Mechanisms of Bone Metastasis

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mechanisms of disease
Mechanisms of Bone Metastasis

G. David Roodman, M.D., Ph.D.
one metastases are a frequent complication of cancer, occurring in up to 70 percent of patients with advanced breast or prostate cancer1 and in approximately 15 to 30 percent of patients with carcinoma of the lung, colon, stomach, bladder, uterus, rectum, thyroid, or kidney. The exact incidence of bone metastasis is unknown, but it is estimated that 350,000 people die with bone metastases annually in the United States.2 Furthermore, once tumors metastasize to bone, they are usually incurable: only 20 percent of patients with breast cancer are still alive five years after the discovery of bone metastasis.3 The consequences of bone metastasis are often devastating. Osteolytic metastases can cause severe pain, pathologic fractures, lifethreatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. Patients with osteoblastic metastases have bone pain and pathologic fractures because of the poor quality of bone produced by the osteoblasts. For all these reasons, bone metastasis is a serious and costly complication of cancer.
From the Department of Medicine, Division of HematologyOncology, University of Pittsburgh, the University of Pittsburgh Cancer Institute, and the Department of Veterans Affairs Medical Center all in Pittsburgh. Address reprint requests to Dr. Roodman at the University of Pittsburgh, School of Medicine/Hematology, Kaufmann Medical Bldg., Suite 601, 3471 5th Ave., Pittsburgh, PA 15213, or at roodmangd@ msx.upmc. edu. N Engl J Med 2004;350:1655-64.
Copyright 2004 Massachusetts Medical Society.
types of bone metastasis

Metastases have been characterized as osteolytic or osteoblastic (Fig. 1). This classification actually represents two extremes of a continuum in which dysregulation of the normal bone remodeling process occurs (Fig. 2). Patients can have both osteolytic and osteoblastic metastasis or mixed lesions containing both elements. Most patients with breast cancer have predominantly osteolytic lesions, although at least 15 to 20 percent of them have predominantly osteoblastic lesions.4 In addition, secondary formation of bone occurs in response to bone destruction. This reactive process makes it possible to detect osteolytic lesions by means of bone scanning, which identifies sites of active bone formation. Only in multiple myeloma do purely lytic bone lesions develop. In contrast, the lesions in prostate cancer are predominantly osteoblastic.5 However, there is also increased bone resorption in the osteoblastic lesions of prostate cancer, and agents that block bone resorption can decrease bone pain and the risk of pathologic fractures.6
bone as a preferred site of metastasis

Several factors account for the frequency of bone metastasis. Blood flow is high in areas of red marrow,7 accounting for the predilection of metastases for those sites. Furthermore, tumor cells produce adhesive molecules that bind them to marrow stromal cells and bone matrix. These adhesive interactions cause the tumor cells to increase the production of angiogenic factors and bone-resorbing factors that further enhance tumor growth in bone.8 Bone is also a large repository for immobilized growth factors, including transforming growth factor b, insulin-like growth factors I and II, fibroblast growth factors, platelet-derived growth factors, bone morphogenetic proteins, and calcium.9 These growth factors, which are released and activated during bone resorption,10 pro-
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A
Osteoclast
vide fertile ground in which tumor cells can grow. This seed-and-soil hypothesis of the mechanism of bone metastasis was first advanced by Stephan Paget in 188911 and is supported by findings in animal models of bone metastasis.
control of normal bone remodeling

