and recently by Siclari and colleagues,[17] and the importance of interactions between malignant cells and the bone microenvironment in the development of bone metastases has been the focus of intensive research. Factors produced by tumor cells that cause increased bone resorption include prostaglandin-E and a variety of cytokines and growth factors, such as transforming growth factor (TGF) α and β, epidermal growth factor, vascular endothelial growth factor, tumor necrosis factor, and interleukins-1, -6, -8, and -11.

Several proteolytic enzymes are proposed to be involved in the early phases of formation of bone metastases, including matrix metalloproteinase (MMP)-2 and -9 and cathepsin K.[18] Normal bone trabeculae are lined by a thin layer of uncalcified matrix, which protects the calcified bone from osteoclastic activity, and the action of proteolytic enzymes might be a prerequisite for osteoclastic bone resorption. In addition, MMPs are involved in bone metastases formation both through their ability to degrade basement membrane and facilitate tumor cell dissemination, but also by causing release of growth factors and cytokines bound to the bone matrix, thereby supporting further tumor cell proliferation.[19] Malignant cells might also increase bone resorption by stimulating tumor-associated immune cells to release osteoclast-activating factors. It has been shown that human melanoma cells produce a factor that stimulates macrophages to release tumor necrosis factor and interleukin-1 in vitro. Furthermore, purification of a cytokine-releasing factor from medium conditioned by melanoma cells has identified it as granulocyte-macrophage colony-stimulating factor, which activates osteoclastic bone resorption.[20] The complex interaction between tumor cells, osteoblasts, osteoclasts, and associated immune cells is summarized in Figure 57-3 .

 
 

Figure 57-3  Diagrammatic summary of the cellular and molecular interactions involved in bone resorption and new bone formation in metastatic disease of the skeleton. BMPs, bone morphogenetic proteins; EGF, epidermal growth factor; FGF, fibroblast growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IGF, insulin-like growth factor; IL-1, interleukin 1; IL-6, interleukin 6; PDGF, platelet-derived growth factor; PTHrP, parathyroid hormone-related protein; TGF, transforming growth factor (a and b); TNF, tumor necrosis factor.

 

 

In addition to the local paracrine factors just described, osteoclastic activity can also be stimulated in malignant disease by systemic factors, particularly PTHrP. This peptide is immunologically distinct from PTH, but the two hormones have significant homology at the N terminus of the molecule, which is necessary for osteoclast stimulation. Ectopic production of this hormone, particularly in lung cancer, is a cause of osteoclastic bone resorption and hypercalcemia even in the absence of bone metastases.

The importance of PTHrP in the pathogenesis of osteolysis induced by metastatic breast cancer has been elegantly elucidated.[21] In bone metastases, the secreted PTHrP acts in a paracrine manner to stimulate osteoclastic bone resorption. Not only does this lead to skeletal damage, but it also seems to confer a selective growth advantage on the tumor cells. This results from the release of factors for tumor growth from bone during the osteolytic process. Hence, a vicious circle is established in which the growth of metastatic cells is potentiated, leading to enhanced osteolysis and secretion of additional growth factors to stimulate tumor cell proliferation.[17] This paracrine activity occurs even in the absence of hypercalcemia or increased circulating PTHrP levels. PTHrP stimulates osteoclastic resorption by increasing osteoblast and stromal cell production of receptor activator of nuclear factor-κB (RANK) ligand.[20] RANK ligand binds to its receptor, RANK, on osteoclast lineage cells, resulting in differentiation to mature osteoclasts and stimulation of osteoclast activity. In the normal bone environment, osteoblast secretion of osteoprotegerin (OPG) neutralizes RANK ligand, thus terminating its stimulatory effects on osteoclasts. The MCF-7 estrogen-dependent breast cancer cell line has been found to decrease osteoblastic OPG messenger RNA levels, thus enhancing osteoclast formation.[22] This imbalance is further compounded by release of TGF-β and insulin-like growth factor from resorbing bone, which further promotes tumor production of PTHrP, thus promoting a perpetuating cycle of osteolytic bone destruction.

Tumor cells might also have direct cell-to-cell interaction with bone marrow cells. One study recently found that prostate cancer cells are able to express a soluble form of RANK ligand, a finding that implies a direct ability of prostate cancer cells to affect bone resorption. [23] [24]

Sclerotic Bone Metastases

Although osteolytic disease is usually most evident at sites of bone metastases, osteosclerosis sometimes can predominate, particularly in prostatic cancer. Prostate cancer, in contrast to breast cancer, tends to cause osteoblastic lesions in bone, leading to dense, sclerotic-looking metastases on plain radiographs, and osteoblast growth factors, such as TGF-β and platelet-derived growth factor, have been purified from prostatic tumor cells. One of the factors that might be involved in prostatic bone lesions is the growth factor endothelin-1 (ET-1), which is produced by prostate cancer cells. Circulating levels have been found to be increased in patients with osteoblastic bone metastases from androgen-refractory prostate cancer, compared with patients whose cancer is confined to the prostate and normal controls.[25]ET-1 has been found to stimulate osteoblast activity in animal models and to inhibit osteoclast activity, whereas antagonists of endothelin have been found to inhibit bone formation in vivo.[26] Furthermore, a recent study found that ET-1 production by prostate cancer cells is reduced by androgens but is stimulated in androgen-insensitive prostate cancer cells by factors (such as TGF-β).[27] This finding is clinically relevant, because metastatic prostate cancer typically develops androgen resistance. It is possible that PTHrP is also involved in the pathogenesis of prostate cancer bone metastases, because coexpression of PTHrP and its receptor has been found in both the primary tumor and in bone metastases of patients with prostate cancer.[28]

Evidence from morphometric studies and measurement of urinary markers of osteolytic bone resorption has led to the hypothesis that initially, osteoclastic bone resorption is important in prostate cancer, followed by intense osteoblastic activity.[29] This might not necessarily always be the case, however. A recent study found that the prostate cancer cell line PC-3 implanted into tibia of SCID mice caused osteolytic lesions, possibly through secretion of RANK ligand.[30] When another prostate cancer cell line (LAPC-9) was used, however, osteoblastic lesions developed even when no osteoclasts were present. Therefore, in this study the authors concluded that osteoclastic activity might not be a prerequisite for the formation of osteoblastic lesions.

There is an increasing interest in the role of the osteoblasts in bone metastases, and it has recently been established that the Wnt signaling system plays a key role in bone development and turnover.[31]Subsequent studies have found that several molecules in this system are implicated in the development of bone metastases.[32] In prostate cancer, tumor-derived Wnt induces osteoblastic activity in bone metastases, which in the early stages of disease may be counteracted by the presence of the Wnt agonist DKK1 (an inhibitor of osteoblast differentiation), thereby favoring lytic lesions. In the later stages of progression of prostate cancer bone metastases, the balance between Wnt and its inhibitors is suggested to be shifted toward Wnt, favoring osteoblastic lesions.

In myeloma bone disease, bone marrow stromal cells are important for the pathogenesis of multiple myeloma. Interleukin-6 seems to be an important growth and survival factor for myeloma cells and for conferring resistance to treatment with dexamethasone, a commonly used treatment for multiple myeloma. Barille and colleagues also found that matrix metalloproteinases (MMPs), known to be important in normal and malignant remodeling, contribute to the pathogenesis of myeloma. Bone marrow stromal cells secrete interstitial collagenases (MMP-1) and gelatinase A (MMP-2). MMP-1 initiates bone resorption, degrading type I collagen, which becomes a substrate for MMP-2.[33] Malignant plasma cells have been found to upregulate MMP-1 and activate MMP-2.[34]

Dysregulation of the Wnt signaling system has also been implicated in myeloma bone disease, where the production of DKK1 by myeloma cells is reported to be associated with the presence of lytic bone lesions.[35]

DIAGNOSIS

Differential Diagnosis

Metastatic involvement of the skeleton typically affects multiple sites and causes pain, bony tenderness, and increasing disability. The diagnosis is often straightforward but occasionally can be difficult to make, and confusion with benign pathology is particularly a problem for elderly patients, in whom degenerative disease and osteoporosis are common. Particularly difficult clinical situations include elderly women with painful collapsed vertebrae who have a past history of breast cancer and in whom it can be difficult to distinguish osteoporotic collapse from metastatic destruction, and elderly men with prostatic cancer and pelvic pain with sclerotic radiologic changes in the pelvis attributable to either metastases or Paget's disease of bone.

In all cases, appropriate imaging tests are necessary and must be interpreted in conjunction with the clinical picture, information from measurement of biochemical markers of bone metabolism, and—when appropriate—serum tumor markers. Occasionally, bone biopsy under radiologic control or at open operation is necessary. Table 57-2 summarizes the typical clinical, radiologic, bone scan, and biochemical abnormalities of the more common skeletal pathologies.


Table 57-2   -- Clinical, Radiologic, and Biochemical Features of Common Skeletal Disorders That May Mimic Bone Metastases

Diagnosis

Clinical Features

Radiologic

Biochemical

Bone metastases

Pain common

Bone scan very rarely completely normal

Alkaline phosphatase usually elevated

 

Usually multiple sites

Discrete lytic or sclerotic lesions on radiographs

Increased urinary markers of bone resorption

 

Axial skeletal involvement typical

Fracture/vertebral pedicle destruction

Hypercalcemia common

 

Soft tissue extension on CT/MRI

 

Degenerative disease

Elderly

Spinal involvement results in symmetric increased tracer uptake on scan

Usually normal

 

Limb involvement common

Radiograms usually confirmatory

 

 

Pain and stiffness

 

 

 

Long history

 

 

Osteoporosis

Elderly female

Normal scan unless recent fracture or vertebral collapse

Usually normal serum parameters

 

Painless unless fracture or vertebral collapse

Diffuse osteopenia on radiograms

Slight elevation of urinary indices

 

 

Normal marrow on MRI

No hypercalcemia

Paget's disease of bone

Elderly

Diffuse involvement of bone on scan

Alkaline phosphatase greatly elevated

 

Bone deformity common

Sclerotic expanded appearance on radiograms

Increase in urinary hydroxyproline excretion

 

Involved site warm due to increased blood flow

 

Hypercalcemia very rare

 

Skull often involved and enlarged

 

 

Traumatic fractures

History of trauma usual

Intense linear uptake on scan

Usually normal

 

Spontaneous rib fractures after chest wall irradiation common

Rib lesions typically aligned, not randomly distributed

 

 

No evidence of destruction around fracture site on radiographs (unless radiation induced)

 

 

 

Diagnostic Methods

Skeletal Radiography

A skeletal radiogram indicates the net result of bone resorption and repair. To be recognized on a plain radiograph, a destructive lesion in trabecular bone must be greater than 1 cm in diameter, with loss of approximately 50% of the bone mineral content. When radiography is used as the primary investigation for bone metastases, such as in multiple myeloma, a skeletal survey is performed. On the basis of the usual distribution of metastases, this normally includes radiograms of the lateral skull and cervical spine, anteroposterior and lateral thoracic and lumbar spine, and anteroposterior pelvis and chest radiograms taken at low KVp to visualize the ribs optimally.

It is the predominance of lysis or sclerosis that gives rise to the characteristic radiographic appearances of bone metastases. When bone resorption predominates, focal bone destruction occurs, and bone metastases have a lytic appearance. Conversely, in bone metastases characterized by increased osteoblast activity and associated with a fibrous stroma (e.g., in prostate cancer), the lesions appear sclerotic. Even when one element predominates, both processes are greatly accelerated in the affected bone. Though probably a general phenomenon, this is most apparent in the appropriately termed “mixed” lesions, seen most commonly in breast cancer, in which both lytic and sclerotic components are clearly visible.

Lytic metastases are the most common type arising from breast, lung, thyroid, renal, melanoma, and gastrointestinal malignancies ( Fig. 57-4 ). There is thinning of trabeculae, and the margins are usually ill defined, representing regions of partially destroyed trabeculae between the central destruction and the radiologically normal bone. The width of the margin reflects the aggressiveness of the lesion, with a narrow zone of transition in the less aggressive lesions. If the metastasis is in the medulla, there could be endosteal scalloping, whereas cortical lesions produce subperiosteal scalloping or a focal cortical defect.

 
 

Figure 57-4  Lytic metastases in the skull.

 

 

Sclerotic metastases are usually from prostate cancer but also arise from breast, lung, and carcinoid tumors ( Fig. 57-5 ). Excessive new bone formation gives rise to thickened, coarse trabeculae, which usually appear on radiograms as nodular, rounded, fairly well-circumscribed sclerotic areas. Sometimes, less well-defined, mottled, irregular areas of increased bone density occur, which can coalesce to produce a diffuse sclerotic appearance to the skeleton.

 
 

Figure 57-5  Sclerotic metastases in the pelvis.

 

 

Radionucleotide Bone Scan

The radionuclide bone scan provides quite different information from the skeletal radiogram. The bone-seeking radiopharmaceutical is absorbed onto the calcium of hydroxyapatite in bone, a reaction that is influenced by osteoblastic activity and skeletal vascularity, with preferential uptake of tracer at sites of active bone formation. The bone scan, therefore, reflects the metabolic reaction of bone to the disease process, whether neoplastic, traumatic, or inflammatory. When bone metastases develop, there is usually sufficient increase in blood flow and reactive new bone formation to produce a focal increase in tracer uptake, often before bone destruction can be seen radiologically, and with the exception of patients with multiple myeloma, the bone scan is a more sensitive technique than plain radiograms for the detection of skeletal pathology. Lesions in the pubis, ischium, and sacrum may on occasion be obscured on the bone scan as a result of bladder activity, and not all established metastases may be visualized.

A bone scan is generally performed by acquiring multiple images of the skeleton 3 to 4 hours after the intravenous injection of 99mtechnetium-labeled methylene-diphosphonate. If a lesion is identified, particularly when solitary, further investigation is necessary. A suggested protocol for investigation is shown in the accompanying algorithm ( Fig. 57-6 ). Appropriate plain radiographs of a focal lesion should be obtained in the first instance. If these are normal and clinically a metastasis is likely, then CT or magnetic resonance imaging (MRI) of the area could be diagnostic.

 
 

Figure 57-6  Diagnostic methods for the investigation of a patient with possible bone metastases. *Patients with multiple myeloma are best investigated by performing a skeletal survey.

 

 

Although bone scan appearances are nonspecific, recognizable patterns of bone scan abnormalities might suggest a specific diagnosis. Metastases are usually multiple, irregularly distributed foci of increased tracer uptake that do not correspond to any single anatomic structure ( Fig. 57-7 ). Generally, they affect the axial skeleton, but metastatic disease can involve the appendicular skeleton, and approximately 7% of patients have involvement of the distal skeleton, the proportion increasing in certain tumor types such as renal cell carcinoma.[36] Although bone metastases are usually multiple when diagnosed, as many as 20% of women with breast cancer present with a solitary hot spot on the bone scan with or without pain.[37]

 
 

Figure 57-7  Radionuclide bone scan appearances of metastases in the lumbar spine and pelvis.

 

 

Because detection of a lesion depends on the presence of a focal increase in osteoblast activity, a false-negative scan will occur when there is pure lytic disease. This is typical of multiple myeloma, which is best investigated radiographically but also can occur in other tumors when there are rapidly growing lytic lesions. In extreme cases, where there has been significant bony destruction, a photon-deficient area (cold spot) can develop ( Fig. 57-8 ). Sclerotic metastases, on the other hand, are generally clearly visualized on the bone scan, the only exception being very slow-growing metastases, in which the alteration in metabolic activity is so subtle that it might not be distinguishable from normal background activity.

 
 

Figure 57-8  A, Photodeficient (cold lesion) in the sacrum resulting from a rapidly progressive destructive bone metastasis as demonstrated by CT scan slice taken through the lesion (B).

 

 

When there are extensive skeletal metastases, the focal lesions might coalesce to produce diffusely increased uptake—the so-called “super scan” of malignancy ( Fig. 57-9 ). This occurs most often in prostatic cancer but also is seen in other tumors, such as breast cancer. An increase in the contrast between bone and background soft tissue and faint or absent renal images are the typical appearances.

 
 

Figure 57-9  “Super scan” of malignancy. Note absent renal images and diffuse uptake of tracer throughout the skeleton.

 

 

Computed Tomography

A CT scan produces images with excellent soft-tissue and contrast resolution. Bony destruction and sclerotic deposits are well shown ( Fig. 57-10 ), and any soft-tissue extension of bone metastases is demonstrated clearly. CT is most appropriate for diagnosing spinal metastases, but because the whole spine cannot be scanned readily, CT is normally reserved for assessment of patients with positive bone scans and negative radiograms in an attempt to clarify the pathology.

 
 

Figure 57-10  CT scan image through the right shoulder showing mixed lytic and sclerotic disease.

 

 

Magnetic Resonance Imaging

MRI has the advantage over CT of providing multiplanar images that permit (as one example) imaging of the entire spine in the sagittal plane ( Fig. 57-11 ). The solid constituents of cortical bone give no signal on MRI and appear black, whereas the high water content of fat and bone marrow results in strong signals, making these tissues appear white. This signal is variable depending on the pulse sequence used. Detection of bone metastases by MRI depends on differences in MR signal intensity between tumor tissue and normal bone marrow. Metastatic tumor is therefore visualized directly, in contrast to the indirect changes observed by x-ray or radionuclide bone scanning. Like CT, MRI has proved useful for evaluating patients with positive bone scans and normal radiograms and for elucidating the cause of a vertebral compression fracture. MRI is excellent for demonstrating bone marrow infiltration and has also been reported to be more sensitive than the bone scan for the early detection of metastases.[38]

 
 

Figure 57-11  T1-weighted magnetic resonance image of spine with metastases in T11 and L5 appearing darker than normal marrow.  (From Richards MA: Magnetic resonance imaging. In: Rubens RD, Fogelman I [eds]: Bone Metastases—Diagnosis and Treatment. London, Springer Verlag, 1991, p 91.)

