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 that contains a variety of marrow-residing cells (including osteoblasts, osteoclasts, bone marrow stromal cells, immune cells, mesenchymal stem cells, adipocytes, fibroblasts, and 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 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.¹⁴

Bone resorption is mediated by the osteoclast, a multinucleated giant cell derived from granulocyte-macrophage precursors, whereas bone formation is carried out by osteoblasts, which are derived from mesenchymal fibroblast-like cells. In a healthy person, 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. 51-1).

Recent studies in model systems have shown that direct contact with breast cancer cells cause substantial changes to the surrounding bone microenvironment at early stages, prior to the formation of bone lesions.¹⁵ The presence of tumor cells ultimately results in the development of cancer-induced bone disease that disrupts the fine-tuned balance between osteoblast and osteoclast activity, either causing excess bone resorption (as associated with lytic bone lesions), or increased levels of bone formation (as in osteosclerotic bone lesions) (Fig. 51-2). In many cases mixed lesions are present, which have both lytic and sclerotic features. In the late stages of cancer, tumor masses may also damage the skeleton by compression of vasculature and consequent ischemia.

Tumor Cell-Bone Cell Interactions

Malignant cells secrete factors that stimulate osteoclastic activity both directly and indirectly, 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, as summarized in a recent review.¹⁶ 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 (TNF), and interleukin (IL) 1, 6, 8, and 11 (Fig. 51-3).

Several proteolytic enzymes are proposed to be involved in the early phases of formation of bone metastases, including matrix metalloproteinases (MMPs; e.g., MMP-2 and MMP-9) and cathepsin K.¹⁷ 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 formation of bone metastases 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.¹⁸ 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 TNF and IL-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.¹⁹

In addition to the local paracrine factors just described, osteoclastic activity can also be stimulated in malignant disease by systemic factors, particularly PTHrP.²⁰ This peptide is immunologically distinct from parathyroid hormone, but the two hormones have significant homology at the amino terminus of the molecule, which is necessary for osteoclast stimulation. Ectopic production of this hormone, particularly in persons with 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.²⁰ In bone metastases, the secreted PTHrP acts in a paracrine manner to stimulate osteoclastic bone resorption, which not only leads to skeletal damage but also appears to confer a selective growth advantage on the tumor cells. This advantage is conveyed by 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 further growth factors to stimulate tumor cell proliferation. 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 (RANKL). RANKL 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 RANKL, terminating its stimulatory effects on osteoclasts.²¹ The MCF-7 estrogen-dependent breast cancer cell line has been found to decrease osteoblastic OPG messenger RNA levels, enhancing osteoclast formation. This imbalance is compounded by release of TGF-β and insulin-like growth factor (IGF1) from resorbing bone, which further promotes tumor production of PTHrP, perpetuating the cycle of osteolytic bone destruction. The OPG-RANK-RANKL triad of molecules are central not only to normal bone physiology but have a key role in the development of bone metastasis, with several different tumor cell types producing one or more of these factors.²²

Sclerotic Bone Metastases

Although osteolytic disease is usually most evident at sites of bone metastases, osteosclerosis sometimes can predominate, particularly in prostate 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.²³ 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 control subjects. 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.²⁴ 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.²⁵ 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 co-expression of PTHrP and its receptor has been found in both the primary tumor and in bone metastases of patients with prostate cancer.²⁶

Evidence from morphometric studies and measurement of urinary markers of osteolytic bone resorption has led to the hypothesis that osteoclastic bone resorption initially is important in prostate cancer and is followed by intense osteoblastic activity.²⁷ This scenario might not always be the case, however. When the prostate cancer cell line PC-3 is implanted into the tibia of severe combined immunodeficiency (SCID) mice, osteolytic lesions develop, possibly through secretion of RANKL.²⁸ However, when another prostate cancer cell line (LAPC-9) was used, osteoblastic lesions developed even when no osteoclasts were present. Therefore these authors concluded that osteoclastic activity might not be a prerequisite for the formation of osteoblastic lesions.

