The escape of cancer cells from a tumour and invasion into distant tissues marks a transition from potentially curable disease to malignancy where cure is unlikely. The metastasis of cancer cells to the skeleton is a particularly dreaded complication of malignancy that disrupts normal bone homeostasis and remodelling, weakening bone and causing pathological fractures (Ref. Reference Clines and Guise1). Bone is the third most common site of metastases of solid tumours after the liver and the lung, often involving the pelvis, spine and ribs and less commonly occurring in appendicular areas (Ref. Reference Galasko, Weiss and Gilbert2). Advanced breast and prostate cancer have a high prevalence of skeletal metastases in the range of 60–70% in autopsy studies, while bone metastases in lung, kidney and thyroid cancer have a prevalence closer to 30–40% (Ref. Reference Guise and Mundy3).
Clinical features
Bone pain is the most frequent type of cancer-related pain, often involving the spine. As this is often an initial symptom, distinguishing metastatic bone disease from common causes of back pain such as vertebral disc disease and muscle strain can be difficult (Ref. Reference Deyo and Diehl4). However, there are ominous warning signs that should alert the physician to the possibility that the patient's discomfort is due to a malignancy. Progressive pain in an older individual or a patient with a history of cancer warrants further investigation. Other worrisome signs include weight loss, and pain worse with rest and in the supine position. A patient with lower extremity motor nerve dysfunction, dysreflexia, or loss of bowel or bladder function requires prompt evaluation for spinal root impingement or cord compression (cauda equina syndrome).
Pathological fractures as a result of metastatic bone disease cause acute pain and disability. Vertebral crush fractures will often result in height loss and pain, and are often the initial symptom of bone metastases. Metastasis to other weight-bearing bones such as the femur and pelvis results in significantly more disability.
Diagnosis
The diagnosis of metastatic bone disease relies on radiographic imaging and possible biopsy of the area in question, especially in a patient without an established diagnosis of malignancy. For patients with high clinical suspicion, plain radiographs are indicated for initial evaluation of focal bone pain. Plain films are most sensitive for vertebral collapse and osteolytic (bone-resorbing) processes, but are less reliable for the identification of osteoblastic (bone-forming) lesions (Ref. Reference Deyo and Diehl4). However, while most lesions are described as either lytic or sclerotic, in reality skeletal metastases are typically mixed and plain radiographs of affected areas are often abnormal. Radionuclide bone scans can confirm the diagnosis. The nuclear tracer, typically technetium-99 methylene diphosphonate, has an affinity for sites of active bone formation, whether the sites are lytic or sclerotic. Radionuclide bone scans are more sensitive than plain films for osteoblastic metastases because increases in blood flow and bone mineral turnover that are detected by bone scans are evident earlier than radiographic evidence of overt bone remodelling (Ref. Reference Jarvik and Deyo5). Computed tomography (CT) or magnetic resonance imaging may also be utilised when results of plain films or bone scans are in question (Ref. Reference Jarvik and Deyo5). Positron emission tomography (PET) might have improved sensitivity in detecting bone metastasis and monitoring progression of disease. Combination imaging modalities such as CT/PET will likely have a larger diagnostic role in the future (Refs Reference Du6, Reference Hur7).
Laboratory studies are unable to diagnose skeletal metastases definitively, but are helpful in monitoring progression. A marked elevation of total alkaline phosphatase in a patient with a malignancy would raise the possibility of hepatic or skeletal involvement. An increase in the bone-specific alkaline phosphatase, a biochemical fraction of total alkaline phosphatase, would indicate an increase in bone mineral turnover and the likely presence of skeletal metastases. Peptide byproducts produced during the formation of type I collagen are helpful in monitoring osteoporosis therapies and may also assist the clinician in monitoring progression of skeletal metastases. It is not clear whether biochemical markers are as sensitive as radionucleotide bone scans to detect the presence or the extent of skeletal metastases. There is preliminary evidence, however, that markers of bone turnover may have utility in determining the response to therapy and may provide prognostic information (Refs Reference Costa8, Reference Coleman9, Reference Brown10).
Molecular mechanisms
Metastatic bone disease is generally divided into osteoblastic and osteolytic disease, but most cancers lie within a spectrum of these two extremes. Osteolytic metastases are considerably more common, are usually destructive and are much more likely to be associated with pathological fracture and hypercalcaemia. Properties of both the tumour cell and the skeleton determine the likelihood that any particular tumour will metastasise to bone. Stephen Paget, during his observations of breast cancer in 1889, proposed the ‘seed and soil’ hypothesis to explain this phenomenon: ‘When a plant goes to seed, its seeds are carried in all directions; but they can only grow if they fall on congenial soil.’ In essence, the microenvironment of the organ to which the cancer cells metastasise may serve as a fertile soil on which the seeds (or cancer cells) may grow. This century-old concept remains a basic principle of our understanding of cancer metastasis, guiding current progress in the research of molecules produced by bones and tumour cells to enrich the vicious cycle of secondary tumour growth (Ref. Reference Clines and Guise1).