 

 

 

Positron Emisssion Tomography

Scanning with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) provides the opportunity to visualize function. However, its role in the identification of bone metastases is far from clear. FDG has the advantage of demonstrating all metastatic sites, and in the skeleton it is assumed that its uptake is directly into tumor cells. For bone metastases from breast and lung cancer, FDG-PET has similar sensitivity, though poorer specificity, than the isotope bone scan. However, the evidence is inconsistent, with several studies suggesting that FDG-PET is less sensitive than conventional imaging in breast cancer. There is convincing evidence that FDG-PET is less sensitive than the bone scan for prostate cancer, whereas for multiple myeloma FDG-PET it is clearly better than the bone scan, presumably because FDG is identifying marrow-based disease at an early stage.[39]

Biochemical Markers of Bone Metabolism

The effects of tumor cells on bone cell function can influence serum and urinary levels of biochemical markers of bone metabolism. In recent years, the number of available markers and the clinical relevance has increased rapidly; their value in the diagnosis of bone metastases has been studied in several tumor types.

Bone Formation Markers

BONE ALKALINE PHOSPHATASE.

Bone alkaline phosphatase (BALP) hydrolyzes pyrophosphate, thereby removing an inhibitor of osteogenesis while creating the inorganic phosphate that is required for generation and deposition of hydroxyapatite.[40] This enzyme is secreted as a “bud” from the osteoblast cell membrane to the bone matrix vesicles, allowing bone mineralization to proceed.

There are several alkaline phosphatase isoforms secreted by the various organs into the serum. Predominant isoforms originate from bone, liver, intestine, and placenta. Because of these wide sources of activity, limited information may be obtained from a total alkaline phosphatase measurement. However, the bone-specific isoform (BALP) is a relatively specific marker for osteogenesis. Elevated BALP levels occur in Paget's disease, renal rickets, bone cancer, osteomalacia, and celiac disease. In addition, BALP may be increased in patients with liver diseases because it is normally cleared from the serum by the liver.[41]

OSTEOCALCIN.

Osteocalcin is the major noncollagen protein in the bone matrix.[42] It is produced by osteoblasts, odontoblasts, and hypertrophic chondrocytes, and is thought to function as a localization site for hydroxyapatite crystals during bone matrix synthesis. Both osteolysis and osteogenesis release osteocalcin into the serum, from which it is eliminated via renal clearance and degradation.[42] Therefore, osteocalcin levels might reflect overall bone metabolism, not just osteogenesis. Detection of serum or plasma osteocalcin may be impaired by high lipid levels because of osteocalcin-lipid binding. Moreover, multiple isoforms exist in the circulation, and current assays have a limited ability to detect them all. Urinary osteocalcin levels may also be assayed, but, because of recovery and degradation, urinary osteocalcin levels typically reflect only basal bone turnover instead of acute changes in bone metabolism.[42]

PROPEPTIDES OF PROCOLLAGEN TYPE I.

Collagen type I composes approximately 90% of the organic bone matrix. Extracellular processing occurs before the final collagen fibril assembly wherein the N-terminal (N-terminal propeptide of procollagen type 1 [PINP]) and C-terminal (C-terminal propeptide of procollagen type 1 [PICP]) regions are generated in a 1 : 1 ratio with collagen and released into the serum. Therefore, levels of PINP and PICP may reflect the level of osteogenesis. However, type I collagen is synthesized is some other tissues, which may contribute to the serum PINP and PICP levels. Serum PICP levels have been correlated with bone formation, and decreased levels have been reported after bisphosphonate therapy or hormone replacement therapy. Both PINP and PICP are removed by the liver, but PINP can also be deposited directly into bone and has been found to constitute 5% of the noncollagenous protein in bone.[43] However, recent reports have suggested that PINP has greater diagnostic validity than PICP, and in a multivariate Cox analysis, PINP was shown to be an independent predictive factor for survival in patients with prostate cancer.[44]

Bone Resorption Markers

CALCIUM.

Resorption of bone releases calcium, hydroxyproline, and collagen fragments into the circulation. These are cleared by the kidney and excreted largely unchanged into the urine. Serum calcium measurements are performed routinely, but changes within the normal range give little guide to disease activity. Hypocalcemia is seen when osteoblastic metastases predominate; this is more typically associated with prostate cancer but does sometimes occur in advanced breast cancer.

Urinary calcium excretion is a more sensitive indicator of alterations in calcium homeostasis. The molar ratio of calcium to creatinine in an early morning urine sample collected after an overnight fast is a convenient, reproducible method of quantifying calcium excretion. The problem with urinary calcium is that it is not a specific resorption inhibitor but only reflects the net effects of bone formation and resorption and is influenced by diet, the circulating levels of both PTH and PTHrP, and the concomitant administration of drugs such as bisphosphonates (which influence bone resorption independently of any tumor-related effects). Urinary calcium excretion is not increased significantly in the majority of patients with metastatic bone disease, a finding that reflects the effects of bone formation and the renal handling of calcium.

HYDROXYPROLINE.

Urinary hydroxyproline excretion is a conventional parameter for measuring bone resorption in benign bone disease; it indicates matrix destruction more specifically but has been generally unreliable in the assessment of metastatic bone disease as a result of contributions from both diet and soft-tissue destruction by metastases.[41]

PYRIDINOLINE AND DEOXYPYRIDINOLINE.

Pyridinoline (PYD) and deoxypyridinoline (DPD) are produced from the post-translational modification of lysine and hydroxylysine. They stabilize mature type I collagen in all major connective tissues, cross-linking the telopeptide domain of one collagen fibril to the helical region of an adjacent one. During bone resorption, PYD and DPD are released from bone in approximately a 3 : 1 ratio as free molecules or attached to collagen fragments. They are not recovered by the bone and are excreted via the kidneys with no known metabolic degradation. Urinary excretion is closely related to the rate of bone resorption. Although PYD and DPD are present in other tissues, bone is the major reservoir and has a higher turnover than most connective tissues. In fact, DPD is found almost exclusively in bone. However, the contribution from soft tissues may make these markers less accurate than other markers, especially in the case of PYD.

C-TELOPEPTIDE AND N-TELOPEPTIDE.

C-telopeptide (CTX) and N-telopeptide (NTX) are the C-terminal and N-terminal peptides, respectively, of mature type I collagen with the cross-links attached and are released during bone resorption.[6]Degradation products of collagen are of various sizes that may undergo additional breakdown in the liver or kidney to their constituent amino acids and cross-links (PYD and DPD) and are excreted in the urine. However, osteoclast-derived fragments are different from those formed in nonskeletal tissues. The cross-linked peptide is primarily attached as an α2 isoform for NTX from bone and as an α1 isoform from other tissues. The CTX peptide exists as α or β isoforms, with β isoforms found more often in mature bone.[41] Assays for NTX utilize an antibody to the α2 chain and are usually performed on urine samples. However, urinary results must be adjusted for urine dilution, which may add to measurement variability. Urinary CTX measurements have poor precision at concentrations lower than 200 mg/L, so serum or plasma samples are often used. Serum CTX measurements utilize an antibody to the β isoform.

PYRIDINOLINE CROSS-LINKED C-TERMINAL TELOPEPTIDE OF TYPE I COLLAGEN.

PYD cross-linked C-terminal telopeptide of type I collagen (ICTP) is another metabolic product of mature type I collagen resorption. Increased levels of serum ICTP correlate well with bone resorption levels in patients with either high or low bone turnover.[44] Serum ICTP level increases of as much as 20% have been reported in patients with osteolytic metastases.[45] Indeed, ICTP levels are elevated in lung cancer patients with bone metastases compared with patients without bone metastases, and in multiple myeloma patients with negative radiograms but positive MRI results. [45] [46] Immunochemical characterization of serum ICTP reveal that cathepsin K–mediated bone resorption cleaves the collagen at the antigenic site, and the resulting ICTP fragment is not detected by the assay.[45] However, MMP-mediated release leaves the antigenic site intact, and in this situation the resulting ICTP fragment is detectable. These results explain why the current assay for ICTP is insensitive to physiologic changes in bone turnover such as those induced by estrogen or bisphosphonate treatment but a potentially useful marker in skeletal metastases.

TARTRATE-RESISTANT ACID PHOSPHATASE SERUM TYPE 5b.

Tartrate-resistant acid phosphatase serum type 5b (TRAcP-5b) is secreted by osteoclasts after they have attached to the bone surface. The enzyme then enters the circulation where it is inactivated and degraded and active enzyme levels in the circulation reflect recently released enzyme as a result of bone resorption. TRAcP-5b has been suggested as a useful marker for bone resorption. However, some studies have suggested that TRAcP-5b may reflect osteoclast numbers rather than activity.[47]

BONE SIALOPROTEIN.

BSP is a noncollagenous bone matrix protein secreted by osteoclasts and is part of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family. It is secreted by other cells and is present in all mineralized tissues. Elevated serum BSP levels have been reported in patients with prostate cancer, breast cancer, and colon cancer.[48] In fact, BSP levels in patients with bone metastases secondary to prostate cancer were an independent prognostic factor for survival.[49] Elevated serum BSP levels have also been reported in patients with multiple myleoma.[50]

Osteoclastogenesis Markers

RECEPTOR ACTIVATOR OF NUCLEAR factor-κB LIGAND/OSTEOPROTEGERIN.

RANK and the RANK ligand (RANKL) are required for osteoclastogenesis. OPG is a soluble decoy receptor that binds RANKL, thereby blocking stimulation of osteogenesis. RANKL exists as two isoforms: a membrane-bound form and a shorter soluble form. In patients with bone metastases secondary to breast cancer, prostate cancer, or lung cancer, both OPG and RANKL were not significantly elevated compared with patients without bone metastases.[51] However, among patients with multiple myeloma, serum levels of soluble RANKL and the RANKL/OPG ratio were elevated and correlated with markers of disease activity.[52]

Bone Markers as Predictive and Prognostic Indicators

Because commonly used radiographic methods do not detect bone metastases in the very early stages of development, the question arises whether serial measurements of bone markers might identify the impending development of bone metastases. Thus far, data relating to this question are sparse. However, once bone metastases have developed, bone markers can provide useful prognostic information. Clinical evidence of correlations between bone marker levels and patient outcomes have been recently reported from retrospective analyses of several large trials in patients with bone metastases. [10] [53]Elevated on-study bone marker levels correlated with negative clinical outcomes in patients with metastatic prostate cancer, lung cancer, or other solid tumors.

Specifically, patients with elevated urinary NTX levels either at baseline or at their most recent assessment had an approximate twofold increase in their risk of disease progression and an approximate two- to threefold increase in their relative risk of skeletal-related events (SREs) compared with patients with low NTX levels. Among patients with prostate cancer, elevated NTX levels were associated with a 4.6-fold increased risk of death, and a 2.7-fold increased risk of death was observed in patients with lung cancer or other solid tumors compared with those with low NTX. In contrast, BALP levels were not a consistently strong prognostic indicator.

NTX levels have also been shown to provide valuable prognostic information in a larger analysis of patients receiving bisphosphonate treatment for bone metastases from a wide range of solid tumors and multiple myeloma.[53] Among patients with solid tumors, elevated NTX levels were associated with a significant twofold increased risk of disease progression (P < 0.001). Furthermore, elevated NTX levels were associated with a significant four- to sixfold increased risk of dying on study in all patients except those with multiple myeloma (P < 0.001 for all).

EVALUATION OF THE PATIENT

A variety of treatments, including radiotherapy, endocrine treatment, chemotherapy, and bisphosphonates, are used for the treatment of metastatic bone disease, and evaluation of their effects is important for both routine clinical practice and research. The current imaging methods used to assess response to these treatments are qualitative and routinely include plain radiographs, radionuclide bone scans, and, in particular situations, CT scans. Assessing the response of bone metastases to therapy is notoriously difficult; the events in the healing process are slow to evolve and quite subtle, with sclerosis of lytic lesions only beginning to appear 3 to 6 months after the start of therapy. Bone is the only site of metastatic disease that has separate criteria for evaluation of response to treatment, based on bone repair and destruction rather than on changes in tumor volume. A complete review of the bone radiographs since the start of treatment is necessary to evaluate response—a slow and tedious process.

Assessing response to treatment in bone is more difficult than evaluation of disease in viscera and soft tissues, where tumor measurements can usually be taken. This difficulty results in reports of lower response frequencies to systemic treatments in the skeleton compared with other sites of disease. Complete response in nonosseous sites affected by breast cancer occurs in 10% to 20% of patients, but a complete response in bone with return of normal trabecular pattern or resolution of sclerotic metastases is very rare. Although a low rate of complete response might represent some biologic phenomenon of site-specific resistance, this is unlikely, and the discrepancy in response frequency is almost certainly a reflection of the insensitivity of the assessment methods. Consequently, patients with metastatic disease confined to the bone are frequently excluded from many therapeutic trials, and patients with widespread metastatic disease (including bone) rely on the changes observed in soft tissue or visceral disease to judge response to treatment.

Although we recognize that the changes seen on serial radiograms remain the “gold standard” for evaluating response to therapy, new methods of assessing response are needed, both to improve patient management and to evaluate specific treatments. Several alternatives or adjuncts to assessment based on plain radiograms have been suggested. None is ideal, each having advantages and disadvantages as outlined in the following sections.

Assessment of Symptoms and Activity Status

The relief of symptoms is the principal aim of palliative therapy and rationally should be the most important marker of response to treatment. The use of pain as a marker of response in clinical trials has not found universal acceptance, however, and there is still no single internationally accepted pain questionnaire in oncology, although the Brief Pain Inventory is frequently used in clinical trials. Subjective response to treatment for bone disease requires information on pain intensity, analgesic consumption, and mobility.[54]

Quality-of-life assessment is now an important aspect of clinical trials methodology and, notwithstanding all the difficulties of analysis and interpretation, well-validated generic tools such as the Functional Living Index in Cancer patients (FLIC) and the EORTC QOL-C30 questionnaire can provide useful information on subjective response to treatment in the routine clinical setting. A specific quality-of-life tool for patients with bone metastases is currently under development by an international consortium.

Imaging of Bone Metastases

Radiologic assessment of response is based on radiographic evidence of bone healing. It is generally accepted that sclerosis of lytic metastases with no radiologic evidence of new lesions constitutes tumor regression (a partial response). Confounding factors include the appearance of sclerosis in an area that was previously normal on the radiogram. This could represent progression of a new metastasis but could also indicate a response, reflecting a radiographic example of the healing flare phenomenon within a lesion that was present at the start but was not destructive enough to be radiographically visible. Interpretation is further complicated by variations in film exposure and by the effects of overlying bowel gas. The evaluation of response in osteosclerotic lesions is even more difficult, with most patients with sclerotic metastases eventually classified as either “no change” in response to therapy or unassessable. Here, decisions about the efficacy of treatment have to be based on symptomatic response or (when present) on change in extraskeletal disease.

Although the plain radiogram remains the assessment tool for judging response in clinical trials, it is clearly an inadequate technique. This lack of precision for radiographic assessment of response is exemplified by the observation that, in terms of survival, patients with radiographic evidence of sclerosis (partial response) and those with no change in radiographic appearance for at least 3 months have a similar outcome.[55]

The use of bone scanning for assessment of response to therapy has always been contentious; when lytic metastases predominate, it is often unreliable. A reduction in the intensity and number of lesions (hot spots) on the bone scan was previously considered to represent response, and progressive disease was assumed if an increase in intensity or number of hot spots was seen. This interpretation is too simplistic, however. After successful therapy for metastatic disease, the healing processes of new bone formation cause an initial increase in tracer uptake (akin to callus formation), and scans performed during this phase are likely to show increased intensity and number of hot spots. After treatment for 6 months, the bone scan appearances might improve, as the increased production of immature new bone—the cause of the hot spots—eventually ceases and isotope uptake gradually falls. This “deterioration” followed by subsequent “improvement” in the bone scan appearances after successful therapy has been termed the flare response and is now a well-recognized phenomenon in both breast and prostate cancers ( Fig. 57-12 ). Conversely, a reduction in isotope uptake can occasionally be seen in rapidly progressive disease, when overwhelming bone destruction allows little chance for new bone formation, sometimes culminating in a photon-deficient (cold spot) lesion on the bone scan.

 
 

Figure 57-12  A, CT appearances of metastases in a lumbar vertebra. B, Evidence of bone healing 2 months after irradiation.

 

 

Bone scanning in advanced disease should certainly be interpreted with great caution when performed within 6 months of a change in therapy; it is most useful for restaging at the time of relapse, to identify sites for radiologic assessment, and to bring to the attention of the clinician those sites at risk of pathologic fracture where prophylactic surgery could be indicated.