Interest is increasing 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.²⁹ Subsequent studies have found that several molecules in this system are implicated in the development of bone metastases.³⁰ 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 dickopf-1 (DKK1), thereby favoring lytic lesions. In the later stages of progression of prostate cancer bone metastases, the balance between Wnt and its inhibitors appears to be shifted toward Wnt, favoring osteoblastic lesions.

In myeloma bone disease, bone marrow stromal cells are important for the pathogenesis of multiple myeloma. IL-6 appears 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. MMPs, which are known to be important in normal and malignant remodeling, also 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. Malignant plasma cells have been found to upregulate MMP-1 and activate MMP-2.³¹

Dysregulation of the Wnt signaling system has also been implicated in myeloma bone disease. The production of DKK1 (an inhibitor of osteoblast differentiation) by myeloma cells is reported to be associated with the presence of lytic bone lesions,³² whereas inhibition of DKK1 prevents the development of lytic bone disease in models of multiple myeloma.³³

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 of the axial skeleton should be performed.

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. Although it is probably a general phenomenon, this effect is most apparent in the appropriately termed “mixed” lesions, seen most commonly in persons with 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. 51-4). Thinning of trabeculae occurs, 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, endosteal scalloping could be present, whereas cortical lesions produce subperiosteal scalloping or a focal cortical defect.

Sclerotic metastases are usually from prostate cancer but also arise from breast, lung, and carcinoid tumors (Fig. 51-5). 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 appear, which can coalesce to produce a diffuse sclerotic appearance to the skeleton.

Radionuclide Bone Scan

A radionuclide bone scan provides quite different information than that provided by a skeletal radiogram. The bone-seeking radiopharmaceutical agent 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, a sufficient increase in blood flow and reactive new bone formation usually occurs to produce a focal increase in tracer uptake, often before bone destruction can be seen radiologically. With the exception of patients with multiple myeloma, the bone scan is a more sensitive technique than plain radiographs for the detection of skeletal pathology. Lesions in the pubis, ischium, and sacrum may on occasion be obscured on a 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 technetium-99m–labeled bisphosphonate. If a lesion is identified, further investigation is necessary, particularly when it is solitary. A suggested protocol for investigation is shown in the accompanying algorithm (Fig. 51-6). Appropriate plain radiographs of a focal lesion should be obtained in the first instance. If findings of these radiographs are normal and yet clinically a metastasis is likely, CT or magnetic resonance imaging (MRI) of the area could be diagnostic.

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. 51-7). 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, with the proportion increasing in certain tumor types such as renal cell carcinoma.³⁴

Because detection of a lesion depends on the presence of a focal increase in osteoblast activity, a false-negative scan will occur when pure lytic disease is present. A false-negative scan is typical of multiple myeloma, which is best investigated radiographically, but a false-negative scan also can occur in other tumors when rapidly growing lytic lesions are present. In extreme cases where significant bony destruction has occurred, a photon-deficient area (cold spot) can develop (Fig. 51-8). Sclerotic metastases, on the other hand, are generally clearly visualized on the bone scan, with 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.

When extensive skeletal metastases are present, the focal lesions can coalesce to produce diffusely increased uptake—the so-called “super scan” of malignancy (Fig. 51-9). This scenario occurs most often in prostate cancer but also is seen in other tumors, such as breast cancer. Increases in the contrast between bone and background soft tissue and faint or absent renal images are the typical appearances.

Computed Tomography

A CT scan produces images with excellent soft tissue and contrast resolution. Bony destruction and sclerotic deposits are well visualized (Fig. 51-10), and any soft tissue extension of bone metastases is demonstrated clearly. CT can help with the diagnosis of spinal metastases and is particularly useful to localize lesions for biopsy.³⁵

Magnetic Resonance Imaging

MRI permits imaging of the entire spine in the sagittal plane (Fig. 51-11). With a T1-weighted scan acquisition, 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 is more sensitive than a bone scan for the early detection of spinal metastases.³⁶

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 the field of 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.⁴²

Quality of life (QOL) 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 and the European Organization for Research and Treatment of Cancer (EORTC) QOL-C30 questionnaire can provide useful information on subjective response to treatment in the routine clinical setting. A specific QOL tool for patients with bone metastases has recently been validated (EORTC-BM22)⁴⁴ and could be considered for assessment of patient outcomes in routine clinical practice and in clinical trials.