The mechanisms by which a solitary tumour is able to escape and invade other distant structures are beginning to be understood. Once tumour cells enter the circulation, they traverse vascular organs, including the red bone marrow, where they migrate through wide-channelled sinusoids to the endosteal bone surface. The process of metastasis can be generally divided into mechanisms that involve cancer cell escape from the primary tumour, adhesion to and invasion of a distant organ, and propagation in a hospitable environment.
Cancer cell escape
The malignant potential of cancer cells is dependent on the ability to degrade the basement membrane and extracellular matrix proteins, to escape from the primary tumour and invade surrounding tissues, and enter the circulatory and lymphatic systems. Animal models of bone metastasis support a role for the matrix metalloproteinases (MMPs) in this process. The MMPs are a family of at least 28 zinc-dependent proteinases that degrade extracellular matrix proteins (Ref. Reference Egeblad and Werb11). The expression of MMPs has been found to be increased in most cancer types including breast and prostate (Refs Reference Bachmeier12, Reference Upadhyay13), and high levels of MMPs have been associated with poor prognosis (Refs Reference Nakopoulou14, Reference Ranuncolo15). In an animal model of prostate cancer osteolytic bone metastasis, MMP-7-deficient mice had less osteolysis due to defective processing of the cytokine RANKL (ligand of ‘receptor activator of NF-κB’) and reduced osteoclast activation (Ref. Reference Lynch16). Despite these convincing associations with MMPs and metastasis, the results of MMP inhibitor Phase III clinical trials have been disappointing. These inconsistencies might reflect the fact that MMP expression is associated and not causally linked with tumour cell aggressiveness and that animal models of tumourigenesis might not recapitulate human disease.
Collective evidence from recent studies suggests that platelets promote metastasis. While it has long been recognised that cancer patients are hypercoaguable, such an increased risk of thrombosis may be due to direct and reciprocal interactions between the cancer cells and platelets. Platelets may ‘coat’ circulating tumour cells, thereby protecting them from attack from the immune system and enhancing their ability to adhere to disrupted vascular endothelium (Ref. Reference Palumbo17). MDA-MB-231 breast cancer cells promote platelet aggregation and the release of lysophosphatidic acid (LPA) (Ref. Reference Boucharaba18). LPA receptors on cancer cells enhanced cellular proliferation, stimulated the production of osteolytic factors, such as interleukin (IL)-8, and increased the size of MDA-MB-231 subcutaneous tumours and osteolytic bone lesions in a mouse model of osteolytic bone metastasis. Moreover, integrilin, an αIIbβ3 antagonist and inhibitor of platelet aggregation, reduced osteolytic bone lesion area in this model (Ref. Reference Boucharaba18).
Cancer cell homing and adhesion
The stromal-cell-derived factor 1a (SDF1a or CXCL12) is present in tissues that represent common sites of metastasis, including bone marrow (Refs Reference Muller19, Reference Sun20, Reference Wang, Loberg and Taichman21). This ligand has an affinity for the chemokine receptor CXCR4, which is highly expressed in breast and prostate cancer cells. The expression of this protein was further increased in a highly osteolytic subclone of the breast cancer cell line MDA-MB-231, suggesting a critical role of this receptor in cancer cell homing and bone metastasis (Ref. Reference Kang22). Blockade of the SDF1a–CXCR4 interaction in vitro inhibited the migration of prostate cancer cells through bone marrow endothelial cells (Ref. Reference Taichman23) and reduced metastatic load in a prostate cancer bone metastasis animal model (Ref. Reference Sun20). Another adhesion molecule, αvβ3 integrin, binds the RGD peptide sequence that is found on a variety of extracellular matrix proteins and appears to be important in homing and possibly invasion of tumour cells into the bone endosteum (Refs Reference Sung24, Reference Felding-Habermann25). In animal models of bone metastasis, αvβ3 antagonists prevented invasion of cancer cells into bone in preliminary data (Ref. Reference Zhao26). These data support the notion of a metastatic niche formed by bone marrow and bone stromal cells that promotes metastatic cancer cell growth.