CT evaluation is effective for diagnosing metastases, particularly in the spine, but it is also occasionally valuable as a parameter of response to metastatic disease. Metastatic lesions that are considered to be representative of the metastatic process (target lesions) and suitable for serial examination with a standard window width and level appropriate for bone are optimum for selection. If required, a region of interest can be defined and the spectrum of Hounsfield values within it calculated by the computer. Changes in the spectrum with time can be determined, with a shift to the right (more positive) indicating replacement of lytic bone (which has a low Hounsfield value) by new sclerotic bone (which has a relatively high Hounsfield number).

CT evaluation is particularly useful for assessing areas that are poorly visualized on plain radiographs (e.g., the sacrum) and might permit assessment of sclerotic bone disease. Within sclerotic metastases, areas of osteolysis are usually present and can be identified by CT. Sclerosis of this lytic component would suggest response to treatment, whereas new areas of lysis appearing within a sclerotic region probably represent progression of disease.

The use of MRI for monitoring response to treatment is not used routinely, and in many parts of the world limited equipment availability makes MRI unlikely to be suitable for routine use. As in primary bone tumors, however, MRI could have a role for detailed evaluation of a specific lesion, for example before surgery.

The role of PET scanning in assessment of response remains uncertain.[56] Uptake of 18F-FDG is related at least in part to function within the tumour and in theory could be useful just as it has been shown to be in the early assessment of soft-tissue tumours.

Tumor Markers

In breast cancer, unlike the germ cell malignancies, there is no highly specific tumor marker for either diagnosis or monitoring of disease. Some breast tumors, however, do produce tumor antigens that can be detected by radioimmunoassay. The most widely studied are carcinoembryonic antigen, which is elevated in 50% to 80% of patients with metastatic breast cancer, and CA 15-3, which is elevated in 60% to 90% of cases with advanced disease. Dynamic changes must be interpreted with caution. Although some patients show the expected increase in markers with progression and decrease in markers with regression, others who respond show an initial surge in tumor marker followed later by the expected decline.

Using an index derived from carcinoembryonic antigen and CA 15-3 in combination with erythrocyte sedimentation rate, a study in patients with metastatic breast cancer found a significant correlation with clinical assessment of response using Union Internationale Contre Cancer (UICC) criteria at 2, 4, and 6 months after systemic endocrine treatment.[57] A multicenter evaluation of the same index confirmed that changes in the markers were in line with and often predated therapeutic outcome criteria for both remission and progression.[58]

Prostate specific antigen (PSA). is a marker of prostatic pathology and can be elevated in any prostate disease: benign prostatic hypertrophy, prostatitis, and cancer. The highest tissue production occurs in prostate cancer, and PSA has proved useful in the early diagnosis, staging, and follow-up of patients.[59] The level of PSA is dependent on the volume of cancer, the volume of benign prostatic hypertrophy in the prostate, and the differentiation of the tumor, with less production of PSA from poorly differentiated tumors. PSA levels usually decline after androgen deprivation therapy (ADT) and provide a reliable guide to response; elevations of PSA usually antedate other clinical evidence of progression by at least 12 months.[60]

Biochemical Assessment of Response

The stimulation of osteoclast function that results in osteolysis and disruption of the normal coupling between osteoblast and osteoclast function leads to changes in a variety of biochemical parameters. When treatment is prescribed for a patient with bone metastases, the effects of that treatment on the tumor cell population will influence bone cell activity. These changes can be appreciated within the first few weeks of starting effective therapy; for this reason, biochemical markers that reflect the rates of bone formation and resorption, respectively, might provide an early assessment of response to treatment (Table 57-3 ).


Table 57-3   -- Biochemical Markers of Bone Resorption and Formation

Resorption

Formation

URINE

SERUM

Calcium

Alkaline phosphatase

Hydroxyproline

Osteocalcin

PYD

PICP

DPD

PINP

NTX

 

Crosslaps

 

Free DPD

 

Free PYD

 

Galactosyl hydroxylysine

 

SERUM

 

Calcium

 

ICTP

 

Galactosyl hydroxylysine

 

DPD, deoxypyridinoline; ICTP, type I collagen C telopeptide; NTX, N-telopeptide of type I collagen; PINP, N-terminal propeptide or type I procollagen; PICP, C-terminal propeptide or type I procollagen; PYD, pyridinoline.

 

 

 

Hypercalcemia is usually indicative of progressive disease, and this is certainly the case if the hypercalcemia has developed more than a few weeks after the start of a new systemic treatment. Rarely, hypercalcemia can be a manifestation of the tumor flare, occurring within a week or so of starting tamoxifen, and in this case it might herald a response to treatment.[61]

More recently, attention has turned to the possible use of collagen cross-link measurements for the assessment of response in bone. Walls and colleagues[62] studied the collagen cross-links PYD and DPD in 36 patients with breast cancer with bone metastases. In women who developed progressive disease, both markers increased and preceded radiologic evidence by a median of 2 months. By contrast, in women who responded to hormone therapy, the markers did not change significantly.

Similarly, Vinholes and associates[63] studied 37 patients with newly diagnosed bone metastases from breast cancer. NTX levels were significantly lower than baseline values (P = 0.05) at 1 and 4 months in responding patients, compared with values for patients with progressive disease. Furthermore, a greater than 50% increase in NTX excretion correctly predicted disease progression in 78% of patients. In a larger, more recent study, 97 evaluable patients with metastatic bone disease from a variety of primary sites were followed during systemic therapy to correlate marker changes with response to treatment.[64] Good correlations of urinary NTX, ICTP, and BALP changes with response were observed, with a rise in NTX of greater than or equal to 52% having the highest positive predictive value (71%) for identifying progression of disease.

Although it is now well accepted that bone-targeted systemic therapy—particularly the use of the bisphosphonates—can reduce morbidity of skeletal metastases of breast cancer substantially, the optimization and timing of these therapies remains to be established. Bone markers potentially offer a powerful and relatively simple tool to assist the clinician in developing the most appropriate treatment strategies. Moreover, there is a prospect of using bone markers to tailor treatment to the individual patient.

There is evidence that the individual pretreatment values of a bone marker, particularly NTX, correlate with response to treatment. In patients with metastatic bone pain treated with pamidronate, the baseline values of NTX were significantly higher (P < 0.02) in nonresponding patients compared to clinical responders.[65] This study also showed that normalization of bone resorption markers correlated with response to treatment. Clinical benefit, as indicated by an improvement in a pain score, was seen only among those patients achieving a normal bone resorption rate after administration of pamidronate. No response was seen in the patients with persistently elevated levels. This suggested that the aim of bisphosphonate therapy should be to produce a fall in marker levels, preferably into the normal range. A subsequent study has shown that this principle may be extended to the use of bone markers to distinguish between the benefits of different bisphosphonates.[66] In one study, 51 patients were allocated randomly to treatment with either oral clodronate, intravenous clodronate, or intravenous pamidronate. Symptomatic response was more frequent in the pamidronate group than in patients receiving clodronate, and this was reflected by a correspondingly greater decrease in the bone resorption markers CTX and NTX.

The ability of bisphosphonate therapy to reduce the frequency of skeletal complications also seems to be correlated with a reduction in bone resorption markers. Retrospective analyses of large randomized trials with zoledronic acid have shown that among patients with solid tumors, elevated NTX levels despite treatment were associated with a significant two- to threefold increased risk of skeletal complications (P < 0.001).[53]

TREATMENT

In general, the treatment of bone metastases is aimed at palliating symptoms, with cure only rarely a realistic aim (e.g., in lymphoma); treatment varies depending on the underlying disease. External beam radiotherapy, endocrine treatments, chemotherapy, and radioisotopes are all important. In addition, orthopedic intervention may be necessary for the structural complications of bone destruction, and some patients with bone metastases develop hypercalcemia requiring specific treatment (see Chapter 48 ). Optimal management requires a multidisciplinary team that includes not only medical and radiation oncologists, orthopedic surgeons, general physicians, radiologists, and nuclear medicine physicians, but also palliative medicine specialists and the symptom control team.

A schema for the management of bone metastases is shown in the accompanying algorithm ( Fig. 57-13 ). Treatment decisions depend on whether the bone disease is localized or widespread, the presence or absence of extraskeletal metastases, and the nature of the underlying malignancy. Radiotherapy is frequently relevant throughout the clinical course of the disease. Resistance to systemic treatments can be expected to develop, necessitating periodic changes of therapy in an effort to regain control of the disease.

 
 

Figure 57-13  Treatment of bone metastases.

 

 

External Beam Radiation Therapy

Shortly after the discovery of x-rays by Roentgen in 1895, radiation therapy was tried as an empiric treatment for bone metastases, and relief of bone pain was observed. Since these early reports, radiotherapy has become established as the treatment of choice for the palliation of painful single sites.

Most treatments for bone pain use an external beam of ionizing radiation, either γ-rays or x-rays. Opposing anterior and posterior fields are used to produce an even dose distribution across the volume to be treated. Although surface anatomy can be used to localize the treatment area, use of a treatment simulator is preferable for accurate localization, particularly if treatment of adjacent areas is likely in the future.

Irradiation of bone can result in a number of pathologic changes that can include atrophy, osteitis, necrosis, and sarcomatous change. Postmortem studies have provided some insight into the structural effects of irradiation on bone-containing metastases. Initially, there is degeneration and necrosis of tumor cells, followed by a proliferation of collagen. Subsequently, a rich vascular fibrous stroma is produced, within which intense osteoblast activity lays down new woven bone. This is then gradually replaced by lamellar bone, and the intratrabecular stroma is repopulated by bone marrow tissue. Radiologically, it can be seen that recalcification of lytic areas begins 3 to 6 weeks after irradiation, with maximum recalcification occurring 2 to 3 months after the time of irradiation.

There is no doubt that local irradiation is effective for bone pain. Overall, response rates of around 85% are reported, with complete relief of pain achieved in one-half of patients.[67] Pain relief usually occurs rapidly, with more than 50% of responders showing benefit within 1 to 2 weeks. If improvement in pain has not occurred by 6 weeks or more after treatment, it is unlikely to be achieved.

Traditionally, treatment techniques and doses have varied considerably between different centers, with prolonged fractionated treatments preferred in North America and single treatments or short fractionation schedules most frequently utilized in Europe. A considerable number of randomized trials have been performed comparing different fractionation schedules. No particular approach seemed to be superior in terms of pain relief. American practice is influenced by the studies by the Radiation Therapy and Oncology Group. A variety of dose fractionation schedules were used ranging from 15 Gy in five fractions to 40.5 Gy in 15 fractions in a prospective randomized study of more than 1000 treatments for metastatic bone pain. An overall response rate of 90% was observed, with approximately half of responders maintaining pain relief until death. Median duration of pain relief in the complete responders was 12 to 15 weeks. The complete response rate was 35% after 40.5 Gy in 15 fractions, compared with a response rate of only 28% after 25 Gy in five fractions (P = 0.0003).[68] In Europe several trials have shown no difference in outcome between fractionated treatment and a single treatment, notably a large Dutch trial of 1157 patients with painful bone metastases who were randomized to receive either a single fraction of 8 Gy or a treatment schedule of six fractions of 4 Gy each.[69] No statistically significant differences in pain response, analgesic consumption, treatment side effects, or quality of life were identified. A meta-analysis of eight trials comparing single versus multiple fractions revealed similar response rates; 1011 of 1391 (73%) treated with a single fraction and 958 of 1321 (73%) who received multiple fractionation achieved a symptomatic response.[70] Hence, accumulating evidence strongly favors single-fraction radiotherapy as the treatment of choice for many patients with painful bone metastases.

The option of retreatment of a painful site requires careful review of previous treatment fields, dose, and fractionation to ensure that normal tissue tolerance, particularly of the spinal cord, is not exceeded. When higher radiation doses are administered, retreatment may be precluded; targeted radioisotope therapy is an alternative approach in such patients. After a single 8-Gy fraction, however, retreatment is usually possible, with more than 50% of patients with recurrence of bone pain responding to a second 8-Gy treatment—a finding that further supports the move occurring in many centers toward single-fraction treatments for routine palliation of metastatic bone pain.

When there are multiple scattered sites of painful bone metastases, wide field/hemibody irradiation is an alternative to treating each site individually with local irradiation. Using single fractions of 6 to 7 Gy to the upper hemibody and 6 to 8 Gy to the lower hemibody, pain relief is reported in about 75% of patients, often occurring rapidly and sometimes within 24 to 48 hours of treatment.[67] Hemibody irradiation is inevitably more toxic than localized external beam treatment. Virtually all patients who receive lower hemibody irradiation suffer gastrointestinal toxicity with nausea and diarrhea, requiring premedication with intravenous hydration, steroids, and antiemetics to reduce these effects. The serious toxicities of hemibody irradiation are bone marrow suppression and radiation pneumonitis. Significant bone marrow suppression is seen in about 10% of patients receiving a single half-body treatment and in most patients who have sequential upper and lower hemibody treatment; these developments often compromise the use of subsequent chemotherapy. Radiation pneumonitis is both dose- and dose-rate-dependent; the occasional cases that do occur are difficult to treat and can be fatal.

Targeted Radioisotope Therapy

The therapeutic use of radioactive-labeled tracer molecules is currently an area of considerable interest and research. The principles of the technique are well established after decades of experience with iodine-131 (131I) for the treatment of follicular thyroid cancer. Targeted radiotherapy has theoretic advantages over external beam radiotherapy in that the radiation dose is delivered specifically to the tumor and normal tissues are spared unnecessary irradiation. Theoretically, it should also be possible to administer high doses of radiation to the tumor on a recurrent basis if necessary. Despite the theoretic attractions of radioisotope therapy, however, technical difficulties have limited the use of therapeutic radiopharmaceuticals thus far.

Therapeutic radionuclides have characteristics different from those used for diagnostic purposes. Ideally, radionuclides for therapy should have a fairly long half-life, allowing adequate accumulation of the radiopharmaceutical within the target tissue. The γ-particle emission should be small to reduce unwanted radiation to nontarget tissues, but present in sufficient amounts to permit localization of the radionuclide by gamma camera imaging. Predominantly α- or β-emitting radionuclides are the most suitable, but, apart from 131I, they have been very expensive to produce. Although many α- and β-emitting radionuclides exist, relatively few have been evaluated clinically.

Because follicular carcinoma of the thyroid commonly metastasizes to bone, the treatment of bone metastases with 131I is now well established, and excellent results can be obtained. In patients with a significant uptake of 131I into the metastases, long-term palliation is usually possible. Treatment is generally well tolerated, although some patients develop a radiation reaction in the salivary glands. More important, however, is the 1% to 2% incidence of radiation-induced leukemias.[71]

Neuroblastomas, and tumors of neuroectodermal origin in general, frequently metastasize to bone. Some 90% of these neoplasms incorporate the radiopharmaceutical 131I-meta-iodo benzyl guanadine (131I-MIBG), and this has now been used to treat many children with metastatic neuroblastoma. Bone marrow suppression is often severe, and ideally, bone marrow harvesting should be performed as a precautionary measure on patients with extensive bone metastases.

131I-MIBG has also been used therapeutically to treat bone metastases from malignant pheochromocytoma, medullary carcinoma of the thyroid, and carcinoid tumors with limited success. Between one-third and one-half of patients achieve symptomatic benefit, but long-term remissions are rare.

Strontium-89 (89Sr) is a β emitter that imitates calcium and is taken up preferentially at sites of new bone formation. It has been shown to localize at the sites of prostatic bone metastases, with greater accumulation occurring in the metastatic lesions than is observed in normal bone. [71] [72] The biologic half-life of strontium in metastases is long compared with that of normal bone, with whole-body retention of 89Sr treatments ranging from 11% to 88% depending on the degree of skeletal involvement. The radiation dose to individual vertebral metastases from a single 150-MBq dose of 89Sr has been shown to vary from 9 Gy to 92 Gy depending on the extent of metastatic spread. Of great clinical importance is the low dose of radiation to the bone marrow, which is only about one-tenth of that to the bone metastases.

The selective β-particle irradiation provides pain relief in up to 80% of patients, with 10% to 20% becoming pain free.[72] On average, the response lasts for 6 months, with only mild hematologic toxicity. Several randomized clinical trials have been performed. These have included a double-blind, placebo-controlled trial of 89Sr, with active therapy clearly superior in terms of pain relief (P < 0.01).[72] 89Sr has also been compared with conventional radiotherapy (hemibody or local) for the palliation of bone metastases from prostatic cancer. 89Sr was at least as effective as external beam radiotherapy in achieving palliation and seemed also to delay or prevent the development of new sites of pain.

Samarium-153 (153Sm) is both a β- and a γ-ray emitter, making it suitable for combined therapy and imaging. It has a short half-life (46 hours) and, linked to ethylene diamine tetramethylene phosphonate (EDTMP) for use as a radiopharmaceutical, concentrates preferentially in skeletal metastases. Clinical reports indicate that 153Sm-EDTMP can provide excellent palliation of pain in both breast[73] and prostate cancer.[74] The short half-life also makes 153Sm-EDTMP suitable for repeated treatments.

Rhenium-186, an investigational radiopharmaceutical, which is also a β- and a γ-ray emitter, in complex with hydroxyethylidene diphosphonate is used therapeutically. Studies suggest encouraging clinical results with a 70% response rate.[75] Bone marrow toxicity is mild and reversible, making the compound potentially suitable for repeated administration. However, comparative studies of this agent with other therapeutic radionuclides are needed before its clinical role can be defined clearly.