Imaging of Bone Metastases

Although the plain radiograph remains the assessment tool used to judge response in many clinical trials, it is clearly an inadequate technique. The 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 patients with no change in radiographic appearance for at least 3 months have a similar outcome.⁴²

The use of bone scanning for assessment of response to therapy has always been contentious and is certainly unreliable when lytic metastases predominate. 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 an increased number of hot spots. After treatment for 6 months, the bone scan appearances might improve as the increased production of immature new bone 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. 51-12). 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.

Bone scanning in advanced disease is most useful for restaging at the time of relapse, identifying sites for radiologic assessment, and drawing attention to the sites at risk of pathological fracture where prophylactic surgery could be indicated.

CT evaluation is valuable as a parameter of response to metastatic disease. Metastatic lesions 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 selected. If required, a region of interest can be defined and the spectrum of Hounsfield values within it can be calculated by the imaging software. 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.

MRI for monitoring response to treatment is not used routinely. As in primary bone tumors, however, MRI can have a role for detailed evaluation of a specific lesion, for example, before surgery.

The role of PET scanning in assessment of response has become clearer in recent years.⁴⁵ The regular, well-defined tumor margins that are necessary for reproducible anatomic measurements are of lesser importance in functional imaging. Functional imaging criteria, such as the recently developed Positron Emission Tomography Response Criteria in Solid Tumors, have allowed response to be measured in the absence of anatomic change through assessment of metabolic activity but have not yet been accepted for routine use.⁴⁵

Tumor Markers

In breast cancer, unlike in germ cell malignancies, no highly specific tumor marker is available for either diagnosis or monitoring of disease. However, some breast tumors 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 carcinoma antigen (CA) 15-3, which is elevated in 60% to 90% of persons 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. A combination of carcinoembryonic antigen, CA 15, and erythrocyte sedimentation rate may provide an indication of response. In a study in patients with metastatic breast cancer, a significant correlation with clinical assessment of response was found using Union Internationale Contre Cancer criteria at 2, 4, and 6 months after systemic endocrine treatment. 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.⁴⁶

Prostate-specific antigen (PSA) is a marker of prostatic pathology and can be elevated in any prostate disease, although the highest tissue production occurs in prostate cancer. PSA has proved useful in the early diagnosis, staging, and follow-up of patients.⁴⁷ 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) is initiated and generally provide a reliable guide to response; elevations of PSA usually antedate other clinical evidence of progression by at least 12 months.⁴⁸ The PSA doubling time is a useful predictor of overt metastases in castrate-resistant prostate cancer (CRPC)⁴⁸ and has been used to select suitable patients to enable evaluation of new treatments developed to delay or prevent metastasis.

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, can provide an early assessment of response to treatment.38,39

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.

More recently, attention has turned to the possible use of collagen cross-link measurements for the assessment of response in bone. Several pilot studies have shown that bone resorption markers will usually fall if disease is controlled, whereas bone formation markers show an initial rise in the first 1 to 3 months of successful treatment because of the flare response followed by a fall as the response is consolidated.39,42

Although it is now well accepted that bone-targeted systemic therapy—particularly bisphosphonates—can reduce morbidity of skeletal metastases of breast cancer substantially, the optimization and timing of these therapies remain 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. However, this prospect remains a research question, and use of bone markers is not recommended by current guidelines.49,50

Evidence indicates that the individual pretreatment values of a bone marker correlate with response to treatment. In patients with metastatic bone pain, normalization of bone resorption markers correlated with response to treatment.⁵¹ Clinical benefit, as indicated by an improvement in a pain score, was seen only among the patients achieving a normal bone resorption rate after administration of pamidronate. No response was seen in the patients with persistently elevated levels, which 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.⁵²

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 both skeletal complications and death (P < .001).⁵³

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.⁵⁴

Most treatments for bone pain use an external beam of ionizing radiation, either γ-rays or x-rays. Opposing anterior and posterior fields are often used to produce an even dose distribution across the volume to be treated. A treatment simulator is used for accurate localization and to simplify treatment of adjacent areas in the future.