Cancer cell growth in bone
Osteolytic bone disease
Paracrine interactions occur between cancer cells and the bone microenvironment, and are the basis for the ‘seed and soil’ hypothesis of Stephen Paget. The actions of parathyroid hormone-related protein (PTHrP) and transforming growth factor β (TGF-β) in promoting breast cancer osteolysis support this hypothesis and have served as a model for discovering other signalling pathways that regulate cancer metastasis to bone (Fig. 1). PTHrP is produced by breast cancers, particularly in patients with metastatic disease, but is produced relatively specifically in the bone microenvironment (Ref. Reference Guise27). The increased local bone PTHrP concentration drives RANKL expression and inhibits osteoprotegerin (OPG) secretion from osteoblasts and stromal cells, and thereby activates osteoclastogenesis via RANK located on osteoclast precursors (Ref. Reference Thomas28). Activated osteoclasts resorb bone, resulting in the release of factors, such as TGF-β, embedded within the bone matrix. The release of TGF-β further stimulates breast cancer cells. Thus the vicious cycle begins: tumour cell production of PTHrP stimulates osteoclastic bone resorption and release of more TGF-β, which in turn stimulates more tumour-produced PTHrP.
Bone resorption in breast cancer osteolytic metastasis. Metastatic breast cancer cells invade bone and secrete factors into the bone microenvironment that support osteoclastogenesis. In turn, pathological osteoclastic bone resorption releases immobilised growth factors from the bone matrix into the bone microenvironment that further stimulate breast cancer cells. Signalling pathways involved in normal bone remodelling and osteoclastic bone resorption are utilised by metastatic breast cancer cells to promote growth in bone. (a) Tumour-produced PTHrP, IL-6 and IL-11 increase osteoblast RANKL and decrease OPG activity, resulting in increased osteoclastogenesis. (b) IL-8, TNF-α and VEGF secreted by tumour cells also enhance osteoclast formation but are independent of the RANK–RANKL axis. (c) MMPs produced from tumour cells may prime the bone surface for osteoclast attachment. (d) The escalation in bone resorption leads to the release of factors immobilised in the mineralised bone matrix such as TGF-β, members of the IGF family and calcium. TGF-β stimulates tumour cells to produce even more osteolytic factors (possibly via signalling through SMADs and the transcription factor RUNX-2): thus the ‘vicious cycle’ of osteolytic bone metastases begins. In addition, IGFs provide growth and survival signals and increased calcium concentration may also lead to tumour cell activation. (e) Breast cancer cells promote platelet aggregation and release of platelet-derived LPA. Activation of LPA receptors on breast cancer cells increases proliferation. Abbreviations: IGF, insulin-like growth factor; IL, interleukin; LPA, lysophosphatidic acid; MMP, matrix metalloproteinase; OPG, osteoprotegerin; PTHrP, parathyroid hormone-related protein; RANK, receptor activator of NF-κB; RANKL, ligand of receptor activator of NF-κB; RUNX-2, runt-related transcription factor 2; SMAD, ‘mothers against decapentaplegic’ homologue; TGF-β: transforming growth factor β; TNF-α, tumour necrosis factor α; VEGF, vascular endothelial growth factor.
Blockade of PTHrP and/or TGF-β to reduce bone metastasis represents an ideal strategy in the treatment of bone metastasis and has been a focus of research in preclinical models. The TGF-β receptor 1 kinase inhibitor SD-208 reduced osteolysis in mice bearing the breast cancer cell line MDA-MB-231 in preliminary work (Ref. Reference Mohammad29). Likewise, overexpression of SMAD-7, an inhibitory signalling molecule of TGF-β signalling, in a melanoma cell line reduced bone lesions in a mouse model of melanoma bone metastasis (Ref. Reference Javelaud30). The transcription factor RUNX-2, principally known for its role in osteoblastogenesis, is expressed in breast cancer cells and modulates the response to TGF-β through its interaction with the SMAD transcription factors. Blocking RUNX-2 activity in breast cancer cells reduces tumour growth and osteolysis in mouse models of bone metastasis (Ref. Reference Javed31). Neutralising the effects of PTHrP also has therapeutic benefit. Use of a monoclonal antibody to PTHrP (Reference Clines and Guise1-Reference de la Mata34) resulted in significantly fewer and smaller osteolytic lesions in a mouse model of breast cancer bone metastasis (Ref. Reference Guise27). Recently, the transcription factor GLI-2, a target of sonic hedgehog signalling, was found to regulate breast cancer PTHrP expression. Reducing GLI-2 expression in MDA-MB-231 cells downregulated PTHrP and significantly reduced tumour induced osteolysis (Ref. Reference Sterling32).