Most recently the bone-seeking, α-particle-emitting radiopharmaceutical Alpharadin 223RaCl2 (radium chloride) has been developed. In addition to effective palliation of bone pain, early results suggest an antiumor effect with declines in PSA levels in a population of patients with advanced prostate cancer.[76]

Systemic Therapy

Systemic therapy for bone metastases can be directed against the tumor cell to reduce both cell proliferation and, in consequence, the production of cytokines and growth factors. Alternatively, systemic treatment is directed toward blocking the effect of these substances on host cells. Chemotherapy, biologically targeted agents, endocrine treatments, and bone-seeking isotopes have direct antitumor effects, whereas agents such as the bisphosphonates and denosumab are effective by preventing host cells (primarily osteoclasts) from reacting to tumor products. Systemic therapy, therefore, has either direct or indirect actions.

In general, the systemic treatment for metastatic bone disease is the same as that available for other metastatic manifestations of the malignancy. Treatment must therefore be discussed according to tumor type. Breast and prostate cancers are the most important, first because there are effective (albeit palliative) systemic treatments available, and second because these two tumors represent the majority of patients with bone metastases. For a fuller discussion of systemic cancer management, the relevant site-specific chapters should be consulted.

Breast Cancer

For breast cancer, endocrine therapy is the treatment of choice for the initial treatment of metastatic disease. Exceptions to this are when visceral disease is so extensive and/or aggressive that it is inadvisable to wait 6 to 8 weeks for a possible response—for example, when there are lymphangiitic pulmonary metastases or liver metastases with compromised hepatic function. In these two situations, cytotoxic chemotherapy is the initial treatment of choice.

Hormones act predominantly on cancer cells that express high-affinity binding proteins (receptors) for estrogen and progesterone (PgR). These hormone-receptor complexes, in turn, act on the cell nucleus to mediate the specific cell response of the hormone. Significant (>50%) tumor shrinkage (a complete or partial objective response) after endocrine treatment occurs in one-third of unselected patients but is more likely among those with either steroid-receptor-positive tumors, a long disease-free interval from diagnosis to relapse, or bone or soft tissue metastases rather than visceral disease.

Selection of specific endocrine treatment for patients is based on menopausal status. Premenopausal patients are now usually treated with a combination of tamoxifen and ovarian ablation, the latter achieved by the use of LHRH agonists, surgical bilateral oophorectomy or in some centres ovarian irradiation. For postmenopausal patients the choice of agents is large with aromatase inhibitors, tamoxifen, fulvestrant, and progestogens the most frequently used. Although in general the median duration of response to endocrine therapy is around 15 months, prolonged responses to first-line hormone treatments lasting several years are not uncommon in patients with bone metastases.

Numerous recent developments in cytotoxic and biological treatments are of relevance to the patient with metastatic bone disease. Patients with disease progressing after endocrine therapy, and those with rapidly progressive life-threatening disease or those who are known to have estrogen receptor- and progestogen receptor-negative tumors, should be considered for cytotoxic chemotherapy. This is usually combined with trastuzumab in patients with tumors overexpressing the HER2neu growth factor receptor. Objectively responding patients usually gain relief of symptoms (including bone pain) and might become able to resume their previous activities.

Responses among women with bone metastases are nearly always only partial, with a median duration of response of 9 to 12 months. The precise choice of drugs and schedule of administration to obtain the best results is not yet certain and vary from one patient or clinical problem to another. The anthracyclines (doxorubicin and epirubicin) and the taxanes (docetaxel and paclitaxel) are particularly active but at full doses are sometimes too toxic for elderly or frail patients. Chemotherapy can be especially hazardous for patients with extensive bone disease because of both poor bone marrow tolerance after replacement of functioning marrow by tumor and the effects of previous irradiation. In view of this, regimens with relatively little myelotoxicity are usually preferable. The use of hematopoietic growth factors may be required to permit chemotherapy to be administered safely.

Prostate Cancer

In prostate cancer, bone is the dominant site for metastatic disease and in many patients is the only symptomatic problem. The appearances on plain radiography are predominantly osteoblastic and because of this, radiologic response is notoriously difficult to evaluate. Nevertheless, at least 80% of prostate tumors show some degree of hormone responsiveness.

Worldwide, the luteinizing hormone-releasing hormone (LHRH) agonists are the most commonly used form of endocrine therapy, although surgical castration remains a first-line treatment in some parts of the world. Stilbestrol is no longer appropriate first-line therapy because of its feminizing effects and cardiovascular risks. The role of combined endocrine therapy causing total androgen blockade (LHRH + antiandrogen) and the timing of endocrine interventions have, and continue to be, areas of intense clinical trial investigation.

Patients with advanced prostate cancer tend to be elderly and often of poor performance status. Because of this and the presence of widespread bone involvement, their tolerance of toxic chemotherapy regimens is often poor, and this has significantly limited the use of this treatment modality. Until recently there was little evidence that cytotoxic drugs prolonged survival for patients with advanced prostate cancer. Mitoxantrone and prednisone has been shown in a randomized trial to provide better palliation of symptoms and improved quality of life compared with that achieved with prednisone alone.[77]More recently, docetaxel has been shown to be an active cytotoxic agent in endocrine-resistant prostate cancer and is able to improve median survival by about 3 months. Cautious use of this agent in appropriate patients is now recommended.[78]

Other Tumors

Skeletal morbidity is a major problem in multiple myeloma, and either widespread lytic metastases or diffuse osteopenia can occur. Around 50% of patients respond to chemotherapy, with a reduction in paraprotein levels and subjective improvement. Alkylating agents, anthracyclines, vinca alkaloids, and the corticosteroids are the most frequently prescribed first-line agents. Despite the subjective improvement that is seen, bone healing is rare, with lytic lesions persisting despite control of the disease for months or years. Survival in multiple myeloma has been shown to be improved by the selective use of high-dose chemotherapy with bone marrow or peripheral blood stem cell support, and this is part of standard first-line treatment in fit patients under the age of 65.[79] Newer agents including thalidomide and related analogs, bortezomib, and arsenic trioxide provide many more options that have transformed the clinical course of multiple myeloma in recent years into that of a chronic disease.

Bone involvement in curable malignancies is uncommon. In patients with germ cell tumors, bone involvement is an adverse prognostic feature, but despite this, cure with chemotherapy is usual. Bone involvement at diagnosis in lymphoma is relatively uncommon. When localized it does not significantly affect the prognosis in Hodgkin's disease but does carry an adverse prognosis in non-Hodgkin's lymphoma. Curative therapy is still possible, however, and there is no evidence that bone represents a “sanctuary site.”

Chemotherapy is of only limited and temporary benefit in relatively chemotherapy-resistant solid tumors such as non–small cell lung cancer or melanoma. Patients with skeletal metastases from these tumors derive most benefit from local palliative radiotherapy and bisphosphonates. Alternative (and more effective) systemic treatment approaches are urgently needed for many of these maligancies. Biologic agents, especially the angiogenesis inhibitors sorafinib and sunitinib, are showing great promise in renal cell cancer, and small molecules and antibodies are being developed at a rapid pace across a range of tumors.[80]

Bisphosphonates

In the last two decades the bisphosphonates have become established as a valuable additional approach to the range of current treatments. All bisphosphonates are pyrophosphate analogs, characterized by a P-C-P containing central structure rather than the P-O-P of pyrophosphate, and a variable R′ chain that determines the relative potency, side effects, and the precise mechanism of action.[81] The P-C-P backbone renders bisphosphonates resistant to phosphatase activity and promotes their binding to the mineralized bone matrix. The structures of the commonly used bisphosphonates are illustrated in Figure 57-14 .

 
 

Figure 57-14  Structural formulas of commonly used bisphosphonates in relation to pyrophosphate.

 

 

After administration, bisphosphonates bind avidly to exposed bone mineral around resorbing osteoclasts, leading to very high local concentrations of bisphosphonate in the resorption lacunae (up to 1000 mM). During bone resorption, bisphosphonates are internalized by the osteoclast, where they cause disruption of several biochemical processes involved in osteoclast function, ultimately leading to apoptotic cell death. These include destruction of the cytoskeleton, disruption of the sealing zone at the bone surface, and loss of the ruffled border across which the hydrolytic enzymes and protons necessary for bone dissolution are normally secreted. The molecular mechanism of action of the bisphosphonates are now established, with nitrogen-containing bisphosphonates having been shown to inhibit enzymes of the mevalonate pathway, which are responsible for events that lead to the post-translational modification of a number of proteins including the small guanosine triphosphatases such as Ras and Rho.[81] Non-nitrogen-containing bisphosphonates, such as clodronate, have been found to induce osteoclast apoptosis through the generation of cytotoxic adenosine triphosphate analogs.[82]Recent studies also suggest that bisphosphonates could have direct apoptotic effects on tumor cells, and that this effect may be enhanced by combination with other anticancer agents.[83]

After intravenous administration of a bisphosphonate, approximately 25% to 40% of the injected dose is excreted by the kidney, and the remainder is taken up by bone.[84] All bisphosphonates suffer from poor bioavailability when given by mouth. They must be taken on an empty stomach, because they bind to calcium in the diet and can cause gastrointestinal toxicities such as nausea, vomiting, indigestion, and diarrhea.[85]

Irrespective of the mechanism(s) of action, bisphosphonates have been used successfully in the treatment of conditions characterized by increased osteoclast-mediated bone resorption, such as Paget's disease of bone or osteoporosis. In oncology they have become the standard treatment for tumor-induced hypercalcemia and a valuable, new form of medical therapy for bone metastases.[86]

Rationale for the Wider Use of Bisphosphonates

As indicated previously, it is now generally accepted that osteoclast activation is the key step in the establishment and growth of bone metastases. Biochemical data indicate that bone resorption is of importance not only in classic “lytic” diseases such as myeloma and breast cancer but also in prostate cancer, with values of resorption markers in the latter at least as high as those seen in breast cancer and other solid tumors. [10] [53] As a result, the osteoclast is a key therapeutic target for skeletal metastases irrespective of the tissue of origin.

Bisphosphonates to Prevent Skeletal Morbidity and Relief of Bone Pain

Although radiotherapy is the treatment of choice for localized bone pain, many patients have widespread, poorly localized bone pain, whereas others experience recurrence of bone pain in previously irradiated sites. The bisphosphonates provide an additional treatment approach for the relief of bone pain across a range of tumor types, and the effects seems to be independent of the nature of the underlying tumor or radiographic appearance of the metastases, with sclerotic lesions responding similarly to lytic metastases.[87]

Additionally, based on the results of large randomized controlled trials conducted in the late 1990s, the bisphosphonates became the standard of care for the treatment and prevention of skeletal complications associated with bone metastases in patients with breast cancer and multiple myeloma. More recently, they have demonstrated benefits in patients with bone metastases secondary to other cancers including prostate cancer,[88] lung cancer,[88] and other solid tumors ( Table 57-4 ). [89] [90]


Table 57-4   -- Effects of Bisphosphonates on Skeletal Morbidity: Results of Randomized Trials

 

 

BREAST CANCER

Agent and Route

N

Results

Investigator

Clodronate 1600 mg PO vs. placebo

173

Reduced SMR

Paterson[92]

 

 

305 vs. 219 events/100 woman years (P< 0.001)

 

Pamidronate 45 mg IV vs. control

295

Increased time to bone progression

Conte[95]

 

 

168 vs. 249 days (P = 0.02)

 

Pamidronate 90 mg IV vs. placebo

382

Reduced proportion experiencing SRE

Hortobagyi[97]

 

 

65% vs. 46% (P < 0.001)

 

 

 

Delay in first SRE

 

 

 

7.0 vs. 13.1 months (P = 0.0005)

 

Pamidronate 60 mg IV vs. control

401

Median time to skeletal progression

Hultborn[96]

 

 

9 vs. 14 months (P < 0.01)

 

Pamidronate 90 mg IV vs. placebo

374

Reduced proportion experiencing SRE

Theriault[98]

 

 

67% vs. 56% (P = 0.027)

 

 

 

Delay in first SRE

 

 

 

6.9 vs. 10.4 months (P = 0.049)

 

Ibandronate 2/6 mg IV vs. placebo

467

Reduced SMR with 6-mg dose, 2 mg ineffective

Body[104]

 

 

SMR 2.18 vs. 1.61 (P = 0.03)

 

Zoledronic acid 4 mg IV vs. placebo

227

Reduced proportion experiencing SRE

Kohno[101]

 

 

50% vs. 30% (P = 0.003)

 

 

 

Reduced SMR by 43% (P = 0.016)

 

 

 

MULTIPLE MYELOMA

Agent and Route

N

Results

Investigator

Clodronate 1600 mg PO vs. placebo

350

Improved 2-year progression-free survival 24% vs. 12% (P < 0.05)

Lahtinen[105]

Pamidronate 90 mg IV vs. placebo

392

Reduced proportion experiencing SRE 24% vs. 41% (P < 0.001)

Berenson[107]

Clodronate 1600 mg PO vs. placebo

614

Less skeletal morbidity and pain on progression

McCloskey[106]

 

 

MULTIPLE MYELOMA AND BREAST CANCER

Agent and Route

N

Results

Investigator

Zoledronic acid 4/8 mg IV vs. pamidronate 90 mg IV

1648

Zoledronic acid (4 mg) showed clinical activity equivalent to that of pamidronate (90 mg)

Rosen [102] [103]

 

 

In breast cancer patients, 43% had a SRE with 4 mg zoledronic acid, compared with 45% with pamidronate.

 

 

 

In myeloma, 47% of patients had a SRE with zoledronic acid and 49% with pamidronate

 

 

 

PROSTATE CANCER

Agent and Route

N

Results

Investigator

Clodronate (4 × 520) mg oral vs. placebo

311

Reduction in number of SREs vs. placebo not significant (49% vs. 41%, P = NS)

Dearnaley[110]

Pamidronate 90 mg IV vs. placebo

378

Number of SREs equal in pamidronate and placebo arms, P = 1.0

Small[112]

Zoledronic acid 4/8 mg vs. placebo

643

Proportion of patients experiencing at least one SRE during the study was 25% lower in the zoledronate arm than in the placebo arm (P = 0.021)

Saad [88] [113]

 

 

OTHER TUMOR TYPES

Agent and Route

N

Results (Bisphosphonate vs. Placebo/Control)

Investigator

Zoledronic acid 4/8 mg vs. placebo

773

Significant delay to time of first skeletal event in Zoledronic acid arm compared with placebo (P = 0.023)

Rosen[89]

 

 

Significant reduction in proportion of patients having an event (47% vs. 38%, P = 0.039)

 

SRE, skeletal related event; SMR, skeletal morbidity rate.

 

 

 

BREAST CANCER.

The greatest experience with bisphosphonates is in the management of bone metastases from breast cancer, and the value of the agents is now undisputed.[91]

Oral Bisphosphonates.

The absorption of bisphosphonates from the gut is poor, variable, and dramatically inhibited by food intake. To make matters worse, the absorbed fraction of oral bisphosphonates decreases even further when the absolute ingested amount is lower; thus, the more potent bisphosphonates are even less well absorbed than etidronate and clodronate. Nevertheless, both oral clodronate and ibandronate have been shown in randomized trials to have some clinical efficacy (see Table 57-4 ). [92] [93]

Paterson and coworkers randomized 173 patients with bone metastases from breast cancer to receive either clodronate capsules, 1600 mg daily, or placebo capsules of identical appearance in addition to appropriate anticancer treatment(s).[92] In the patients who received clodronate, there was a significant reduction in skeletal morbidity (219 vs. 305 events per 100 patient years). Most of the benefit was accounted for by a reduction in hypercalcemic episodes and the incidence of vertebral fractures, with no significant effect on nonvertebral fractures, radiotherapy requirements, changes in antitumor therapy, or survival.

Oral ibandronate is the newest and most potent oral agent and is available in Europe and many other countries outside North America. A film-coated formulation of ibandronate has been developed that has been shown to produce a dose-dependent reduction, at doses that are generally well tolerated, in both urinary calcium and collagen cross-link excretion.[93] Phase III placebo-controlled trials of the oral formulation have been completed. The endpoint of a significant reduction in the proportion of patients experiencing a SRE was not met. However the skeletal morbidity rate was significantly less with ibandronate, and the investigators concluded that the activity of oral ibandronate is similar to other bisphosphonates.[94] This new oral agent has obvious attractions to both patients and health care providers, but the place of ibandronate cannot be clearly defined until comparative data with other bisphosphonates are available.

Intravenous Bisphosphonates.