Irradiation of bone can result in a number of pathological changes. Initially, degeneration and necrosis of tumor cells occurs, 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 new woven bone is then gradually replaced by lamellar bone, and the intratrabecular stroma is repopulated by bone marrow tissue, depending on the radiation dose. Radiologically, it can be seen that recalcification of lytic areas begins 3 to 6 weeks after irradiation, with maximum recalcification occurring 3 to 6 months after the time of irradiation.

There is no doubt that local irradiation is effective in relieving bone pain. Overall, response rates of around 85% are reported, with complete relief of pain achieved in half of patients.⁵⁴ 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, with prolonged fractionated treatments preferred in North America and single treatments or short fractionation schedules most frequently used in Europe. A number of randomized trials have been performed comparing fractionation schedules. No particular approach seemed to be superior in terms of pain relief. 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.⁵⁵ No statistically significant differences in pain response, analgesic consumption, treatment adverse effects, or QOL were identified.

Subsequently, a metaanalysis 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.⁵⁶ Hence accumulating evidence strongly favors single-fraction radiotherapy as the treatment of choice for many patients with painful bone metastases.⁵⁷

The option of retreatment of a painful site requires careful review of previous treatment fields, dose, and fractionation and the time since the initial treatment to ensure that normal tissue tolerance, particularly of the spinal cord, is not exceeded. When higher radiation doses have been 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 who have 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.⁵⁷

When painful bone metastases are present at multiple scattered sites, wide-field/hemibody irradiation is an alternative to treating each site individually with local irradiation, although this approach is not commonly used. With use of 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.⁵⁴ Hemibody irradiation is inevitably more toxic than localized external beam treatment. Virtually all patients who receive lower hemibody irradiation experience gastrointestinal toxicity. The serious toxicities of hemibody irradiation are bone marrow suppression and occasional 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, potentially compromising the use of subsequent chemotherapy. Despite these adverse effects, wide-field irradiation is probably underused in the palliation of advanced stages of malignancy.

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 for the treatment of follicular thyroid cancer. Targeted radiotherapy has theoretic advantages over external beam radiotherapy in that the radiation dose may be delivered more specifically to the tumor and normal tissues may partially be spared unnecessary irradiation. Theoretically, it should also be possible to administer high doses of radiation to the tumor on a recurrent basis if necessary.

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.⁵⁸ Treatment is generally well tolerated, although some patients experience a radiation reaction in the salivary glands. More important, however, is the 1% to 2% incidence of radiation-induced leukemias.

Neuroblastomas, and tumors of neuroectodermal origin in general, frequently metastasize to bone. Some 90% of these neoplasms incorporate the radiopharmaceutical agent ¹³¹I-meta-iodo benzyl guanidine (¹³¹I-MIBG), which 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 for 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 half of patients achieve symptomatic benefit, but long-term remissions are rare.

Strontium-89 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, and whole-body retention of ⁸⁹Sr treatments ranging from 11% to 88% depending on the degree of skeletal involvement.⁵⁹ The biological half-life of strontium in metastases is long compared with that of normal bone. 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. On average, the response lasts for 6 months, with only mild hematologic toxicity.⁵⁹

⁸⁹Sr has been compared with conventional radiotherapy (hemibody or local) for the palliation of bone metastases from prostate cancer and was at least as effective as external beam radiotherapy in achieving palliation and prevention of new sites of pain.⁶⁰

Samarium-153 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), concentrates preferentially in skeletal metastases. Clinical reports indicate that ¹⁵³Sm-EDTMP can provide excellent palliation of pain in both breast and prostate cancer.⁶¹ The short half-life of ¹⁵³Sm also makes ¹⁵³Sm-EDTMP suitable for repeated treatments.

Rhenium-186, an investigational radiopharmaceutical, is also a β- and a γ-ray emitter that is complexed with hydroxyethylidene diphosphonate for therapeutic use. Encouraging clinical results with mild and reversible bone marrow toxicity suggests that the agent may be suitable for repeated administration.⁶² 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. The high-energy α particles provide a high dose of radiotherapy to cells within 1 µm of the bone surface with minimal systemic effects. In addition to effective palliation of bone pain, declines in PSA levels in a population of patients with advanced prostate cancer were seen in a small phase 2 study.⁶³ Recently, a phase 3 study in persons with advanced prostate cancer that evaluated the addition of Alpharadin to best supportive care in persons with advanced CRPC was reported. In addition to beneficial effects on quality of life and the incidence of skeletal morbidity, there was a 3.6-month significant improvement in overall survival (OS).⁶⁴

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 can have 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 multiple 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.