In addition to PTHrP, cancer cells produce other factors critical for osteolysis. Data from published and preliminary work demonstrated that IL-6, IL-8 and IL-11, and vascular endothelial growth factor (VEGF), are secreted by osteolytic breast cancer cell lines and potentiate the effects of PTHrP on osteoclastic bone resorption (Refs Reference Kakonen33, Reference de la Mata34, Reference Bendre35). Insulin-like growth factors (IGFs) are also released into the local bone environment during osteolysis and have a role in the proliferation of bone metastasis (Refs Reference Sachdev and Yee36, Reference Yoneda37). IGF-2, then -1, were the most abundant factors in bone matrix, followed by TGF-β, after which were lower concentrations of bone morphogenetic proteins (BMPs), fibroblast growth factors 1 and 2, and platelet-derived growth factor (PDGF) (Ref. Reference Hauschka38).
Osteoclastic resorption of bone releases high concentrations of ionised calcium and phosphate during dissolution of the bone, which may also contribute to the vicious cycle of bone metastasis. The calcium-sensing receptor (CaSR), a G-protein-coupled, seven-transmembrane-domain receptor, is expressed by breast cancer cells and responds to small variations in extracellular calcium concentration (Ref. Reference Yamaguchi, Chattopadhyay and Brown39). CaSR regulates tumour secretion of PTHrP (Refs Reference Buchs40, Reference Sanders41), an effect that is enhanced by TGF-β.
Osteoblastic bone disease
Prostate cancer has a predilection to metastasise to the skeleton and produce osteoblastic lesions. Factors released by prostate cancer cells stimulate the osteoblast and produce pathological new bone (Fig. 2). Tumour-produced endothelin 1 (ET-1) is a principal factor of the osteoblastic response to metastasis (Ref. Reference Yin42). ET-1 stimulates the osteoblast, via the endothelin A receptor (ETAR), to form pathological new bone (Ref. Reference Yin42). ET-1 activates the WNT signalling pathway by reducing autocrine production of the WNT antagonist dickkopf homologue 1 (DKK-1) through unclear mechanisms (Ref. Reference Clines43). The WNT signaling pathway is a key osteoblast regulatory pathway critical for normal osteoblast differentiation and function. Tumour cells themselves also regulate the local concentration of DKK-1 independently of ET-1. PC3 prostate cancer cells, which secrete DKK-1, stably transfected with Dkk1 siRNA were converted from an osteolytic to an osteoblastic phenotype in an animal model of bone metastasis (Ref. Reference Hall44). Conversely, DKK-1 overexpression in the mixed osteoblastic/osteolytic prostate cancer cell line C4-2B produced osteolytic lesions in an animal model (Ref. Reference Hall44). These studies show a clear inverse relationship between DKK-1 and osteoblast activity. DKK-1 is a central regulator of osteoblast activity and osteoblastic bone metastasis and this role is likely dually dependent on the downregulation of microenvironment DKK-1 secretion from osteoblasts via tumour-produced ET-1 and from prostate cancer cells themselves. These mechanisms are complementary, each representing an important pathway of DKK-1 regulation in prostate cancer bone metastasis.
Bone formation in prostate cancer osteoblastic metastasis. Prostate cancer cells stimulate osteoblast proliferation and new bone formation though secretion of factors into the bone microenvironment, including ET-1, FGFs, BMPs and PDGF. Tumour-produced ET-1 stimulates osteoblast activity by decreasing secretion of the WNT pathway inhibitor DKK-1. Tumour production of proteases, most notably prostate-specific antigen, cleaves PTHrP, TGF-β and IGF from its binding protein, resulting in the generation of fragments with osteoblast-stimulating activity. Abbreviations: BMP, bone morphogenetic protein; DKK-1, dickkopf homologue 1; ET-1, endothelin 1; FGF, fibroblast growth factor; IGF, insulin-like growth factor; PDGF, platelet-derived growth factor; PTHrP, parathyroid hormone-related protein; TGF-β, transforming growth factor β.
The relative importance of other factors that promote osteoblastic bone metastasis is under intense investigation. A puzzling question has been the role of PTHrP in osteoblastic metastases, especially those due to prostate cancer, which nearly always express PTHrP. A possibility is suggested by the observation that prostate-specific antigen (PSA) is a serine proteinase, which cleaves PTHrP after residue 23 (Refs Reference Mundy45, Reference Roodman46). The resulting fragment fails to activate the classical PTH/PTHrP receptor (Ref. Reference Cramer, Chen and Peehl47). Data from preliminary work indicated that the inactive fragment PTHrP-1–16 increased cyclic AMP in cardiomyocytes by activating ETAR. Binding was attributed to a four amino acid near-identity between PTHrP-1–16 and ET-1 in the N-terminus (Ref. Reference Schluter, Katzer and Piper48). In ex vivo organ cultures, PTHrP-1–23 is a potent stimulator of osteoblastic bone formation rather than bone destruction (Ref. Reference Mohammad, Guise and Chirgwin49). The results suggest that PSA proteolysis, rather than inactivating PTHrP, converts it from an osteolytic factor to a potent osteoblastic one, but these findings need to be confirmed in vivo. This process may occur in breast and prostate cancer bone metastasis as both tumours secrete PSA and PTHrP. Proteolytic cleavage of IGF from its binding protein and the processing of latent TGF-β to the active form by PSA may also contribute to osteoblast stimulation (Refs Reference Fielder50, Reference Killian51). PSA may have additional direct effects on the osteoblast (Refs Reference Mundy45, Reference Roodman46, Reference Cohen52). Despite convincing in vitro evidence that PSA has biological activity contributing to bone metastasis, in vivo studies demonstrating a clear causal relationship are lacking (Ref. Reference Williams53).