In the first randomized study of intravenous pamidronate, Conte and associates[95] randomized 295 patients with breast cancer and bone metastases to chemotherapy with or without intravenous pamidronate, 45 mg every 3 weeks (a dose intensity of pamidronate that is now considered suboptimal). Blinded, extramural review of serial radiographs was performed and identified a 48% increase in the median time to progression in bone in favor of the patient group who received pamidronate (249 vs. 168 days, P = 0.02). The other major endpoint of this trial was bone pain. A marked improvement in pain was seen more often in the pamidronate group (44% vs. 30%, P = 0.025), indicating that intravenous pamidronate adds to the symptom relief achieved by chemotherapy alone. Similar results were reported in a Scandinavian trial, in which 401 patients receiving chemotherapy for advanced breast cancer were randomly allocated to receive either an intravenous pamidronate infusion (60 mg every 4 weeks) or a placebo infusion of the same dose intensity of pamidronate that was given in the Conte study.[96]

Subsequently, the results of two double-blind, placebo-controlled trials of 90 mg pamidronate infusions every 3 to 4 weeks in addition to cytotoxic or endocrine treatments for patients with breast cancer and lytic bone metastases established bisphosphonate treatment as the standard of care in breast cancer. [97] [98] These two studies were of similar design, with the exception of the systemic anticancer treatment at study entry. As in all subsequent bisphosphonate trials the primary endpoint of these studies was the influence of pamidronate on the number of patients experiencing SREs as well as the time to first SRE and the rate of SREs as determined by either a simple annual rate or more complex multiple event analysis techniques. SREs were defined as

  

   

Occurrence of pathologic long bone and vertebral fractures

  

   

Development of spinal cord compression

  

   

Need for radiation for pain relief or to treat or prevent pathologic fractures or spinal cord compression

  

   

Requirement for surgery to bone

  

   

Episodes of hypercalcemia of malignancy

In the chemotherapy study,[97] 382 patients received either pamidronate 90 mg or placebo every month in combination with systemic chemotherapy. The median time to the SRE was significantly longer in the pamidronate group than in the placebo group (13.1 vs. 7.0 months, P = 0.005), and the proportion of patients in whom any SRE occurred was significantly lower (43% vs. 56%, P = 0.008). Benefits were maintained for at least 2 years. Pain, analgesic use, and Eastern Cooperative Oncology Group (ECOG) performance status were monitored throughout the study period. Because there was inevitably a tendency for the underlying cancer to progress during the study period, there was an overall deterioration in mean performance status, pain, and analgesic consumption. The deterioration, however, was significantly less in the pamidronate group for all of these endpoints. Quality of life was also better maintained in the pamidronate group. Survival was similar in other treatment groups.

In the endocrine study, 374 patients were randomized to receive hormone therapy with pamidronate 90 mg or placebo every month.[97] As in the chemotherapy study, pamidronate reduced the number and rate of SREs. The time to first SRE (excluding hypercalcemia of malignancy) was 6 months for the placebo group and 10 months for those receiving pamidronate (P < 0.049). The benefits of pamidronate were slower to appear than in the chemotherapy study, but again the effect was maintained for at least 2 years. The effects on pain and analgesic consumption were even more clearly evident in this study. Again, there was no difference in survival by treatment group.

Zoledronic acid is the most potent bisphosphonate available. A phase I study of 30 patients with hypercalcemia indicated that dose levels as low as 0.02 mg/kg (1–2 mg total dose) were effective in achieving normocalcemia.[99] Following a dose-finding, phase II study of zoledronic acid at doses of 0.5 g, 2 g, and 4 mg zoledronic acid given on a 4-weekly schedule, 4 mg zoledronic acid was selected for phase III evaluation.[100] A plaeebo-controlled trial of zoledronic acid was performed in Japan.[101] In this study, Kohno and coworkers randomly assigned women with bone metastases from breast cancer to treatment with zoledronic acid (n = 114) or placebo (n = 114) every 4 weeks. After 1 year, the percentage of patients with at least one SRE (excluding hypercalcemia of malignancy) was significantly reduced by 20% by zoledronic acid (29.8% vs. 49.6% for placebo; P = 0.003). Zoledronic acid also significantly delayed the time-to-first SRE (P = 0.007) and reduced the risk of SREs by 41% in multiple event analysis (P = 0.019) compared with placebo.

Elsewhere in the world zoledronic acid was compared to pamidronate in a randomized, double-blind, phase III trial.[102] The trial was designed as a noninferiority trial, in which the primary efficacy variable was the proportion of patients experiencing at least one SRE. A group of 1130 patients with advanced breast cancer and at least one metastatic bone lesion were randomized to receive either 4 mg zoledronic acid or 8 mg zoledronic acid via a short intravenous infusion, or 90 mg pamidronate via a 2-hour infusion. Treatments were administered every 3 to 4 weeks. Initially, zoledronic acid was administered as a 5-minute infusion in 50 mL of 0.9% saline or 5% dextrose. This was amended to a 15-minute infusion in 100 mL of saline or dextrose because of concerns over renal toxicity. Similarly, the 8-mg dose of zoledronic acid was reduced to 4 mg because of continuing concerns over renal safety.

After 25 months of follow-up, the reduction in the overall proportion of patients with a SRE and the skeletal morbidity rate were similar in patients receiving zoledronic acid and pamidronate. However, zoledronic acid 4 mg reduced the risk of developing skeletal complications (including hypercalcemia of malignancy) as determined by multiple event analysis by an additional 20% compared with pamidronate in the overall population (P = 0.025).[103] Thus, the risk of skeletal complications with zoledronic acid is approximately one-half the rate experienced in the prebisphosphonate era ( Fig. 57-15). All markers of bone resorption or formation decreased from baseline to the end of the study, but at all time points the urinary marker of bone resorption NTX was significantly less in the zoledronic acid 4-mg group than in the pamidronate group. Median overall survival was similar at approximately 2 years in the study groups. The most common adverse events were bone pain, nausea, fever, and fatigue, and as with the other adverse effects, they occurred generally with a similar frequency in each group. The incidence of renal dysfunction among the patients receiving 4 mg zoledronic acid (given on the 15-minute schedule) was indistinguishable from that for the pamidronate patients.

 
 

Figure 57-15  Incremental improvement in the risk of skeletal-related events with use of pamidronate and more recently zoledronic acid in the treatment of bone metastases from breast cancer.

 

 

Ibandronate is another highly potent amino-bisphosphonate that is licensed in Europe for the treatment of hypercalcemia of malignancy, the treatment of metastatic bone disease, and the prevention and treatment of osteoporosis. A phase III placebo-controlled trial of monthly infusions in breast cancer has shown a significant reduction in skeletal-related morbidity with ibandronate 6 mg.[104] Additionally, improvements in pain and quality of life were clearly demonstrated at this dose. However, as with the oral formulation, the clinical value of intravenous ibandronate is unclear until comparative trials with established bisphosphonates are completed.

MULTIPLE MYELOMA.

Multiple myeloma is typically characterized by a marked increase in osteoclast activity and proliferation. This excessive resorption of bone can be detected histomorphometrically at an early phase in the development of the disease, and this itself could, through the release of interleukin-6 by the osteoclasts, play a contributory role to the growth of myeloma cells in bone. Bisphosphonates could thus be of great benefit in these patients.

Oral Bisphosphonates.

In a randomized, placebo-controlled trial of 350 patients with newly diagnosed myeloma, it was demonstrated that 2.4 g of clodronate daily for 2 years results in a significant reduction in the proportion of patients developing progression of osteolytic bone lesions (24% vs. 12%). There was only a mild, albeit significant, effect on the incidence of bone pain, however, and no effect on the occurrence of fractures or overall survival.[105] Another randomized, placebo-controlled trial of 614 patients evaluated the efficacy of 1600 mg daily of clodronate given from the time of diagnosis. Treatment with clodronate was associated with a 50% decrease in the proportion of patients with severe hypercalcemia (5.1% vs. 10.1%, P = 0.06) and a reduction in reported nonvertebral fractures (6.8% vs. 13.2%, P = 0.04). Additionally, a 30% reduction in the number of vertebral fractures (80 vs. 146, P = 0.012) was observed in a subset of patients with serial spine radiograms available for review.[106]

Intravenous Bisphosphonates.

In the last 10 years, intravenous bisphosphonates have become routine clinical management for most patients with multiple myeloma. This followed the very clear results demonstrated in a 21-month placebo-controlled trial of pamidronate 90 mg conducted in 392 patients.[107] The proportion of patients developing SRE(s) was significantly lower in the group receiving pamidronate than the group receiving placebo (24% vs. 41%, P < 0.001). Quality-of-life scores, performance status, pain scores, the incidence of pathologic fractures, and the need for radiotherapy were all favorably influenced by pamidronate therapy.

Zoledronic acid has also been evaluated in multiple myeloma; 450 patients with advanced myeloma were included in a randomized trial comparing zoledronic acid with pamidronate.[102] No significant differences between the two agents were identified. Of the patients treated with zoledronic acid 4 mg, 50% experienced one or more SREs, compared with 54% in the group receiving pamidronate. The risk of an SRE was 7% lower with zoledronic acid, but this difference was not statistically significant.[103]

Intravenous ibandronate has been investigated in a randomized trial; however, the 2-mg dose chosen was unfortunately inactive and not statistically different from placebo.[108] It is now known that a dose of ibandronate 6 mg is required to reduce skeletal morbidity from metastatic bone disease.[104]

PROSTATE CANCER.

Bisphosphonates have been shown to reduce biochemical markers of bone resorption in patients with osteoblastic bone lesions that are associated with advanced prostate cancer. Additionally, several phase II studies have assessed bone pain and analgesic use with some benefit in these acute endpoints.[86] However, these trials were statistically underpowered to detect significant effects on skeletal complications, and the results were not sufficiently convincing to lead to either regulatory approval for or widespread use of bisphosphonates for metastatic bone disease in prostate cancer. Furthermore, until recently, randomized, placebo-controlled trials of bisphosphonates had failed to demonstrate a significant reduction in skeletal complications from bone metastases in patients with advanced prostate cancer.

Oral Bisphosphonates.

In a study of 57 patients with hormone-refractory prostate cancer and bone pain at study entry, Smith[109] concluded that etidronate had no significant effects on pain levels or analgesic usage over and above placebo. The Medical Research Council in the United Kingdom performed a phase III trial of oral clodronate (Loron, 1040 mg twice daily) in 311 men with metastatic bone disease from prostate cancer.[110] A slight reduction in the proportion of patients receiving clodronate who experienced a SRE, an improvement in time to progression and increased median survival were observed, but none of these differences was statistically significant.

Intravenous Bisphosphonates.

A more recent clinical trial involving 208 patients investigated both pain and analgesic usage. In this study, intravenous clodronate was added to a background treatment of mitoxantrone and prednisolone. The study also included objectively measurable skeletal complications as clinical endpoints. No significant differences between clodronate and placebo were seen.[111]

Pamidronate has also been studied in 236 patients with prostate cancer and bone metastases treated with intravenous pamidronate (90 mg) or placebo every 3 weeks for 9 months. This trial assessed bone pain as the primary endpoint and included an assessment of SREs as a secondary endpoint. Patients in this trial had very advanced disease (median baseline PSA = 97.8 ng/mL in the pamidronate group), very high levels of bone resorption, and substantial bone pain at study entry. Pamidronate did not reduce the incidence of SREs and had only a slight effect on bone pain.[112]

Despite the failure of all other bisphosphonates, zoledronic acid was investigated in patients with advanced prostate cancer to determine whether the increased potency of this compound would translate into improved clinical benefit. In this study, 643 patients with hormone-refractory prostate cancer and documented bone metastases were randomized to receive either placebo or zoledronic acid at a dose of 4 mg or 8 mg administered every 3 weeks.[88] In the 8-mg arm, the dose was reduced by a protocol amendment to 4 mg because of concerns over renal safety, and conclusions on the efficacy of this cohort are difficult to make. Zoledronic acid was significantly more effective than placebo across all primary and secondary endpoints. The zoledronic acid 4 mg treatment group experienced significantly fewer SRE(s) (33% vs. 44% with placebo; P = 0.021). Furthermore, there were consistent reductions in the proportion of patients with each type of skeletal complication, including nonvertebral fractures. Zoledronic acid also prolonged the time to first skeletal complication by more than 4 months (P = 0.011). Zoledronic acid 4 mg remained superior to placebo when fractures were excluded, indicating that the beneficial effect was not simply as a result of the prevention of osteoporotic fractures. Using the Andersen-Gill multiple-event analysis, it was calculated that zoledronic acid 4 mg reduced the overall risk of skeletal complications by 36%.[113] Zoledronic acid reduced bone pain at all time points. Despite the favorable effects on skeletal morbidity, however, there were no significant effects on disease-related endpoints such as time to progression and survival. Treatment was generally well tolerated, and in particular the risk of renal function deterioration in patients treated with zoledronic acid 4 mg via a 15-minute intravenous infusion was found to be similar to that of placebo-treated patients. The only adverse events that occurred at increased frequency with zoledronic acid were fatigue, anemia, myalgia, and pyrexia.

OTHER TUMORS.

Until recently there had only been anecdotal reports of the use of bisphosphonates in other tumors associated with bone metastases. The pathophysiology of bone metastases is broadly similar in all tumor types, however, and bisphosphonates could thus be expected to be of value in preventing skeletal morbidity, especially if metastatic bone disease was a patient's dominant site of disease. As part of the development program for zoledronic acid, a phase III randomized, placebo-controlled trial was performed in the management of bone metastases from solid tumors other than breast or prostate cancer.[89]The study found that 4 mg of zoledronic acid significantly reduced the proportion of patients with at least one SRE (39% vs. 48%, P = 0.039) and significantly prolonged the time to the first SRE compared with placebo (314 days vs. 168 days, respectively, P = 0.021). This is a particularly important result in a population of patients with a very short median survival time (6 months). Overall, zoledronic acid reduced the risk for SRE(s) by about 30% (hazard ratio 0.693 vs. placebo, P = 0.003). Of particular note was a 58% reduction in the risk of an SRE in the subgroup of patients with renal cell cancer accompanied by an apparent increase in time to progression and overall survival, albeit in an unplanned subset analysis.[90]

Optimum Use of Bisphosphonates in Metastatic Bone Disease

Criteria need to be determined regarding when in the course of metastatic bone disease bisphosphonates should be started and stopped. [114] [115] Because of the logistics and cost of delivering monthly intravenous infusions for all patients with metastatic bone disease, certain empiric recommendations on who should receive treatment are needed.[116] These should take into account the underlying disease type and extent, the life expectancy of the patient, the probability of the patient experiencing a SRE, and the ease with which the patient can attend for treatment (or be treated by a domiciliary service).

Consensus guidance recommendations indicate that all patients with multiple myeloma[116] and radiologically confirmed bone metastases from breast cancer[117] should receive bisphosphonates from the time of diagnosis and continued indefinitely. The development of an SRE is not necessarily a sign of treatment failure or signal to stop treatment; evidence is now available to confirm that bisphosphonates delay second and subsequent complications, not just the first event. However, a recent report suggested that switching to zoledronic acid may be an appropriate option in breast cancer patients in whom pamidronate or clodronate therapy proves unsatisfactory. Clemons and colleagues conducted a phase II clinical trial involving 31 patients with breast cancer who had experienced progressive bone metastasis or SREs while on pamidronate or clodronate therapy. Subjects were switched to monthly administration of zoledronic acid 4 mg. After 8 weeks, 13 of 31 subjects (42%) reported a reduction in pain (P < 0.001). The switch to zoledronic acid was also associated with significant reductions in urinary markers of bone turnover (P = 0.008).[118]

Bisphosphonate treatment—specifically zoledronic acid—is also appropriate for patients with endocrine-resistant metastatic bone disease from prostate cancer. Patients with other tumors and symptomatic metastasis to bone should be considered for bisphosphonate treatment if bone is the dominant site of metastasis, especially if the prognosis is reasonable (longer than 6 months). Patients with renal cell cancer particularly seem to benefit from treatment.

Despite the obvious clinical benefits of bisphosphonates, it is clear that only a proportion of events is prevented, and some patients do not experience a skeletal event despite the presence of metastatic bone disease. It is currently impossible to predict whether an individual patient needs or will benefit from a bisphosphonate. Overall, bisphosphonates reduce the frequency of skeletal events by 25% to 40%; however, bisphosphonates are a relatively costly additional intervention in cancer care that is now potentially applicable to a very large proportion of patients with advanced malignancy. The cost effectiveness of routine long-term treatment has been questioned, and prioritization of bisphosphonate use is essential. [119] [120]

A report on the use of the bone resorption marker NTX suggests that biochemical monitoring could be useful to identify patients at high risk of skeletal complications. In this study of 121 patients with bone metastases, monthly measurements of urinary NTX were made during treatment with a range of bisphosphonates.[121] All SREs, hospital admissions for control of bone pain, and deaths during the period of observation were recorded. NTX was strongly correlated with the number of SREs and/or deaths (P < 0.001). Patients with NTX values above 100 nmol/mmol creatinine were many times more likely to experience an SRE or death than those with NTX below this level (P < 0.01). Thus, a more cost-effective use of bisphosphonates, particularly in patients with additional extensive visceral metastases or solid tumors associated with a short life expectancy, might be to reserve them until patients have raised NTX levels, and to adjust the dose and schedule to maintain a normal rate of bone resorption. Randomized trials to assess this approach are planned.

Uncertainty remains about the appropriate duration and schedule of treatment. Bone marker–directed therapy is under evaluation in randomized clinical trials, and the value of maintenance therapy after 1 to 2 years of treatment may become clear from the Optimize trial ongoing in the United States. Long-term, full-dose monthly intravenous treatment is associated with the development of osteonecrosis of the jaw (a hitherto rarely encountered problem characterized by painful bone destruction, secondary infection, and delayed healing in the mandible and or maxilla).[122] The risk of osteonecrosis of the jaw is related to duration of treatment at around 1% per year on therapy.[123] Good dental hygiene and pretreatment restorative treatment are recommended to reduce the risk of this unpleasant complication of treatment.[124]

New Targeted Therapies in the Treatment of Metastatic Bone Disease

As our understanding of the signaling mechanisms between bone cells themselves and bone cells and tumor cells increases, several targeted agents have entered clinical development. These include inhibition of RANKL, cathepsin K (an osteoclast-derived enzyme that is essential for the resorption of bone), PTHrP, and Src (a key molecule in osteoclastogenesis). Of all these, inhibition of RANKL seems the most promising.