Osteoblasts
The adult skeleton continually turns over and remodels itself through the coordinated activity of osteoclasts and osteoblasts on trabecular surfaces and the haversian system. In normal bone, there is a balanced remodeling sequence: first, osteoclasts resorb bone, and then osteoblasts form bone at the same site.
osteoclasts
Figure 1. Osteoclasts and Osteoblasts in Normal Bone and Bone Metastasis. Panel A shows osteoclasts and osteoblasts in normal bone (toluidine blue, 100). The large osteoclast is actively resorbing bone. Osteoblasts are small, cuboid cells that actively lay down bone matrix. Panel B shows osteolytic bone metastasis (hematoxylin and eosin, 200). Renal carcinoma cells are invading the bone marrow, and osteoclasts (arrows) are actively resorbing bone adjacent to the tumor cells. Panel C shows osteoblastic metastasis (hematoxylin and eosin, 200). Thickened trabeculae and large numbers of osteoblasts are next to the bone surface, and there are tumor cells from adenocarcinoma of the lung between the two large trabeculae. Panel A was provided by Dr. Hua Zhang, Helen Hayes Hospital, New York, and Panels B and C were provided by Dr. Brendan Boyce, University of Rochester, Rochester, New York.
Osteoclasts arise from precursor cells in the monocytemacrophage lineage12 that differentiate into inactive osteoclasts. Activated osteoclasts resorb bone and eventually undergo apoptosis. As shown in Figure 2A, both locally produced cytokines and systemic hormones regulate the formation and activity of osteoclasts. The bone microenvironment plays a critical role in the formation of osteoclasts through the production of macrophage colonystimulating factor and receptor activator of nuclear factor-kB (RANK) ligand (RANKL)13,14 by stromal cells or osteoblasts. RANKL, a member of the family of tumor necrosis factors, is expressed on the surface of osteoblasts and stromal cells and is released by activated T cells.13 Most osteotropic factors, such as parathyroid hormone, 1,25-dihydroxyvitamin D3, and prostaglandins, induce the formation of osteoclasts by increasing the expression of RANKL on marrow stromal cells and osteoblasts rather than by acting directly on osteoclast precursors15,16 (Fig. 3). RANKL binds the RANK receptor on osteoclast precursors and induces the formation of osteoclasts by signaling through the nuclear factor-kB and Jun N-terminal kinase pathways. A soluble form of RANKL produced by activated T cells has been detected in the joint fluid of animals with adjuvant arthritis.17 The importance of RANKL in the formation of osteoclasts has been demonstrated clearly by the technique of homologous recombination in which the RANKL or RANK gene has been deleted in mice (knockout mice). These animals lack osteoclasts, and as a result, severe osteopetrosis develops.18,19
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Figure 2. Regulation of Bone Resorption (Panel A) and Bone Formation (Panel B). Both systemic factors and locally acting factors induce the formation and activity of osteoclasts (Panel A). Systemic hormones such as parathyroid hormone, 1,25-dihydroxyvitamin D3, and thyroxine (T4) stimulate the formation of osteoclasts by inducing the expression of receptor activator of nuclear factor-kB ligand (RANKL) on marrow stromal cells and osteoblasts. In addition, osteoblasts produce interleukin-6, interleukin-1, prostaglandins, and colony-stimulating factors (CSFs), which induce the formation of osteoclasts. Accessory cells such as T cells can produce cytokines that can inhibit the formation of osteoclasts, such as interleukin-4, interleukin18, and interferon-g. TGF-b denotes transforming growth factor b. Plus signs indicate stimulation, and minus signs inhibition. Both systemic factors and locally acting factors can enhance the proliferation and differentiation of osteoblasts (Panel B). These include parathyroid hormone, prostaglandins, and cytokines as well as growth factors such as platelet-derived growth factor (PDGF) produced by lymphocytes. In addition, bone matrix is a major source of growth factors, which can enhance the proliferation and differentiation of osteoblasts. These include the bone morphogenetic proteins (BMPs), TGF-b, insulin-like growth factors (IGFs), and fibroblast growth factors (FGFs). Corticosteroids can induce apoptosis of osteoblasts and block bone formation.
In addition, the development of B cells and T cells is defective in these animals. A decoy receptor for RANKL, osteoprotegerin, is normally present in the bone marrow.20 Osteoprotegerin, a member of the superfamily of tumor necrosis factor receptors, inhibits the differentiation and resorption of osteoclasts in vitro and in vivo. The ratio of RANKL to osteoprotegerin regulates the formation and activity of osteoclasts. Overproduction of osteoprotegerin in transgenic mice causes severe osteopetrosis, whereas the absence of osteoprotegerin results in marked osteopenia.21,22 The importance of RANKL in bone destruction has led to the development of recombinant osteoprotegerin and antibodies against RANKL as potential treatments for bone metastasis. Osteoclasts resorb bone by secreting proteases that dissolve the matrix and producing acid that releases bone mineral into the extracellular space under the ruffled border of the plasma membrane of osteoclasts, which faces bone and is the resorbing organelle of the cell.23 The adherence of osteoclasts to the bone surface is critical for the bone resorptive process, since agents that interfere with osteoclast attachment block bone resorption.24 Agents that af-
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blasts.30 As shown in Figure 2B, many factors can enhance the growth and differentiation of osteoblasts, including platelet-derived growth factor, fibroblast growth factor, and transforming growth factor b.31
osteolytic metastasis