BMP-7, a protein known for its bone-forming actions, is involved in maintaining an epithelial phenotype of prostate cells, and the loss of BMP-7 expression may promote an invasive and metastatic behaviour of prostate epithelium (Ref. Reference Buijs54). IL-11 and connective tissue growth factor (CTGF) expression in breast cancer cells may increase the osteolytic potential of breast cancer cells (Ref. Reference Kang22). PDGF may play a parallel role similar to ET-1 in promoting osteoblastic bone metastasis. Yi et al. (Ref. Reference Yi55) overexpressed PDGF in MDA-MB-231 breast cancer cells and observed osteosclerotic rather than osteolytic metastases. Furthermore, knock-down of PDGF in an aggressive clone of the osteosclerotic breast cancer cell line MCF-7 decreased tumour area in bone and osteoblastic response (Ref. Reference Yi55).
Pain and bone metastasis
Bone pain associated with skeletal metastasis has been an understudied complication of malignancy. Tumour-induced osteolysis, tumour cells themselves and tumour-induced nerve injury have all been proposed as mechanisms that mediate skeletal pain. In addition to its role in promoting an osteoblastic response, tumour-produced ET-1 activates endothelin receptors located on bone sensory pain fibres. Other receptor mediators of pain located on bone pain fibres include the neurotrophic tyrosine kinase receptor (TrkA), transient receptor potential vanilloid 1 (TRPV1), and calcitonin gene-related protein (CGRP) (Ref. Reference Goblirsch, Zwolak and Clohisy56). In support of these receptors as mediators, ETAR and TrkA blockade reduced bone pain associated with cancer metastasis (Refs Reference Peters57, Reference Sevcik58).
Clinical implications/applications
Devising therapeutic strategies to prevent new metastases and inhibit continued growth of established metastases is an important therapeutic goal for cancer management. Research focused on understanding the interactions between cancer cells and bone has directly led to the development of targeted therapies to treat bone metastasis. Options currently available to the clinician include chemotherapy, hormonal therapies, radiation, surgical interventions and bisphosphonates. We review here hormonal therapies, which can have adverse effects in bone, and bone-targeted therapies (Table 1).
Bone-targeted treatments for bone metastases
Abbreviation: ONJ, osteonecrosis of the jaw.
Hormone therapies
The treatment of metastatic bone disease often requires a multidisciplinary approach involving a medical oncologist, radiation oncologist and a surgeon. Systemic chemotherapeutic agents are often used and can have beneficial effects in bone metastases. Endocrine treatments for breast and prostate cancer are considered first-line therapies for tumours that are hormone responsive. Selective oestrogen receptor modulators (SERMs) such as tamoxifen and possibly raloxifene and toremifene effectively block cell growth in oestrogen-responsive breast cancers (Refs 59, Reference Fisher60, Reference Pyrhonen61, Reference Cauley62). Aromatase inhibitors are now approved for use in postmenopausal patients and have largely replaced SERMs for treatment of women with advanced disease (Refs Reference Bonneterre63, Reference Buzdar64, Reference Mouridsen65, Reference Nabholtz66). However, as compared with the SERMs, aromatase inhibitors result in increased bone resorption (Ref. Reference Heshmati67) and fracture risk (Ref. Reference Howell68). Androgen-deprivation therapy in men with advanced prostate cancer can reduce tumour burden and bone pain. Gonadotropin-releasing hormone agonists and antiandrogens are effective and are often preferred over older treatments such as orchiectomy (Ref. Reference Seidenfeld69). However, most prostate cancers will overcome androgen blockade in several years and transform to androgen independence. Similar to oestrogen deprivation, androgen-deprivation therapy significantly impacts bone mineral density and increases fracture risk.