Denosumab is a fully human monoclonal antibody that binds and neutralizes RANKL with high affinity and specificity, thereby inhibiting osteoclast function and bone resorption. Denosumab could potentially be used to treat bone loss caused by bone metastases, multiple myeloma, or osteoporosis. Following a single subcutaneous dose, denosumab caused rapid and sustained suppression of bone turnover in postmenopausal women with low bone mass,[125] as well as in multiple myeloma and breast cancer patients.[126] A subsequent dose-finding phase II study has defined a dose and schedule for phase III development of 120 mg four times weekly. Currently a broad program in metastatic disease, treatment-induced bone loss, and bone metastasis prevention studies are underway.

Protecting the Skeleton

Prevention of Bone Metastases

Bone is the most frequent site of distant relapse, accounting for around 40% of all first recurrences.[1] In addition to the well-recognized release of bone cell-activating factors from the tumor, it is now appreciated that release of bone-derived growth factors and cytokines from resorbing bone can both attract cancer cells to the bone surface and facilitate their growth and proliferation.[127] Inhibition of bone resorption could therefore have an effect on the development and progression of metastatic bone disease and is an adjuvant therapeutic strategy of potential importance.

Encouraging animal studies with a variety of animal tumor models and a range of bisphosphonates have shown inhibition of bone metastasis development and a reduction in tumor burden within bone.[128]More recently, several clinical trials have been reported using the relatively low-potency oral bisphosphonate, clodronate. In the largest study, 1079 women with primary operable breast cancer were randomized to receive either clodronate 1600 mg daily or placebo for 2 years in addition to standard adjuvant systemic treatment. With a median follow-up time of 5 years, a modest reduction in the frequency of bone metastases in the patients treated with clodronate (63 [12%] vs. 80 [15%] patients) was seen.[129] There was no significant effect on non-bone recurrence (112 [21%] vs. 128 [24%] patients), but patients randomized to the clodronate arm had a higher probability of survival (82% vs. 77%, P = 0.047).

In a second study, Diel and colleagues[130] studied 302 patients with breast cancer selected on the basis of immunocytochemical detection of tumor cells in the bone marrow, a known risk factor for the subsequent development of distant metastases. Patients received appropriate adjuvant chemotherapy and endocrine treatment. The incidence of osseous metastases was significantly lower in the clodronate group, and there was also a large, somewhat unexpected, reduction in the incidence of visceral metastases in the clodronate group. Survival was significantly extended. These results have subsequently been updated and show similar results, although the striking effect on extraskeletal visceral relapse is no longer statistically significant.[131] A third study produced conflicting results; the overall 5-year survival was significantly lower in the clodronate group (70% vs. 83%, P = 0.009). although there were some prognostic imbalances favoring the control group that may explain this unexpected result.[132]

A definite adjuvant role for bisphosphonates will require the results from much larger randomized studies. The National Surgical Adjuvant Breast Project has completed accrual (n = 3300) to a placebo-controlled trial of oral clodronate in stage I to III breast cancer in an attempt to resolve the value or otherwise of adjuvant clodronate. Similarly a large trial of adjuvant zoledronic acid (n = 3360) in stage II/III breast cancer has completed accrual. First efficacy results from these studies are not expected before 2008. It is hoped that the added potency of zoledronic acid might have beneficial effects, not only through the inhibition of bone resorption, but also through direct effects on tumor cells in the bone marrow. There is increasing evidence, from a range of cell line and animal model experiments, that zoledronic acid can inhibit tumor cell adhesion and invasion.[133] Additionally, zoledronic acid promotes apoptosis both directly and, more importantly, a schedule-dependent synergy with chemotherapy.[134] These effects are mediated through the mevalonate pathway, using the same molecular pathway that aminobisphosphonates exploit to inhibit osteoclast function. Finally, there are experimental data from animal models indicating that zoledronic acid can suppress angiogenesis.[135]

Effects of Cancer Treatments on Skeletal Health

There are now increasing numbers of long-term survivors from cancer who have received combination chemotherapy, radiotherapy, and hormonal cancer treatment. Many of these individuals are at increased risk of osteoporosis, largely because of the endocrine changes induced by treatment. There might also be clinically relevant, direct effects of cytotoxic drugs on bone. Cancer treatment-induced bone loss is a particularly important long-term problem for women with breast cancer and men receiving ADT.[136] Peak bone mass minus the bone loss associated with age and estrogen deficiency are the main determinants of osteoporotic fracture risk. However, other factors, including genetics, lifestyle, concomitant medication, and nutrition, influence the risk for bone loss.

Bone Loss in Breast Cancer

Cancer treatment-induced bone loss is an increasingly recognized complication in women receiving long-term estrogen-reducing therapies. Estrogen is known to be critical in the maintenance of normal bone mass in women. After menopause a reduction in bone mineral density (BMD) occurs, with the loss most pronounced during the first 3 years, when the rate can be as high as 5% annually, before reducing to a rate of about 0.5% annually thereafter. In the adjuvant setting, all third-generation aromatase inhibitors have demonstrated increased loss of BMD, which may lead to osteoporosis and skeletal complications.[136] In fact, spinal function is negatively affected by bone loss regardless of detectable fractures. Compared with naturally occurring bone loss, aromatase inhibitor-associated bone loss may result in greatly increased BMD loss at 1 year, with rates averaging 5% to 6% in the immediate postmenopausal period.[136]

Several clinical trials have demonstrated increased fracture rates in postmenopausal women with breast cancer receiving aromatase inhibitors.[137] However, a significant proportion of this excess rate of fractures may be due to the absence of the bone-protective effects of tamoxifen. Tamoxifen is known to have a modest estrogenic effect on bone, at least in postmenopausal women, and placebo-controlled trials, for instance in the breast cancer prevention setting, have shown a modest reduction in fracture incidence compared with placebo. Furthermore, in a study of breast cancer patients who received either letrozole or placebo as extended adjuvant therapy, although more patients in the letrozole group had fractures after 5 years, the difference did not reach significance.[138]

A few studies have evaluated women with breast cancer and a treatment-induced premature menopause. Saarto and colleagues[139] studied the effect of clodronate 1600 mg in 148 premenopausal women receiving adjuvant chemotherapy for breast cancer. They observed that rapid bone loss occurred in the women who became amenorrheic after chemotherapy (6% and 2% losses at 2 years in the spine and hip, respectively). Among those receiving clodronate, however, the bone effects of chemotherapy-induced premature menopause were attenuated (2% loss and 1% gain at 2 years in the spine and hip, respectively). In a comparison of risedronate with placebo in a postmenopausal group of patients receiving tamoxifen, Delmas and associates[140] observed an approximate 2.5% increase in BMD at the lumbar spine and femoral neck in the risedronate group compared with the group receiving placebo.

Intravenous bisphosphonate administration is used widely in oncology in the treatment of metastatic disease and could be an attractive option for preventing bone loss in a cancer population. Among patients with breast cancer, 6-monthly zoledronic acid has also been shown to reverse the bone loss induced by a combination of the LHRH analog goserelin plus further estrogen suppression with anastrozole. In this study, the mean loss of bone in the lumbar spine over 3 years in the absence of a bisphosphonate was 17%. However, the bone loss was abrogated by administration of 6-monthly zoledronic acid.[141]

In older postmenopausal women the strategy of immediate 6-monthly zoledronic acid alongside aromatase inhibitor therapy has been compared with initiation of bone protection treatment if osteoporosis or significant bone loss occurs on treatment. The difference in lumbar spine BMD at 1 year was approximately 5%.[142]

Bone Loss in Prostate Cancer

Many men with prostate cancer are at risk of developing osteoporosis, largely because of the ADT they receive for their cancer. ADT may be achieved either by bilateral orchiectomy or, increasingly, by use of a gonadotropin-releasing hormone agonist. These treatments are being introduced earlier and earlier in the course of the disease with the result that men may experience many years of androgen suppression. ADT results in substantially reduced serum concentrations of testosterone (to less than 5% of normal level) and estrogen (to less than 20% of normal level).

It might be expected that androgen deprivation would lead to increased bone loss and increased fracture rate. As yet there seem to have been no large prospective studies of the relationship between fracture rate and ADT, but retrospective studies indicate a significantly increased fracture rate with an estimated 10-year probability of fracture at around 40%.[143] As the potential scale of the problem is being realized, attention is not only focusing on measuring bone density in such patients to assess those at risk, but also on therapeutic options such as bisphosphonates to prevent or treat therapy-related bone loss in prostate cancer. Pamidronate given on a 3-monthly schedule has been shown to prevent loss in BMD in patients with locally advanced prostate cancer.[144] A multicenter prospective study has evaluated the potent bisphosphonate, zoledronate, in locally advanced or recurrent prostate cancer.[145] At 1 year, in the zoledronic acid arm, BMD increased by 5.3% at the lumbar spine and 1.1% in the total hip. In the placebo arm the BMD decreased by 2% in the lumbar spine and 2.8% in the total hip.

COMPLICATIONS OF BONE METASTASES

Bone metastases cause considerable morbidity: pain, impaired mobility, hypercalcemia, pathologic fracture, spinal cord or nerve root compression, and bone marrow infiltration. In two large randomized trials that included patients with breast cancer and multiple myeloma receiving chemotherapy, the mean skeletal morbidity rates (number of skeletal events per year) in the absence of bisphosphonates were 3.5 and 2.0, respectively, indicating that a skeletal event occurs in metastatic bone disease from breast cancer on the average of every 3 to 4 months and in multiple myeloma every 6 months. [97] [107]Despite the clinical importance of metastatic bone disease and the huge expenditure on medical care for skeletal complications, however, there has until recently been relatively little thought given as to how best to coordinate clinical management and deliver optimum care for patients with bone metastases.

Extensive infiltration of the bone marrow by metastatic disease causes leukoerythroblastic anemia and pancytopenia predisposing to infection and hemorrhage. Radiotherapy, often needed for the treatment of bone metastases, can exacerbate this problem, which in turn can compromise the ability to give chemotherapy effectively. Animal experiments have shown that cytotoxic drugs can interfere with osteoblastic function and new bone formation, but the clinical significance of these findings is unknown. Other iatrogenic factors might also aggravate morbidity from bone metastases including corticosteroids and endocrine ablation.

Bone Pain

Bone pain is the most common type of pain from cancer and a significant problem in both hospital and community practice. Pain is usually the presenting symptom and is caused by a variety of factors, including periosteal stretching, compression or infiltration of nerve roots, reflex muscle spasm, and the local effects of cytokines. Features of bone pain are that it is often poorly localized, has a deep, boring quality that aches or burns, and is accompanied by episodes of stabbing discomfort. It is often worse at night, being little helped by sleep and not necessarily relieved by lying down. There is often disturbance of the highly innervated periosteum—possibly giving this pain its neurogenic-like qualities and adding to its intractability.

Spinal instability is the cause of back pain in 10% of patients with cancer.[146] This instability can cause excruciating pain that is mechanical in origin. The patient is comfortable only when lying still, and any movement reproduces severe pain. Consequently, the patient might not be able to sit, stand, or walk. Because the pain is mechanical in origin, radiation therapy or systemic treatment cannot help; the only solution is stabilization of the spine. Stabilization requires major surgery, with risks of significant morbidity and mortality, but with careful selection of patients, excellent results can be obtained.

Hypercalcemia of Malignancy

Hypercalcemia (see also Chapter 48 ) is another emergency associated with metastatic bone disease. Its clinical features include nausea, vomiting, dehydration, and confusion. Although malignant hypercalcemia is usually associated with demonstrable bone metastases, this is not always the case. Hypercalcemia causes a number of signs and symptoms, which vary considerably from patient to patient. These are often nonspecific, affecting many systems in the body, and can be mistaken for symptoms of the underlying cancer or associated treatment if there is not an astute awareness of the possibility of hypercalcemia. If untreated, a progressive rise in serum calcium leads to deterioration in renal function and level of consciousmess. Death ultimately ensues as a result of cardiac arrhythmias and renal failure.

It is now clear that various mechanisms are involved in the pathogenesis of malignant hypercalcemia. These include increased bone resorption (osteolysis) and systemic release of humoral hypercalcemic factors. Bone metastases are common but not invariably present. In some tumors, such as squamous cell cancers, humoral mechanisms are dominant, increasing both renal tubular calcium reabsorption and phosphate excretion. In others—multiple myeloma and lymphoma, for example—osteolysis predominates, whereas in breast cancer both osteolysis and humoral mechanisms seem to be important.

Doubt about the etiology of hypercalcemia in patients with cancer is unusual, but nonmalignant causes must be considered, particularly in the absence of metastases. In the community, hyperparathyroidism is the most common cause of hypercalcemia and may be encountered also in patients with cancer. Measurement of PTH using a modern, specific radioimmunoassay is worthwhile if there is any doubt about the diagnosis; levels of PTH tend to be low or undetectable in malignancy and inappropriately high in hyperparathyroidism.

Intravenous bisphosphonates, in conjunction with rehydration, are now established as the treatment of choice for hypercalcemia. Approximately 70% to 90% of patients will achieve normocalcemia, resulting in relief of symptoms and improved quality of life. Zoledronic acid is the most effective bisphosphonate for the acute treatment of this metabolic emergency.[147]

Pathologic Fractures

Metastatic destruction of bone reduces its load-bearing capabilities, resulting initially in trabecular disruption and microfractures and, subsequently, in total loss of bony integrity. Rib fractures and vertebral collapse are the most common occurrences, resulting in loss of height, kyphoscoliosis, and a degree of restrictive lung disease. The most severe disability, however, is caused by fracture of a long bone or epidural extension of tumor into the spine.

The incidence of pathologic fracture in patients with bone metastases is somewhat uncertain and is dependent on whether rib and vertebral fractures are included and the method of evaluation. In recent series in which regular skeletal surveys were performed the annual risk of a pathologic fracture (in the absence of bisphosphonates) was between 20% in prostate cancer[85] and 40% in breast cancer.[97]Not all of these fractures are symptomatic, and undoubtedly some are due to treatment-induced osteoporosis rather than metastatic infiltration, but nevertheless structural damage to bone is clearly extremely common in metastatic bone disease. Paterson and colleagues,[92] who systematically reviewed serial radiographs in patients participating in a clinical trial of oral clodronate, showed that a woman with bone metastases from breast cancer can expect to experience an average of 1.3 vertebral and 0.4 nonvertebral fractures a year.

The probability of developing a pathologic fracture increases with the duration of metastatic involvement and is therefore, somewhat paradoxically, more common in those patients with bone-only disease who have a relatively good prognosis. A retrospective analysis of 859 patients with bone metastases from breast cancer showed that those with bone-only disease had almost a fourfold increase in the incidence of subsequent pathologic long-bone fractures compared with patients who also had concomitant liver metastases. This finding was attributed to the different survival outcomes between the two groups; the median survival from diagnosis of bone metastases for patients with bone-only disease was 2.2 years, compared with 5.5 months for those with concomitant liver disease.[148] The study also showed that scintigraphic evidence of metastases in the femora and humeri at the time of diagnosis significantly predicted an increased risk of future fractures.

Because the development of a fracture is so devastating to a patient with cancer, increased emphasis is now being placed on attempts to predict metastatic sites at risk of fracture and the use of prophylactic surgery and long-term administration of bisphosphonates to reduce fracture risk. Assessment of patients with symptomatic bone metastases by a specialist orthopedic and/or spinal surgeon should be a much more frequent component of multidisciplinary management than has been the case until now.

Fractures are common through lytic metastases and weight-bearing bones, the proximal femora being the most commonly affected sites. Damage to both trabecular and cortical bone are structurally important, but it is the relevance of cortical destruction that is most clearly appreciated. Several radiologic features that could predict imminent fracture have been identified. Risk factors that have been taken into account include pain, the anatomic site of a lesion, its radiologic characteristics, and its size. Although intensity of pain, which is difficult to quantify, is not clearly associated with fracture risk, pain that is exacerbated by movement seems to be an important factor in predicting impending fracture. Presumably, such functional pain indicates diminution in the mechanical strength of a bone and in one series was followed invariably by fracture.

As far as radiologic appearances are concerned, there is a general consensus that lytic lesions carry a much higher risk of fracture than either mixed or osteosclerotic lesions. Accordingly, a particularly high fracture rate is found in association with metastases from lung cancer. Given the poor prognosis of this tumor, however, such fractures rarely lead to prolonged disability. By contrast, in breast cancer, which follows a much more protracted course, pathologic fracture is a major cause of prolonged disability.

Radiologic assessment also yields information about the size of a lesion and the extent to which the bone is destroyed. When less than two thirds of the diameter of a long bone is affected, pathologic fracture is relatively unusual but above this limit the fracture rate increases markedly, with an incidence of approximately 80% for such lesions. A practical scoring system incorporating anatomic, radiographic, and symptom-related factors has been described to give valuable guidance in the selection of patients for prophylactic fixation.[149]

Prophylactic internal fixation is usually the treatment of choice for such lesions, followed by radiotherapy to inhibit further tumor growth and avoid further bone destruction. It is easier to stabilize a bone while it is still intact, and the rehabilitation and convalescence are shorter and easier. Providing the lesion is irradiated, there is no evidence to suggest that surgery increases the risk of disseminating tumor cells either locally or into the circulation. Indeed, there is some experimental evidence that pathologic fractures are associated with an increased incidence of pulmonary metastases and that prophylactic stabilization decreases this incidence. If a given patient is not fit for surgery, radiotherapy and avoidance of weight-bearing activity are indicated.