Bisphosphonates

In the past 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, adverse effects, and precise mechanism of action.⁶⁵ 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 51-14.

After administration, bisphosphonates bind avidly to exposed bone mineral around resorbing osteoclasts, leading to 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 processes 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 mechanisms of action of the bisphosphonates are now established, with nitrogen-containing bisphosphonates shown to inhibit enzymes of the mevalonate pathway that are responsible for events that lead to the posttranslational modification of a number of proteins, including the small guanosine triphosphatases such as Ras and Rho.⁶⁵ Bisphosphonates that do not contain nitrogen, such as clodronate, induce osteoclast apoptosis through the generation of cytotoxic adenosine triphosphate analogs. Recent studies suggest that bisphosphonates could have direct apoptotic effects on tumor cells and that this effect may be enhanced by combination with other anticancer agents.⁶⁶

After intravenous administration of a bisphosphonate, the kidney excretes approximately 25% to 40% of the injected dose, and the remainder is taken up by bone. All bisphosphonates have poor bioavailability when they are taken by mouth, and they must be taken on an empty stomach to minimize binding to calcium in the diet.⁶⁷

Irrespective of the mechanism(s) of action, bisphosphonates have been used successfully in the treatment of a wide range of bone conditions characterized by increased osteoclast-mediated bone resorption. In oncology they have become the standard treatment for tumor-induced hypercalcemia and part of routine medical therapy to prevent morbidity from bone metastases, and they may have a role in prevention of metastasis in the adjuvant setting.⁶⁸

RANKL Inhibition to Prevent Skeletal Morbidity

RANKL is a member of the TNF superfamily and is the ligand for OPG. RANKL is expressed on the surface of osteoblasts and released into the bone microenvironment, where it binds to and activates its receptor, RANK, on immature osteoclasts. Mice deficient in either RANKL or RANK lack osteoclasts and exhibit severe osteopetrosis. OPG is also expressed on osteoblasts, and this protein inhibits osteoclast formation and is the key regulator of bone mass. Overexpression of OPG in transgenic mice leads to a profound reduction in the number of mature osteoclasts and markedly increases bone density, whereas OPG-knockout mice have increased bone resorption and severe osteoporosis.⁹⁷

Denosumab is a fully human, synthetic antibody that binds to RANKL with high affinity, preventing its interaction with RANK in a way similar to that of osteoprotegerin. In early clinical development, a single subcutaneous dose of denosumab caused rapid suppression of bone turnover in patients with multiple myeloma and breast cancer. The maximal amount of urinary NTX suppression (about 70%) was reached after 7 days and was sustained over the 84 days of the study.⁹⁸ In a dose-finding study in patients with breast cancer and bone metastases,⁹⁸ the onset of inhibition of bone resorption was rapid, and after 13 weeks of treatment, the median reduction in urinary NTX levels was 71% for all patients treated with denosumab versus 79% for those treated with bisphosphonates.⁹⁹ Denosumab treatment at a dose of 120 to 180 mg every 4 weeks provided the most reliable and consistent suppression of urinary NTX. Transient hypocalcemia occurred in 8% of patients treated with denosumab, most commonly in those treated with 180 mg of the drug every 4 weeks. As a result, treatment with 120 mg of denosumab every 4 weeks was selected to provide the optimal balance of efficacy and tolerability.