In osteolytic metastases, the destruction of bone is mediated by osteoclasts rather than tumor cells.32,33 However, the factors responsible for the activation of osteoclasts vary depending on the tumor. In multiple myeloma, osteoclasts accumulate only at boneresorbing surfaces adjacent to myeloma cells; their levels are not increased in areas uninvolved with tumor.34 In addition to the increase in bone resorption, bone formation is suppressed so that bone lesions in patients with myeloma become purely lytic.35 Several osteoclastogenic factors have been implicated in the increased activity of osteoclasts in myeloma.36 The leading candidates are interleukin-1, interleukin-6, macrophage inflammatory protein 1a, and RANKL. Interleukin-1 is a potent stimulant of osteoclast formation,37 but levels of interleukin-1 produced by myeloma cells are extremely low.38 Sati et al.39 and Soutar et al.40 did not detect significantly increased levels of interleukin-1b in myeloma samples, suggesting that interleukin-1 may not be a major mediator of myeloma bone disease. Interleukin-6 is a growth factor or at least blocks apoptosis of myeloma cells.41 It is present in marrow plasma samples from patients with myeloma.42 Interleukin-6 is a potent stimulator of osteoclast formation43 and can enhance the effects of parathyroid hormonerelated peptide on the formation of osteoclasts in vivo.44 Interleukin-6 levels in the marrow have not consistently been correlated with the presence of bone lesions, however.45,46 When myeloma cells adhere to marrow stromal cells, the production of interleukin-6 by marrow stromal cells increases.47 Thus, interleukin-6 appears to have an important role in enhancing the growth or prolonging the survival of myeloma cells, but its role in myeloma bone disease remains to be determined. RANKL is a major mediator of myeloma bone disease. Several studies have suggested that myeloma cells produce RANKL,48,49 but it is unclear whether the amount of RANKL produced by myeloma cells is sufficient to induce the formation of osteoclasts. Instead, it may simply prevent apoptosis of osteoclasts. RANKL is produced by marrow
Figure 3. Receptor Activator of Nuclear Factor-kB Ligand (RANKL) and Osteoclast Formation. RANKL is a potent inducer of osteoclast formation. Osteotropic factors, 1,25dihydroxyvitamin D3, parathyroid hormone (PTH), prostaglandin E-2, and interleukin-1, induce the formation of osteoclasts by up-regulating the expression of RANKL on the surface of marrow stromal cells and immature osteoblasts. RANKL then binds its receptor, RANK, on the surface of osteoclast precursors and signals through the nuclear factor-kB (NF-kB)and Jun N-terminal kinase (JNK) pathways to induce the formation of osteoclasts and promote osteoclast survival. In addition to RANK, a decoy receptor, osteoprotegerin, inhibits RANKL binding to RANK. RANKL can also occur in a soluble form produced by T cells in inflammatory states. The ratio of RANKL to osteoprotegerin determines the level of osteoclastogenesis.
fect the adherence of osteoclasts to bone or inhibit proteases produced by osteoclasts, such as cathepsin K, are under development and may be useful for treating bone metastases.
osteoblasts
Osteoblasts are the bone-forming cells. They arise from mesenchymal stem cells, which form osteoblasts, adipocytes, and muscle cells.25 A transcription factor that is critical for the differentiation of osteoblasts is Runx-2, or core-binding factor a1 (CBFA1). CBFA1 drives the expression of most genes associated with osteoblast differentiation.26 Bone does not develop in mice that lack the CBFA1 gene.27,28 The differentiation of osteoblasts is less well understood than the differentiation of osteoclasts. It is clear that there is an early osteoblast precursor that produces alkaline phosphatase and a more differentiated precursor that produces increasing amounts of osteocalcin and calcified matrix.29 Osteoblasts eventually become osteocytes. Bone morphometric proteins are critical factors that stimulate the growth and differentiation of osteo-
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stromal cells in myeloma. In the microenvironment of bone in myeloma, RANKL production is increased and osteoprotegerin is markedly decreased.50 Blocking the binding of RANKL to the RANK receptor with a soluble form of the RANK receptor or osteoprotegerin inhibits bone destruction in a mouse model of myeloma.51,52 All these data suggest that RANKL is a major mediator of myeloma bone disease. Macrophage inflammatory protein 1a also appears to be a key regulator of bone destruction in myeloma.53,54 Macrophage inflammatory protein 1a is a potent inducer of osteoclast formation in vitro, independently of RANKL, and enhances both RANKL-stimulated and interleukin-6stimulated osteoclast formation.55 In approximately 70 percent of patients, myeloma cells produce macrophage inflammatory protein 1a, and the level of this protein is elevated in bone marrow plasma.53 Macrophage inflammatory protein 1a levels correlate strongly with the presence of osteolytic lesions; moreover, DNA microanalysis of myeloma cells has shown that the expression of the macrophage inflammatory protein 1a gene is markedly increased and correlates with bone disease.56 Furthermore, blocking expression of the gene for macrophage inflammatory protein 1a or the activity of macrophage inflammatory protein 1a in murine models of myeloma decreases both bone destruction and myeloma tumor burden.57,58 Macrophage inflammatory protein 1a also enhances adhesive interactions between myeloma cells and stromal cells by up-regulating the expression of b1 integrins on myeloma cells.57 Adhesive interactions between marrow stromal cells and myeloma cells increase the production of interleukin-6, RANKL, and macrophage inflammatory protein 1a, further increasing bone destruction.
cocultures of two interleukin-6dependent myeloma cell lines with osteoblast-like human osteosarcoma cells reduced the amounts of osteocalcin produced by the cells,61 the identity of the factor or factors responsible is unknown. Recently, Tian and coworkers,62 using genemicroarray analysis and immunohistochemical analysis, found that myeloma cells expressed dickkopf 1 (DKK1), a Wnt-signaling antagonist, and that the presence of high levels of DKK1 correlated with focal bone lesions in patients with myeloma. They further demonstrated that bone marrow serum from these patients that contained more than 12 ng of DKK1 per milliliter inhibited osteoblastic differentiation in a murine myoblast cell line. These data suggest that DKK1 may be involved in the inhibition of osteoblast differentiation in myeloma. It is likely that more than one factor is involved in the suppression of osteoblast activity in myeloma; this situation is analogous to the multiplicity of factors that increase osteoclast activity.
osteolytic metastasis from breast cancer the vicious circle