Before surgery, a radionuclide bone scan and radiographs of the entire length of the affected bone should be obtained. These measures ensure that any other metastases that might subsequently develop into a pathologic fracture are also stabilized and included in the radiotherapy field. A pathologic fracture at the edge of a plate or of an intramedullary nail, particularly when fixed with methylmethacrylate, is more difficult to treat than if there were no implant in the bone.

Pathologic fractures are not necessarily a manifestation of terminal disease, and primary internal stabilization followed by radiotherapy are usually the treatments of choice, and certainly the only modalities likely to both restore mobility and relieve pain. Untreated pathlogic fractures rarely heal, and although radiotherapy might achieve local tumor control, bony union remains unlikely. Radiotherapy inhibits chondrogenesis (a prerequisite for fracture healing), and with large areas of bone destruction there could be insufficient matrix remaining for adequate repair.

The type of internal stabilization chosen depends on the site of the lesion, and the range of stabilization devices and custom-made prostheses increases year on year. When feasible, closed intramedullary nailing is preferred; however, at the end of the long bones, intramedullary nailing alone is inadequate, and alternative techniques are necessary. It is essential that the internal stabilization provide sufficient strength to allow unsupported use of the limb and for the legs to bear weight. Fulfilling this demand could require supplementation with methylmethacrylate (which is inserted into the tumor cavity with the implant fixed across the methylmethacrylate while still soft) and bridging normal bone above and below the lesion.

Pathologic femoral neck fractures do not unite despite internal fixation, and this situation requires replacement arthroplasty. Careful preoperative assessment of the pelvis and femur is necessary, and for this, CT scanning or MRI is often helpful. If there is no metastatic involvement of the acetabulum, a hemiarthroplasty could be all that is required. If the acetabulum is involved, however, total-replacement arthroplasty is indicated, and sometimes pelvic reconstruction is necessary. Many patients have metastases in the distal femur together with proximal involvement, and for these patients, a long-stemmed femoral prosthesis is recommended.

For humeral fractures, internal fixation is also useful, providing more rapid and greater pain relief compared with conservative treatment. Although patients with a very short life expectancy can be managed adequately with conservative treatment, those patients expected to survive longer than 3 months are best managed by internal fixation to ensure pain relief and restoration of function. Replacement arthroplasty could be necessary if the proximal humerus is involved, but most pathologic fractures of the humerus can be treated by intramedullary nailing.

Occasionally, patients present with an isolated metastasis in the distal skeleton. If on careful evaluation there is no other evidence of dissemination of the tumor, resection of the lesion should be considered. Local resection and prosthetic replacement are usually possible, but occasionally, amputation is indicated.

Spinal Instability

Spinal instability can cause excruciating pain that is mechanical in origin and not relieved by radiotherapy or systemic treatment. As with pathologic fractures of long bones, stabilization is required for pain relief and involves major surgery, which is associated with significant morbidity and mortality. There are several methods for spinal stabilization, but in general, the posterior approach is technically easier and allows stabilization of a larger area of the spine. With careful selection of patients, excellent results can be obtained. An associated neurologic deficit is not a contraindication to these procedures.

Percutaneous vertebroplasty and kyphoplasty, a new approach to treating spinal pain and instability, involves injecting an acrylic polymer into a diseased vertebral body. The technique was developed initially for the treatment of painful vertebral hemangiomas, and considerable experience with it has been obtained in the treatment of osteoporotic compression fractures. Its use has now been extended to the treatment of malignant spinal disease. [150] [151] The technique provides effective pain relief, which is achieved more rapidly than with radiotherapy, and it confers the added benefit of providing structural support to the spinal column, thus reducing the risk of vertebral collapse and instability. Although generally a safe procedure, vertebroplasty can be complicated by leakage of the polymer, which predisposes to spinal cord or nerve root compression. The risk of this is less with kyphoplasty.[151] The technique seems to have the potential for wider use, particularly among patients with limited vertebral disease and those for whom major surgical spinal stabilization procedures are unsuitable.

Compression of the Spinal Cord or Cauda Equina

Compression of the spinal cord or cauda equina in patients with metastatic disease of the spine is a medical emergency necessitating prompt diagnosis and treatment (see also Chapter 55 ). Its causes include pressure from an enlarging extradural mass, spinal angulation after vertebral collapse, vertebral dislocation after pathologic fracture, or, rarely, pressure from intradural metastases. The most common primary tumors producing this complication, in decreasing order of frequency, are carcinoma of the breast, lung cancer, prostatic cancer, lymphoma, and renal carcinoma.

Back pain is the most common initial symptom of spinal cord compression; two types of pain can occur—local spinal or radicular. Radicular pain varies with the location of the tumor, being common in the cervical (79%) and lumbosacral (90%) regions and less common with thoracic lesions (55%). Both local spinal and radicular pain are experienced close to the site of the lesion identified at myelography. Motor weakness, sensory loss, and autonomic dysfunction are all common at presentation of spinal cord or cauda equina compression.

The development of back pain in a patient with cancer, coincident with an abnormality on a plain spinal radiogram, should serve as a warning for the possible development of spinal cord compression. Compression of the spinal cord or cauda equina can occur in association with spinal stability or in isolation. When there is a greater than 50% vertebral collapse, compression of the spinal cord becomes more likely. The keys to successful rehabilitation are early diagnosis, high-dose corticosteroids, rapid assessment, and urgent referral for either decompression and spinal stabilization or radiotherapy. Neurologic recovery is unlikely if the spinal compression is not relieved within 24 to 48 hours.

In a retrospective analysis of 70 patients with spinal cord compression secondary to breast cancer, the most frequent symptom was motor weakness (96%), followed by pain (94%), sensory disturbance (79%), and sphincter disturbance (61%).[152] Of these 70 patients, 91% had at least one symptom for more than 1 week. The ability to walk was maintained by 96% of those ambulant before therapy. In those unable to walk, 45% regained ambulation, with radiotherapy and surgery equally effective. Median survival was 4 months. The most important predictor of survival was the ability to walk after treatment. These findings stress the importance of prompt presentation, diagnosis, and treatment and suggest that earlier diagnosis and intervention should improve outcome.

The choice between surgical decompression and radiotherapy depends on a variety of clinical features. Surgical decompression is indicated for patients with recent onset of symptoms and with progressive paraplegia and urinary retention of less than 30 hours’ duration. The site of compression should be localized to no more than two or three vertebral segments, and the patient should have a life expectancy of at least several weeks. For patients in whom the paraplegia has been established for several days or urinary retention has been present for more than 30 hours, surgical decompression rarely results in the recovery of bladder or motor function. Radiotherapy is indicated for those who are either unfit for surgery or do not meet the criteria for surgical decompression.

Several studies in the past suggested that surgical decompression had no advantage over radiotherapy.[153] It should be appreciated, however, that these studies compared dorsal laminectomy—an outdated and now inappropriate procedure—with irradiation. However, surgical decompression should be followed by spinal stabilization. More recently a randomized trial was performed that compared modern surgical techniques with radiotherapy. Patchell and associates randomized 101 patients to surgery plus radiotherapy or radiotherapy alone. Significantly more patients in the surgery group (42/50, 84%) than in the radiotherapy group (29/51, 57%) were able to walk after treatment (odds ratio 6.2 [95% confidence interval 2.0–19.8] P = 0.001). Patients treated with surgery also retained the ability to walk significantly longer than did those with radiotherapy alone (median 122 days vs. 13 days, P = 0.003). Thirty-two patients entered the study unable to walk; significantly more patients in the surgery group regained the ability to walk than patients in the radiation group (10/16 [62%] vs. 3/16 [19%], P = 0.01). The need for corticosteroids and opioid analgesics was also significantly reduced in the surgical group.[154] Therefore, the choice of management should be decided on an individual basis, and there are undoubtedly patients who will benefit greatly from appropriate and prompt surgical management.

SUMMARY

The management of bone metastases requires an experienced multidisciplinary team to ensure timely diagnosis and the appropriate integration of local and systemic treatments. The effects of tumor cells on bone cell function (especially on osteoclast activity) underpin the rationale for the use of bisphosphonate treatment to reduce skeletal morbidity. These bone-specific treatments are now an accepted part of routine clinical management. Additionally, the disruption of bone remodeling results in release of collagen fragments, which seems to have value in predicting skeletal events, prognosis, and monitoring of response.

Further developments in our understanding of the pathophysiology of bone metastases can be expected to provide new therapeutic strategies. Already, improved knowledge of the signaling molecules involved in regulating osteoclast function—notably OPG and RANK ligand—has led to the development of highly active targeted therapies for bone diseases, including cancer and other novel therapeutic approaches in clinical development. Over the next 5 years several of these compounds can be expected to gain regulatory approval, and ultimately combinations of bone-targeted therapies may be recommended to further reduce the clinical burden of metastatic bone disease.