External beam radiation
Prophylactic external beam radiation to prevent fracture in weight-bearing bones, in conjunction with surgical fixation, can prevent significant morbidity. External beam radiation in the treatment of focal bone pain is also quite effective. Most patients report a decrease in pain and approximately half experience some degree of relief in as little as two weeks. Patients with extensive bone metastases can undergo hemibody irradiation but at the expense of increased toxicity. Controversy exists on the optimum dose and schedule of therapy. Multiple studies have examined whether higher doses of radiation with shorter fractions are more beneficial than lower doses and more fractions. However, a recent study examining pain outcomes suggested that a single 8 Gy fraction is equivalent to 30 Gy administered in ten fractions (Ref. Reference Hartsell70).
Radioisotopes
Radioisotopes with an affinity for bone have been studied in patients with metastatic breast and prostate cancer with painful bony metastases. Phosphorus-32 had been used in the past but has been surpassed by newer agents. Strontium-89 (89Sr) is a high-energy beta-particle-emitting radioisotope effective in decreasing pain. In one study, patients with prostate cancer and metastatic bone disease were randomised to receive either 89Sr or external beam radiation (focal or hemibody, depending on the extensiveness of the metastases). Both treatments were highly effective, although there was no significant difference in pain relief scores. However, patients randomised to the 89Sr treatment had fewer subsequent painful bony sites and this result was likely due to the systemic nature of this therapy (Ref. Reference Quilty71). The radioisotope samarium-135 (135Sm) is also effective in alleviating pain in bone metastases (Ref. Reference Serafini72) and has several advantages over 89Sr. 135Sm has a shorter half-life (two days) and can therefore deliver larger doses over a shorter amount of time. This radioisotope emits a lower energy particle, which can translate into reduced bone marrow toxicity.
Surgery
Prophylactic surgical correction of bone metastases is indicated for impending fractures in weight-bearing bones. Osteolytic lesions that encompass a large area of bone have a high likelihood of fracture, with breast and renal cancer metastases having the highest risk (Ref. Reference Higenbotham and Marcove73). Fracture from osteoblastic metastases from malignancies such as prostate occur, but at a lower rate. Although pathological fracture at any location can result in significant pain, fracture of the femur, humerus, pelvis and vertebrae result in the most disability, and fixation at these locations should be performed. Management of impending fracture includes plate osteosynthesis, nailing and insertion of prosthetic implants (Ref. Reference Harrington74). Surgical stabilisation in patients who have spinal instability often results in significant pain relief and resolution of neurological deficit. Adjuvant radiotherapy after fixation can further reduce metastatic destruction.
Kyphoplasty and vertebroplasty are alternatives to surgery, in situations without spinal cord compromise, and may reduce pain and increase function in patients with collapsed vertebral bodies due to metastasis. These procedures involve the percutaneous injection of cement into the collapsed vertebrae, resulting in fracture stabilisation. The benefit of kyphoplasty and vertebroplasty has been reported in patients with spinal metastasis due to breast cancer and multiple myeloma (Ref. Reference Masala75).
Bisphosphonates
The bisphosphonates are currently the mainstay for long-term treatment of osteolytic bone disease. They have an affinity for bone surfaces undergoing active resorption and are released in the bone microenvironment during remodelling. The nitrogen-substituted bisphosphonates, such as alendronate, risedronate and zoledronic acid, are potent inhibitors of the enzyme farnesyldiphosphate synthase, thereby blocking protein isoprenylation and increasing osteoclast apoptosis. It is thought that prenylation of small GTP-binding proteins is important for osteoclast structural integrity and apoptosis prevention (Ref. Reference Roelofs76). Clodronate and etidronate are non-nitrogen-containing bisphosphonates that also induce osteoclast apoptosis, but by a different mechanism of action. They are converted into methylene-containing ATP analogues that inhibit ATP-dependent enzymes, leading to mitochondrial dysfunction and osteoclast apoptosis (Ref. Reference Roelofs76).
Bisphosphonates are unique in the treatment of metastatic bone disease as this is a bone-targeted therapy. Two large trials have been published evaluating pamidronate in patients with stage IV breast cancer; the data were later combined in order to evaluate long-term benefit (Ref. Reference Lipton77). Subjects were randomised to pamidronate 90 mg or placebo every three to four weeks. The primary outcome was skeletal events per year and time to first skeletal-related event (SRE). Despite a significant number of participants not completing the study, the number of events per year in the treatment group was 2.4 compared with 3.7 in the control group. Also, the median time to the first SRE was longer in the treatment group.