The first evidence suggesting that denosumab might be superior to a bisphosphonate for prevention of skeletal morbidity emerged from a randomized, phase 2 study conducted in patients with bone metastases and urinary NTX levels >50 nmol/mmol creatinine, despite treatment with an intravenous bisphosphonate.¹⁰⁰ The patients either continued to receive intravenous bisphosphonate therapy (pamidronate or zoledronic acid) every 4 weeks or were switched to subcutaneous denosumab treatment (180 mg) every 4 weeks (six doses) or every 12 weeks (two doses) for 25 weeks. Normalization of urinary NTX levels (that is, to <50 nmol/mmol creatinine) was achieved in 49 of 69 patients treated with denosumab (71%) and in only 10 of 35 patients treated with a bisphosphonate (29%; P < .001). Moreover, considerably fewer patients treated with denosumab experienced a first SRE during the 25 weeks of the study: 8% (6 of 73 patients) versus 17% (6 of 35 patients, odds ratio 0.31, 95% confidence interval [CI] 0.08-1.18).

Subsequently, three identical double-blind, phase 3, registration studies of denosumab were performed.103–103 These studies included a total of 5723 bisphosphonate-naive patients with bone metastases resulting from breast cancer (n = 2046),¹⁰¹ CRPC (n = 1901),¹⁰² and other advanced solid tumors, including non–small-cell lung cancer (n = 702), myeloma (n = 180), and other types of solid tumors (n = 894).¹⁰³ The patients were randomly assigned to receive four weekly subcutaneous injections of denosumab (120 mg) or intravenous zoledronic acid (4 mg), with supplements of calcium and vitamin D (Table 51-5). The primary end point was the time to first SRE.

In patients with bone metastases resulting from breast cancer, denosumab was statistically superior to zoledronic acid in delaying the first SRE (hazard ratio [HR] 0.82, 95% CI 0.71-0.95, P = .01): the median time to a first SRE was 26.4 months for patients treated with zoledronic acid, whereas the median time to first SRE was not reached during the study in subjects treated with denosumab.¹⁰¹ Similar results were reported in patients with bone metastases resulting from prostate cancer: the median time to a first SRE was 17.1 months for patients treated with zoledronic acid versus 20.7 months for those treated with denosumab (HR 0.82, 95% CI 0.71-0.95, P = .008).¹⁰² In patients with bone metastases resulting from advanced solid tumors and myeloma, denosumab was not inferior to zoledronic acid (HR 0.84, 95% CI 0.71-0.98, P = .03) but failed to demonstrate statistical superiority over bisphosphonates.¹⁰³ Denosumab treatment delayed the occurrence of all types of SREs. However, no differences in OS or investigator-reported disease progression were found between the two treatment groups in any of the studies.

A key difference between the safety profiles of denosumab and zoledronic acid is the lack of an effect of denosumab on renal function, which obviates the need for assessment of the patient’s renal function before each denosumab dose. Acute-phase reactions were less common but hypocalcemia was more frequent in patients treated with denosumab. Most episodes of hypocalcemia were generally mild and easily managed, but^. all patients should be encouraged to take calcium and vitamin D supplements, and monitoring of serum calcium levels is advised, particularly in patients with impaired renal function. As with intravenous bisphosphonates, the most important adverse event associated with the use of denosumab in oncology settings is ONJ. A similar proportion of patients treated with zoledronic acid and denosumab experienced ONJ (1.3% vs. 1.8%, respectively); in total, 89 confirmed cases of ONJ occurred among 5677 patients who received one or more doses of either agent.¹⁰⁴

Optimum Use of Bone-Targeted Agents in Persons with Metastatic Bone Disease

Consensus guidance recommendations indicate that all patients with radiologically confirmed bone metastases from breast cancer should start taking a bisphosphonate or denosumab at the time of diagnosis of bone metastasis and continue with this treatment indefinitely.49,50 The development of an SRE is not necessarily a sign of treatment failure or a signal to stop treatment; evidence is now available to confirm that bone-targeted agents delay second and subsequent complications, not just the first event. However, for persons with multiple myeloma, only bisphosphonate treatment is recommended, because denosumab is not approved for use in persons with multiple myeloma, pending the results from specific ongoing trials.

Bisphosphonate treatment—specifically zoledronic acid—or denosumab is also appropriate for patients with CRPC. Patients with other tumors and metastasis to bone should be considered for bone-targeted treatment if bone is the dominant site of metastasis or the patient has symptoms or a raised level of a biochemical marker of bone metabolism.