REFERENCES

  1. Coleman RE: Clinical features of metastatic bone disease and risk of skeletal morbidity.  Clin Cancer Res2006; 12(Suppl):6243-6249.
  2. Coleman RE, Smith P, Rubens RD: Clinical course and prognostic factors following recurrence from breast cancer.  Br J Cancer1998; 77:336-340.
  3. Bellahcene A, Menard S, Bufalino R, et al: Expression of bone sialoprotein in human breast cancer is associated with poor survival.  Int J Cancer1996; 69:350-353.
  4. Papotti M, Kalebic T, Volante M, et al: Bone sialoprotein is predictive of bone metastases in resectable non-small cell lung cancer: a retrospective case-control study.  J Clin Oncol2006; 24:4818-4824.
  5. Vargas SJ, Gillespie MT, Powell GJ, et al: Localisation of parathyroid hormone related protein mRNA expression in breast cancer and metastatic lesions by in situ hybridisation.  J Bone Miner Res1992; 8:971-979.
  6. Henderson MA, Danks JA, Slavin JL, et al: Parathyroid hormone related protein localisation in breast cancers predict improved survival.  Cancer Res2006; 66:3620-3628.
  7. Van't Veer L, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome in breast cancer.  Nature2002; 415:530-536.
  8. Wang Y, Klijn JGM, Zhang Y, et al: Gene expression profiles to predict distant metastasis of lymph node negative primary breast cancer.  Lancet2005; 365:671-679.
  9. Smid M, Wang Y, Klijn JGM, et al: Genes associated with breast cancer metastatic to bone.  J Clin Oncol2006; 24:2261-2267.
  10. Brown JE, Cook RJ, Major P, et al: Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors.  J Natl Cancer Inst2005; 97:59-69.
  11. Robson M, Dawson N: How is androgen dependent metastatic prostate cancer best treated?.  Hematol Oncol Clin North Am1996; 10:727-747.
  12. Soloway M, Hardeman S, Hickey D: Stratification of patients with metastatic prostate cancer based on extent of disease on initial bone scan.  Cancer1988; 61:195-202.
  13. Sabbatini P, Larson SM, Kremer A, et al: Prognostic significance of extent of disease in bone in patients with androgen-independent prostate cancer.  J Clin Oncol1999; 17:948-957.
  14. Batson OV: The role of the vertebral veins in metastatic process.  Ann Intern Med1942; 16:38-47.
  15. Seeman E, Delmas PD: Bone quality—the material and structural basis of bone strength and fragility.  N Engl J Med2006; 354:2250-2261.
  16. Mundy GR: Metastasis to bone: causes, consequences, and the threapeutic opportunities.  Nat Rev Cancer2002; 2:584-593.
  17. Siclari VA, Guise TA, Chirgwin JM: Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases.  Cancer Metastasis Rev2006; 25:621-633.
  18. Kaplan RN, Rafii S, Lyden D: Preparing the “soil”, the premetastatic niche.  Cancer Res2006; 66:11089-11093.
  19. Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM: Matrix metalloproteinases: biologic activity and clinical implications.  J Clin Oncol2000; 18:1135-1149.
  20. Roodman GD: Role of stromal-derived cytokines and growth factors in bone metastasis.  Cancer2003; 97:733-738.
  21. Rose AA, Siegel PM: Breast cancer-derived factors facilitate osteolytic bone metastasis.  Bull Cancer2006; 93:931-943.
  22. Hofbauer LC, Khosla S, Dunstan CR, et al: The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption.  J Bone Miner Res2000; 15:2-12.
  23. Chikatsu N, Takeuchi Y, Tamusa Y, et al: Interactions between cancer and bone marrow cells induce osteoblast differentiation factor expression and osteoclast-like cell formation in vitro.  Biochem Biophys Res Commun2000; 267:632-637.
  24. Zhang J, Dai J, Qi Y, et al: Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone.  J Clin Invest2001; 107:1235-1244.
  25. Nelson JB, Hedican SP, George DJ, et al: Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate.  Nat Med1995; 1:944-949.
  26. Chiao JW, Moonga BS, Yang YM, et al: Endothelin-1 from prostate cancer cells is enhanced by bone contact which blocks osteoclastic bone resorption.  Br J Cancer2000; 83:360-365.
  27. Granchi S, Bronechi S, Bonaccorsi L, et al: Endothelin-1 production by prostate cancer cell lines is up-regulated by factors involved in cancer progression and down-regulated by androgens.  Prostate2001; 49:267-277.
  28. Bryden AA, Hoyland JA, Freemont AJ, et al: Parathyroid hormone related peptide and receptor expression in paired primary prostate cancer and bone metastases.  Br J Cancer2002; 86:322-325.
  29. Clarke NW, McClure J, George NJ: Morphometric evidence for bone resorption and replacement in prostate cancer.  Br J Urol1991; 68:74-80.
  30. Lee YP, Schwerz EM, Davies M, et al: Use of zoledronate to treat osteoblastic versus osteolytic lesions in a severe-combined-immunodeficient mouse model.  Cancer Res2002; 62:5564-5570.
  31. Logan CY, Nusse R: The Wnt signalling pathway in development and disease.  Annu Rev Cell Dev Biol2004; 20:781-810.
  32. Hall CL, Keller ET: The role of Wnts in bone metastases.  Cancer Metastasis Rev2006; 25:551-558.
  33. Barille S, Akhoundi C, Collette M, et al: Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of pro-MMP-2, and induction of MMP-1 by myeloma cells.  Blood1997; 90:1649-1655.
  34. Derenne S, Amiot U, Barille S, et al: Zoledronate is a potent inhibitor of myeloma cell growth and secretion of IL-6 and MMP-1 by the tumoral environment.  J Bone Miner Res1999; 14:2048-2056.
  35. Tian E, Zhan F, Walker R, et al: The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma.  N Engl J Med2003; 349:2483-2494.
  36. Wang K, Allen L, Fung E, et al: Bone scintigraphy in common tumours with osteolytic components.  Clin Nucl Med2005; 16:1131-1137.
  37. Boxer DI, Todd CEC, Coleman R, Fogelman I: Bone secondaries in breast cancer: the solitary metastasis.  J Nucl Med1989; 30:1318-1320.
  38. MacVicar D: Imaging of the spine in patients with malignancy.  Cancer Imaging2006; 6:s22-s26.
  39. Schmidt GP, Schoenberg SO, Schmid R, et al: Screening for bone metastases: whole body MRI using a 32-channel system versus dual-modality PET-CT.  Eur Radiol2007; 17:939-949.
  40. Balcerzak M, Hamade E, Zhang L, et al: The roles of annexins and alkaline phosphatase in mineralization process.  Acta Biochim Pol2003; 50:1019-1038.
  41. Seibel MJ: Clinical use of markers of bone turnover in metastatic bone disease.  Nat Clin Pract Oncol2005; 10:504-517.
  42. Ivaska KK, Kakonen SM, Gerdhem P, et al: Urinary osteocalcin as a marker of bone metabolism.  Clin Chem2005; 51:618-628.
  43. Calvo MS, Eyre DR, Gundberg CM: Molecular basis and clinical application of biological markers of bone turnover.  Endocr Rev1996; 17:333-368.
  44. Brasso K, Christensen IJ, Johansen JS, et al: Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma.  Prostate2006; 66:503-513.
  45. Sassi ML, Eriksen H, Risteli L, et al: Immunochemical characterization of assay for carboxyterminal telopeptide of human type I collagen: loss of antigenicity by treatment with cathepsin K.  Bone2000; 26:367-373.
  46. Jakob C, Zavrski I, Heider U, et al: Serum levels of carboxyterminal telopeptide of type-I collagen are elevated in patients with multiple myeloma showing skeletal manifestations in magnetic resonance imaging but lacking lytic bone lesions in conventional radiography.  Clin Cancer Res2003; 9:3047-3051.
  47. Alatalo SL, Ivaska KK, Waguespack SG, et al: Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in Albers-Schonberg disease (type II autosomal dominant osteopetrosis).  Clin Chem2004; 50:883-890.
  48. Fedarko NS, Jain A, Karadag A, et al: Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer.  Clin Cancer Res2001; 7:4060-4066.
  49. Jung K, Lein M, Stephan C, et al: Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications.  Int J Cancer2004; 111:783-791.
  50. Woitge HW, Pecherstorfer M, Horn E, et al: Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma.  Br J Cancer2001; 84:344-351.
  51. Leeming DJ, Koizumi M, Byrjalsen I, et al: The relative use of eight collagenous and noncollagenous markers for diagnosis of skeletal metastases in breast, prostate, or lung cancer patients.  Cancer Epidemiol Biomarkers Prev2006; 15:32-38.
  52. Terpos E, Szydlo R, Apperley JF, et al: Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index.  Blood2003; 102:1064-1069.
  53. Coleman RE, Major P, Lipton A, et al: Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid.  J Clin Oncol2005; 23:4925-4935.
  54. Cleeland C: The measurement of pain from metastatic bone disease: capturing the patient's experience.  Clin Cancer Res2006; 12(Suppl):6236s-6242s.
  55. Brown JE, Coleman RE: Assessment of the effects of breast cancer on bone and the response to therapy.  Breast2002; 11:375-385.
  56. Fogelman I, Cook G, Israel O, van der Waal H: Positron emission tomography and bone metastases.  Semin Nucl Med2005; 35:135-142.
  57. Duffy MJ: Serum tumour markers in breast cancer: are they of clinical value.  Clin Chem2006; 52:345-351.
  58. Robertson JFR, Jaeger W, Syzmendera JJ, et al: The objective measurement of remission and progression in metastatic breast cancer by use of serum tumor markers.  Eur J Cancer1999; 35:47-53.
  59. Vicini FA, Vargas C, Abner A, et al: Limitations in the use of serum prostate specific antigen levels to monitor patients after treatment for prostate cancer.  J Urol2005; 173:1456-1462.
  60. Smith MR, Kabbinvar F, Saad F, et al: Natural history of rising serum prostate-specific antigen in men with castrate non metastatic prostate cancer.  J Clin Oncol2005; 23:2918-2925.
  61. Villalon AH, Tattersall MH, Fox RM, Woods RL: Hypercalcaemia after tamoxifen for breast cancer: a sign of tumor response.  Br Med J1979; 20:1329-1330.
  62. Walls J, Assiri A, Howell A, et al: Measurement of urinary collagen cross-links indicate response to therapy in patients with breast cancer and bone metastases.  Br J Cancer1999; 80:1265-1270.
  63. Vinholes J, Coleman R, Lacombe D, et al: Assessment of bone response to systemic therapy in an EORTC trial: preliminary experience with the use of collagen cross-link excretion. European Organization for Research and Treatment of Cancer.  Br J Cancer1999; 80:221-228.
  64. Costa L, Demers LM, Gouveia-Oliveira A, et al: Prospective evaluation of the peptide-bound collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status.  J Clin Oncol2002; 20:850-856.
  65. Vinholes JJ, Purohit OP, Abbey ME, et al: Relationships between biochemical and symptomatic response in a double-blind trial of pamidronate for metastatic bone disease.  Ann Oncol1997; 8:1243-1250.
  66. Jagdev SP, Purohit OP, Heatley S, et al: Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease.  Ann Oncol2001; 12:1433-1438.
  67. Agarawal JP, Swangsilpa T, van der Linden Y, et al: The role of external beam radiotherapy in the management of bone metastases.  Clin Oncol2006; 18:747-760.
  68. Blitzer PH: Reanalysis of the RTOG study of the palliation of symptomatic osseous metastasis.  Cancer1985; 55:1468-1472.
  69. Van der Linden Y, Steenland E, van Howelingen HC, et al: Patients with a favourable prognosis are equally palliated with single and multiple fractionation radiotherapy; results on survival in the Dutch Bone Metastasis Study.  Radiother Oncol2006; 78:245-253.
  70. Wu JS, Wong R, Johnston M, et al: Meta-analysis of dose fractionation trials for the palliation of bone metastases.  Int J Radiat Oncol Biol Phys2003; 55:594-605.
  71. Padrit-Taskar N, Batraki BS, Divgi CR: Radiopharmaceutical therapy for palliation of bone pain from osseus metastases.  J Nucl Med2004; 45:1358-1365.
  72. Lewington VJ: Bone seeking radionuclides for therapy of painful bone metastases.  J Nucl Med2005; 46:38s-47s.
  73. Serafini AN, Houston SJ, Resche I, et al: Palliation of pain associated with metastatic bone cancer using samarium-153 lexodronam: a double-blind placebo-controlled clinical trial.  J Clin Oncol1998; 16:1574-1581.
  74. Sartor O, Reid RH, Hoskin PJ, et al: for the Quadramet 4245m10/11 Study Group: Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer.  Urology2004; 63:940-945.
  75. Lam MG, de Klerk JM, van Rijk PP: 186Re-HEDP for metastatic bone pain in breast cancer patients.  Eur J Nucl Med Mol Imaging2004; 31(Suppl 1):S162-S170.
  76. Bruland O, Nilsson S, Fisher D, et al: High linear energy transfer irradiation targeted to skeletal metastases by the α-emitter 223Ra: adjuvant or alternative to conventional modalities.  Clin Cancer Res2006; 12(Suppl):6250s-6257s.
  77. Tannock IF, Osaba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomised trial with palliative endpoints.  J Clin Oncol1996; 14:1756-1764.
  78. Mike S, Harrison C, Coles B: Chemotherapy for hormone refractory prostate cancer.  Cochrane Database Syst Rev2006; 4:CD005247
  79. Savarase DMF, Hsieh C-C, Stewart FM: Clinical impact of chemotherapy dose escalation in patients with haematologic malignancies and solid tumors.  J Clin Oncol1997; 15:2981-2995.
  80. Rini BI: Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions.  Clin Cancer Res2007; 13:1098-1106.
  81. Roelofs AJ, Thompson K, Gordon S, Rogers MJ: Molecular mechanisms of action of bisphosphonates: current status!.  Clin Cancer Res2006; 15(20 Pt 2):6222s-6230s.
  82. Frith JC, Monkkonen J, Blackburn GM, et al: Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5′-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro.  J Bone Miner Res1997; 12:1358-1367.
  83. Clezardin P: Anti-tumour activity of zoledronic acid.  Cancer Treat Rev2005; 31(Suppl 3):1-8.
  84. Daley-Yates PT, Dodwell DJ, Pongchaidechma M, et al: The clearance and bioavailability of pamidronate in patients with breast cancer and bone metastases.  Calcif Tissue Int1991; 49:433-435.
  85. De Groen PC, Lubbe DF, Hirsch LJ, et al: Oesophagitis associated with the use of alendronate.  N Engl J Med1996; 335:1016-1021.
  86. Coleman RE: Bisphosphonates: clinical experience.  Oncologist2004; 9(Suppl. 4):14-27.
  87. Wong R, Wiffen PJ: Bisphosphonates for the relief of pain secondary to bone metastases.  Cochrane Database Syst Rev2002; 2:CD002068
  88. Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma.  J Natl Cancer Inst2002; 94:1458-1468.
  89. Rosen LS, Gordon D, Tchekmedyian S, et al: Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with non-small cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial.  Cancer2004; 100:2613-2621.
  90. Lipton A, Colombo-Berra A, Bukowski RM, et al: Skeletal complications in patients with bone metastases from renal cell carcinoma and therapeutic benefits of zoledronic acid.  Clin Cancer Res2004; 10:6397S-6403S.
  91. Pavlakis N, Schmidt R, Stockler M: Bisphosphonates for breast cancer.  Cochrane Database Syst Rev2005; 3:CD003474
  92. Paterson AH, Powles TJ, Kanis JA, et al: Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer.  J Clin Oncol1993; 11:59-65.
  93. Coleman RE, Purohit OP, Black C, et al: Double-blind, randomised, placebo-controlled study of oral ibandronate in patients with metastatic bone disease.  Ann Oncol1999; 10:311-316.
  94. Body JJ, Diel IJ, Lichinitzer M, et al: Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies.  Br J Cancer2004; 90:1133-1137.
  95. Conte PF, Mauriac L, Calabresi F, et al: Delay in progression of bone metastases treated with intravenous pamidronate: results from a multicentre randomised controlled trial.  J Clin Oncol1996; 14:2552-2559.
  96. Hultborn R, Ryden S, Gunderson S, et al: Efficacy of pamidronate on skeletal complications from breast cancer metastases. A randomised prospective double blind placebo controlled trial.  Acta Oncol1996; 35(Suppl 5):73-74.
  97. Hortobagyi GN, Theriault RL, Porter L, et al: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases.  N Engl J Med1996; 335:1785-1791.
  98. Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomised, placebo-controlled trial.  J Clin Oncol1999; 17:846-854.
  99. Body JJ, Lortholary A, Romieu G, et al: A dose-finding study of zoledronate in hypercalcaemic cancer patients.  J Bone Miner Res1999; 14:1557-1661.
  100. Berenson JR, Rosen LS, Howell A, et al: Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases.  Cancer2001; 91:1191-1200.
  101. Kohno N, Aoqi K, Minami H, et al: Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial.  J Clin Oncol2005; 20:3299-3301.
  102. Rosen LS, Gordon D, Kaminski M, et al: Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.  Cancer J2001; 7:377-387.
  103. Rosen LS, Gordon D, Kaminski M, et al: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in treatment of skeletal complications in patients with advanced multiple myeloma or breast cancer: a randomized, double-blind, multicenter, comparative trial.  Cancer2003; 98:1735-1744.
  104. Body JJ, Diel IJ, Lichinitser MR, et al: MF 4265 Study Group. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases.  Ann Oncol2003; 14:1399-1405.
  105. Lahtinen R, Laakso M, Palva I, for the Finnish Leukaemia Group , et al: Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma.  Lancet1992; 340:1049-1052.
  106. McCloskey EV, Maclennan ICM, Drayson M, et al: A randomised trial of the effect of clodronate on skeletal morbidity in multiple myeloma.  Br J Haematol1998; 100:317-325.
  107. Berenson JR, Lichtenstein A, Porter L, et al: Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma.  N Engl J Med1996; 334:488-493.
  108. Menssen HD, Sakalova A, Fontana A, et al: Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma.  J Clin Oncol2002; 20:2353-2359.
  109. Smith Jr JA: Palliation of painful bone metastases from prostate cancer using sodium etidronate: results of a randomized, prospective, double-blind, placebo-controlled study.  J Urol1989; 141:85-87.
  110. Dearnaley DP, Sydes MR, Mason MD, et al: A double-blind placebo-controlled randomised trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05).  J Natl Cancer Inst2005; 95:1300-1311.
  111. Ernst DS, Tannock IF, Winquist EW: Randomised, double-blind controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone refractory prostate cancer and pain.  J Clin Oncol2003; 21:3335-3342.
  112. Small EG, Smith MR, Seaman JJ, et al: Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer.  J Clin Oncol:2003; 21:4277-4284.
  113. Saad F, Gleason DM, Murray R, et al: Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with advanced prostate cancer and bone metastasis.  J Natl Cancer Inst2004; 96:879-882.
  114. Plunkett TA, Rubens RD: Bisphosphonate therapy for patients with breast carcinoma: who to treat and when to stop.  Cancer2003; 97(Suppl 3):854-858.
  115. Body J-J: Effectiveness and cost of bisphosphonate therapy in tumor bone disease.  Cancer2003; 97(Suppl 3):859-865.
  116. Hillner BE, Ingle JN, Berenson JR, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in breast cancer.  J Clin Oncol2003; 21:4042-4057.
  117. Kyle RA, Yee GC, Somerfield MR, et al: American Society of Clinical Oncology 2007 clinical practice guideline update on the role of biophosphonates in multiple myeloma.  J Clin Oncol2007; 25:2464-2472.
  118. Clemons MJ, Dranitsaris G, Ooi WS, et al: Phase II trial evaluating the palliative benefit of second-line zoledronic acid in breast cancer patients with either a skeletal-related event or progressive bone metastases despite first-line bisphosphonate therapy.  J Clin Oncol2006; 20:4895-4900.
  119. Hillner BE: Pharmacoeconomic issues in bisphosphonate treatment of metastatic bone disease!.  Semin Oncol2001; 28(Suppl 11):64-68.
  120. Delea T, Langer C, McKiernan J, et al: The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer.  Oncology2004; 67:390-396.
  121. Brown JE, Thomson CS, Ellis SP, et al: Bone resorption predicts for skeletal complications in metastatic bone disease.  Br J Cancer2003; 89:2031-2037.
  122. Ruggiero S, Gralow J, Marx RE, et al: Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer.  J Oncol Pract2006; 2:7-14.
  123. Hoff AO, Toth BB, Altundag V, et al: Osteonecrosis of the jaw in patients receiving intravenous bisphosphonate therapy (abstract 8528).  J Clin Oncol2006; 24(Suppl):475s.
  124. Migliorati CA, Casiglia J, Epstein J, et al: Managing the care of patients with bisphosphonate-associated osteonecrosis. An American Academy of Oral Medicine position paper.  J Am Dent Assoc2005; 136:1658-1668.
  125. Bekker PJ, Holloway DL, Rasmussen AS, et al: A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women.  J Bone Miner Res2004; 19:1059-1066.
  126. Body JJ, Facon T, Coleman RE, et al: A study of the biological receptor activator of nuclear factor-κappa B ligand inhibitor, Denosumab, in patients with multiple myeloma or bone metastases from breast cancer.  Clin Cancer Res2006; 12:1221-1228.
  127. Hiraga T, Williams PJ, Ueda A, et al: Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model.  Clin Cancer Res2004; 10:4559-4567.
  128. Ottewell PD, Coleman RE, Holen I: From genetic abnormality to metastases: murine models of breast cancer and their use in the development of anticancer therapies.  Breast Cancer Res Treat2006; 96:101-113.
  129. Powles TJ, Paterson AE, McCloskey E, et al: Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer.  Breast Cancer Res Treat2006; 8:R13.E-pub Mar 15.
  130. Diel IJ, Solomayer EF, Costa SD, et al: Reduction in new metastases in breast cancer with adjuvant clodronate treatment.  N Engl J Med1998; 339:357-363.
  131. Jaschke A, Bastert G, Solomayer EF, et al: Adjuvant clodronate treatment improves the overall survival of primary breast cancer patients with micrometastases to bone marrow—a longtime follow-up (abstract 529).  ASCO Annual Meeting Proceedings2004; 22(14S):9S.
  132. Saarto T, Vehmanen L, Virkkunen P, Blomqvist C: Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients.  Acta Oncol2004; 43:650-656.
  133. Woodward JK, Neville-Webbe HL, Coleman RE, Holen I: Combined effects of zoledronic acid and doxorubicin on breast cancer cell invasion in vitro.  Anticancer Drugs2005; 16:845-854.
  134. Neville-Webbe HL, Rostami-Hodjegan A, Evans CA, et al: Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells.  Int J Cancer2005; 113:364-371.
  135. Wood J, Schnell C, Green J: Novel anti-angiogenic effects of the bisphosphonates compound zoledronic acid.  J Pharmacol Exp Ther2002; 302:1055-1061.
  136. Lester J, Dodwell D, McCloskey E, Coleman R: The causes and treatment of bone loss associated with carcinoma of the breast.  Cancer Treatment Rev2005; 31:115-142.
  137. McCloskey E: Effects of third-generation aromatase inhibitors on bone.  Eur J Cancer2006; 42:1044-1051.
  138. Perez EA, Josse RG, Pritchard KI, et al: Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17.  J Clin Oncol2006; 24:3629-3635.
  139. Saarto S, Blomqvist C, Valimaki M, et al: Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss which is reduced by clodronate: a randomised study in premenopausal patients.  J Clin Oncol1997; 15:1341-1347.
  140. Delmas PD, Balena R, Confravreux E, et al: Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study.  J Clin Oncol1997; 15:955-962.
  141. Gnant MF, Mineritsch B, Luschin-Ebengreuth G, et al: Zoledronic acid prevents cancer treatment induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colotrectal Cancer Study Group.  J Clin Oncol2007; 25:820-828.
  142. Brufsky A, Harker WG, Beck JT, et al: Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer.  J Clin Oncol2007; 25:829-836.
  143. Allain TJ: Prostate cancer, osteoporosis and fracture risk.  Gerentology2006; 52:107-110.
  144. Smith MR, McGovern FJ, Zietman AL, et al: Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer.  N Engl J Med.2001; 345:948-955.
  145. Smith MR, Eastham J, Gleason DM, et al: Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer.  J Urol2003; 169:2008-2012.
  146. Harrington KD: Orthopaedic surgical management of skeletal complications of malignancy.  Cancer1997; 80(Suppl):1614-1627.
  147. Major PP, Lortholary A, Hon J, et al: Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy—a pooled analysis of two randomized, controlled clinical trials.  J Clin Oncol2001; 19:558-567.
  148. Plunkett TA, Smith P, Rubens RD: Risk of complications from bone metastases in breast cancer: implications for management.  Eur J Cancer2000; 36:476-482.
  149. Mirels H: Metastatic disease in long bones. A proposed scoring system for diagnosisng impending pathological fracture.  Clin Orthop Rel Res1989; 249:256-264.
  150. Liberman I, Reinhardt MK: Vertebroplasty and kyphoplasty for osteolytic vertebral collapse.  Clin Orthop2003; 415(Suppl):S176-S186.
  151. Jensen ME, Kallmes DF: Percutaneous vertebroplasty in the treatment of malignant spine disease.  Cancer J2002; 8:194-206.
  152. Hill ME, Richards MA, Gregory WM, et al: Spinal cord compression in breast cancer: a review of 70 cases.  Br J Cancer1993; 68:969-973.
  153. Findlay GFG: Adverse effects of the management of malignant spinal cord compression.  J Neurol Neurosurg Psychiatry1984; 47:761-768.
  154. Patchell RA, Tibbs PA, Regine WF, et al: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial.  Lancet2005; 366:643-648