A Phase II trial evaluating the effective dose of zoledronic acid and pamidronate in patients with osteolytic lesions due to multiple myeloma or metastatic breast cancer was reported (Ref. Reference Berenson78). Zoledronic acid, at 0.4, 2.0 or 4.0 mg, was compared with 90 mg of pamidronate administered every four weeks up to 10 months. The primary endpoint was the need for radiation therapy to bone during the treatment period, and secondary endpoints included SRE, bone mineral density and bone pain. The 2.0 mg and 4.0 mg zoledronic acid treatment groups had an equivalent rate of radiation therapy requirement as the pamidronate arm, but the 0.4 mg zoledronic acid group underwent radiotherapy at a higher rate. A follow-up Phase III trial with a similar patient population compared zoledronic acid at 4 mg and 8 mg with pamidronate at 90 mg administered every 3 to 4 weeks for 12 months (Ref. Reference Rosen79). SREs were the primary endpoint over 13 months. As a result of a decline in renal function in patients randomised to 8 mg of zoledronic acid, this dose was reduced to 4 mg. The prevalence of SREs and time to first pathological fracture was similar in all three groups but zoledronic acid reduced the need for bone irradiation. The oral bisphosphonate clodronate may have benefit in preventing SREs (Ref. Reference Powles80). In a 5 year study of women with breast cancer without distant metastases, clodronate versus placebo significantly reduced bone metastases (9.6% vs 13.5%) in women receiving standard treatment (Ref. Reference Powles81). Clodronate has been approved for patient use in Europe but not in the USA.
Although prostate cancer bone metastases are typically osteoblastic, biochemical markers of resorption are increased and indicate enhanced osteoclast activity. In fact, the biochemical marker of bone resorption, N-telopeptide, is a strong predictor of death in patients with prostate cancer bone metastases (Refs Reference Coleman9, Reference Brown10). Either directly or indirectly, these data suggest that prostate cancers regulate factors within the bone microenvironment that can stimulate bone resorption in addition to bone formation. Reduced skeletal morbidity in prostate cancer patients with osteoblastic bone metastases treated with bisphosphonates indicates the importance of the osteoclast in osteoblastic bone metastases. Oral clodronate delayed symptomatic progression and death in men with hormone-responsive disease in a preliminary study (Ref. Reference Dearnaley82). In a larger study, 643 men with hormone-refractory metastatic prostate cancer were enrolled and assigned to receive zoledronic acid at 4 mg, zoledronic acid at 8 mg followed later with 4 mg, or placebo every 3 weeks for 18 months. Subjects who received zoledronic acid had less SREs and pain compared with the control group but there was no significant difference in disease progression or performance status (Ref. Reference Saad83). Androgen-deprivation therapy in prostate cancer can adversely affect bone mineral density and the indication for the use of bisphosphonates in this situation is clearer. The results of one study in men with early-stage hormone-responsive disease treated with androgen-ablation therapy showed that 4 mg of zoledronic acid administered every 3 months for 1 year increased lumbar spine bone mineral density (Ref. Reference Smith84).
Another study examined zoledronic acid in treating bone metastases from other solid tumours, including lung, kidney and colorectal. In a Phase III trial, 773 patients with metastatic bone disease were randomised to zoledronic acid at 4 mg or placebo. Infusions were administered every 3 weeks for 21 months. The treatment group had a statistically significant reduction in time to first SRE but without a change in mortality (Ref. Reference Rosen85).
Osteonecrosis of the jaw (ONJ) is associated with bisphosphonates. This side effect is characterised by exposed bone within the oral cavity often associated with pain, infection and soft-tissue ulceration. The risk of ONJ increases with bisphosphonate potency, dose and treatment duration. The risk of ONJ in cancer patients treated with high-dose bisphosphonates is 1–10% (Ref. Reference Khosla86). Because the combined dose of bisphosphonates is significantly higher during the treatment of bone metastasis than of osteoporosis, more than 95% of ONJ cases occur in patients with bone metastases (Ref. Reference Woo, Hellstein and Kalmar87). Conservative treatment for ONJ is recommended and consists of systemic antibiotics and mouth rinses. Debridement is generally not necessary and should only be performed by an experienced oral surgeon.
Novel therapies
Although current therapies available for bone metastases result in a significant reduction in morbidity, such therapies do not promote significant regression of established disease. Thus, bone-targeted therapies are under development. Novel therapies for osteolytic bone disease based on inhibition of the RANK–RANKL system have been proposed and several are in clinical trial. The humanised RANKL antibody denosumab, in Phase III clinical trial for the treatment of osteoporosis, is currently being studied in a Phase II trial in patients with bone metastasis from breast cancer and other solid tumours and multiple myeloma. Interim analysis demonstrated that denosumab reduced the bone resorption marker N-telopeptide (Ref. Reference Dansey, Lipton and Jun88), which suggests less cancer-cell-induced osteoclast activation.