Despite the obvious clinical benefits of bone-targeted treatments, 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 accurately whether an individual patient needs or will benefit from bone-targeted treatments, although elevated bone marker levels, a previous SRE, increasing numbers of lesions, and lytic rather than sclerotic appearance of lesions on radiograms are associated with a higher risk for SREs.⁴¹ Overall, the frequency of skeletal events is reduced by 30% to 50%. Bisphosphonates or denosumab are relatively costly additional interventions in cancer care that are now potentially applicable to a very large proportion of patients with advanced malignancy, and the cost-effectiveness of routine long-term treatment has been questioned. Evidence-based guidance on optimum duration, schedule, and dose is becoming essential. Uncertainty remains about the appropriate duration and schedule of treatment. Bone marker–directed therapy is under evaluation in randomized clinical trials and may help personalize treatment according to the rate of bone turnover, and the value of maintenance therapy after 1 to 2 years of treatment may also become clearer when results are available from the ongoing clinical trials.

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 treatments. Many of these persons are at increased risk of osteoporosis, largely because of the endocrine changes induced by treatment. Clinically relevant, direct effects of cytotoxic drugs on bone also might exist. Cancer treatment–induced bone loss is a particularly important long-term problem for women with breast cancer and men receiving ADT.¹²¹ 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 critical in the maintenance of normal bone mass in women. After menopause a reduction in BMD occurs, with the loss most pronounced during the first 3 years, when the rate averages 2% to 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.¹²¹ Compared with naturally occurring bone loss associated with ageing, 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.¹²¹

Several clinical trials have demonstrated increased fracture rates in postmenopausal women with breast cancer who received aromatase inhibitors.¹²² 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.¹²¹

Intravenous bisphosphonate administration is used widely in oncology to treat metastatic disease and could be an attractive option for preventing bone loss in a cancer population. Among premenopausal patients with breast cancer, 6 monthly treatments with 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 treatments with zoledronic acid.¹²²

In postmenopausal women, the strategy of immediate treatment with zoledronic acid for 6 months alongside aromatase inhibitor therapy has been compared with initiation of bone protection treatment if osteoporosis or significant bone loss occurs upon treatment.115,123 In the Z-FAST study, the differences in lumbar spine and hip BMD at 5 years between patients receiving immediate or delayed treatment were approximately 9% and 6%.¹²³ However, despite this impressive effect on BMD, no significant difference in fracture rates have yet to be demonstrated.

Other bisphosphonates, including oral daily clodronate (1600 mg),¹²⁴ weekly risedronate (35 mg),¹²⁵ and oral monthly ibandronate (150 mg),¹²⁶ as well as monthly subcutaneous denosumab (60 mg for 6 months),¹²⁷ have all been shown to have significant beneficial effects on BMD. The choice of agents in established postmenopausal patients is broad. However, for the rapid bone loss associated with chemotherapy-induced menopause or ovarian suppression, the more potent agents such as zoledronic acid or denosumab appear to be necessary.¹²⁸

Emerging guidance suggests that overall fracture risk in women with breast cancer should be determined using clinical risk factors and BMD when available. A panel of experts from the United Kingdom developed two treatment algorithms, one for premenopausal patients and one for postmenopausal patients.¹²⁹ Although both algorithms use fracture risk factors as part of the criteria for categorizing patients into low-, medium-, and high-risk groups, BMD is still an integral part of the equation. Hadji et al.¹²¹ recommend treating patients receiving aromatase inhibitors who have ≥two identified risk factors (age >65 years, body mass index <20 kg/m², family history of hip fracture, personal history of fragility fracture after age 50 years, corticosteroid use by mouth >6 months, and smoking). The concept of using validated fracture risk factors with or without BMD to assess overall fracture risk in women with breast cancer is consistent with the FRAX algorithm developed for healthy women. Similar guidance is under development for men with prostate cancer who are undergoing ADT.

Bone Loss in Prostate Cancer

Many men with prostate cancer are at risk of the development of osteoporosis, largely because of the ADT they receive for their cancer.¹³⁰ These treatments are being introduced earlier and earlier in the course of the disease, and as a result, 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) with consequent adverse effects on bone turnover.