Modulation of the endothelin axis has shown promise in treating prostate cancer bone metastasis. In a Phase II clinical trial, the ETAR antagonist atrasentan delayed progression and decreased PSA, compared with the control group of men with hormone-refractory disease (Ref. Reference Carducci89). Atrasentan also reduced markers of bone turnover in men with prostate cancer bone metastases (Ref. Reference Nelson90). In a large Phase III placebo-controlled trial in men with advanced prostate cancer, atrasentan did not reduce overall disease progression (Ref. Reference Carducci91). However, atrasentan did significantly reduce skeletal complications and bone metastasis progression in the majority of subjects who had bone metastasis (Ref. Reference Nelson92).
Research in progress and outstanding research questions
Osteoblasts, osteoclasts and haematopoietic cells in the bone microenvironment communicate during normal bone remodelling, responding to mechanical loading and hormonal changes that occur with age. Metastatic cancer cells with an affinity to bone flourish within this microenvironment. These cells have the ability not only to proliferate in bone but to coax osteoblasts and osteoclasts to produce factors within the bone microenvironment that further stimulate cancer cell growth. That PTHrP secreted by breast cancer cells stimulates osteoclastic bone resorption, resulting in the release of immobilised TGF-β from bone matrix, was an early discovery that led to the concept of the ‘vicious cycle’. Although traditionally used as a molecular model for osteolytic bone metastasis, a similar synergistic relationship between cancer cells and bone may in fact also occur during osteoblastic bone metastasis.
Conventional cancer therapies are aimed at systemic eradication of cancer cells but tailored therapies focused on modulating the response of host cells and tissues to metastatic cancer cells are the future of cancer therapy. Bisphosphonates reduce the osteoclastic response to bone metastasis, skeletal-related complications of malignancy, and tumour burden in animal models. Preliminary studies also suggest bisphosphonates confer a survival benefit in humans (Ref. Reference Powles81). Other promising agents that may lessen pathological bone resorption include denosumab and cathepsin K inhibitors (Ref. Reference Le Gall93). In some situations, bone metastases may further tip the balance towards osteolysis by suppressing osteoblastic new bone formation via suppression of WNT signalling. Therapies aimed at neutralising the actions of sclerostin and DKK1, inhibitors of WNT signalling, may prove effective in osteolytic bone metastasis. Targeting the osteoblastic response to prostate cancer is also expected to hold promise. Atrasentan, an ETAR antagonist, reduced the progression of prostate cancer bone metastasis, and preliminary results of another ETAR antagonist, ZD4054, indicate mortality benefit as well (Ref. Reference James94).
Clinicians initiate bone-targeted therapies such as bisphosphonates when bone metastases are clinically evident. However, starting therapy earlier when micrometastases develop would likely increase the time to progression and possibly survival. This hypothesis is supported by clinical evidence showing that the presence of breast cancer micrometastases translates to reduced overall survival (Ref. Reference Braun95). Therefore, developing advanced diagnostic tests to detect early bone metastasis would represent a significant advance. Strategies to detect dormant and disseminated malignant breast and prostate circulating tumour cells and to determine genetic characteristics that purport a poor prognosis are being developed (Refs Reference Janni96, Reference Pfitzenmaier97).
Preemptive bone-targeted therapies may prove effective in patients with early disease but at risk for bone metastases. Technologies that identify primary tumour chromosomal aberrations, gene mutations and gene expression profiles that increase potential bone affinity of cancer cells may have prognostic utility (Refs Reference Nakagawa98, Reference Chandran99). One study analysed 107 primary breast tumours from patients who had early disease but later developed metastasis. Using gene microarray analysis, 69 genes were identified that were differentially expressed in tumours that later metastasised to bone (Ref. Reference Smid100). Resembling genetic predisposition to heart disease and diabetes, individuals may also be genetically predisposed to bone metastasis. Genetic polymorphisms that alter the bone microenvironment and increase the hospitability to cancer cells have been suggested (Ref. Reference Tsuchiya101).
Recent discoveries in the pathogenesis and treatment of bone metastases have been possible because of a more complete understanding of the molecular interactions between cancer cells and bone. What is the future of bone-targeted therapies? Medications cytotoxic to tumour cells continue to be developed. Neutralising antibodies and small-molecule inhibitors that block the homing of cancer cells to bone and reduce the response of tumour in bone would reduce early micrometastases. Novel agents that alter the bone microenvironment making the host tissue inhospitable to cancer cells may also prove effective. We expect that no one treatment will abolish bone metastases but combination treatments that target individual pathways responsible for bone metastases will be the most effective.
Acknowledgements and funding
The authors are supported by grants from the NIH (CA118428, CA069158, DK065837 and DK067333), the Department of Defense, The Prostate Cancer Foundation, and The University of Virginia (Cancer Center, Mellon Institute, Gerald D. Aurbach Endowment). We also thank the reviewers for their insightful comments.