ADT leads to accelerated bone loss and an increase in fracture rate, as evidenced by large retrospective epidemiological studies.¹³⁰ As the potential scale of the problem is being realized, attention is focusing on measuring bone density in patients starting ADT to assess those at risk and on therapeutic options such as bisphosphonates to prevent or treat therapy-related bone loss in persons with prostate cancer. Alendronate, risedronate, pamidronate, and zoledronic acid have all been shown to prevent loss in BMD in patients with locally advanced prostate cancer.¹³¹ In one study of zoledronic acid, BMD increased by 5.3% at the lumbar spine and 1.1% in the hip in men treated with zoledronic acid but declined by 2% in the lumbar spine and 2.8% in the hip with placebo.¹³²

Denosumab is the only agent to have a specific license for treatment-induced bone loss associated with ADT. In a placebo-controlled trial of denosumab in 1468 men receiving ADT for nonmetastatic prostate cancer,¹³³ 36 months of denosumab treatment was associated with a significantly reduced incidence of new vertebral fractures (1.5% with denosumab vs. 3.9% with placebo; relative risk [RR] 0.38; 95% CI 0.19-0.78). The incidence of fracture at any site was also reduced in the denosumab group, although this difference was not significant: 38 fractures (5.2%) with denosumab, versus 53 (7.2%) with placebo (RR 0.72, 95% CI 0.48-1.07). BMD increased from baseline at all sites in the denosumab group, whereas it declined in the placebo group, leading to substantial absolute differences in BMD between the two groups (6.7% at the lumbar spine and 4.8% at the total hip) after 36 months of study.

Bone Pain

Bone pain is the most common type of pain from cancer and is a significant problem in both hospital and community practice. Pain is usually the manifesting 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.¹³⁴ 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 Chapter 37) 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 that vary considerably from patient to patient. These signs and symptoms 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 consciousness. 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 mechanisms 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 also be encountered in patients with cancer. Measurement of parathyroid hormone using a radioimmunoassay is worthwhile if there is any doubt about the diagnosis; levels of parathyroid hormone 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 QOL. Zoledronic acid is the most effective bisphosphonate for the acute treatment of this metabolic emergency.¹³⁵

Pathological 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 pathological 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 pathological fracture (in the absence of bisphosphonates) was between 20% in persons with prostate cancer⁷³ and 40% in persons with breast cancer.⁷⁰ Not all of these fractures are symptomatic, and undoubtedly some are due to treatment-induced osteoporosis rather than metastatic infiltration. Nevertheless, structural damage to bone is extremely common in metastatic bone disease.

The probability of developing a pathological fracture increases with the duration of metastatic involvement and is therefore, somewhat paradoxically, more common in patients with bone-only disease who have a relatively good prognosis.¹³⁶

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 or denosumab 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 cortical destruction that is most clearly appreciated. Risk factors 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.

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, pathological 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, pathological 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.¹³⁷

Prophylactic internal fixation is usually the treatment of choice for lesions deemed at high risk for fracture, 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. If a 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 pathological fracture are also stabilized and included in the radiotherapy field. A pathological 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.

For pathological fractures of long bones, 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 pathological 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, insufficient matrix could remain 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.

Pathological 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 are 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 pelvic reconstruction sometimes 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; it provides 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, patients expected to survive longer than 3 months are best managed by internal fixation to ensure pain relief and restoration of function. Replacement arthroplasty may be necessary if the proximal humerus is involved, but most pathological fractures of the humerus can be treated with 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.¹³⁴ As with pathological fractures of long bones, stabilization is required for pain relief and involves major surgery. Several methods can be used to achieve 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.¹³⁸ 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 complication is less with kyphoplasty. 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. Its causes include pressure from an enlarging extradural mass, spinal angulation after vertebral collapse, vertebral dislocation after pathological fracture, or, rarely, pressure from intradural metastases. The most common primary tumors producing this complication, in decreasing order of frequency, are carcinomas of the breast, lung, and prostate, lymphoma, and renal clear cell 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 and prompt rapid referral for imaging and assessment by a specialist spinal team.¹³⁹ Spinal cord compression is covered in detail in Chapter 49.