Tumor cells in breast cancer produce factors that directly or indirectly induce the formation of osteoclasts. In turn, bone resorption by osteoclasts releases growth factors from the bone matrix that stimulate tumor growth and bone destruction.63 This reciprocal interaction between breast-cancer cells and the bone microenvironment results in a vicious circle that increases both bone destruction and the tumor burden (Fig. 4). Bone is an abundant source of inactive growth factors, which are activated during the bone-resorptive process10 and which can then stimulate the growth of breast-cancer cells. Parathyroid hormonerelated peptide is probably the factor produced by breast-cancer cells and most solid tumors that stimulates the formation of osteoclasts.64,65 Both parathyroid hormonerelated peptide and parathyroid hormone bind the same receptor (PTHR1) and induce the expression of RANKL on marrow stromal cells. Parathyroid hormone is the main peptide regulator of calcium homeostasis, and parathyroid hormonerelated peptide has biologic effects on bone similar to those of parathyroid hormone.66 In the amino acid sequences of parathyroid hormone and parathyroid hormonerelated peptide, 8 of the first 13 amino acids are identical,
osteoblast dysfunction in myeloma

Bone lesions in myeloma are purely lytic there is no osteoblastic response. This phenomenon explains the clinical observation that in about half the cases of myeloma, bone scans are normal in the presence of severe osteolytic bone destruction.59 The basis of the decreased osteoblastic response in myeloma is unknown. Myeloma cells can produce tumor necrosis factor a, which inhibits osteoblastic growth and differentiation.60 However, tumor necrosis factor a has not been implicated in the suppression of bone formation in myeloma. Although
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Figure 4. The Vicious Circle of Osteolytic Metastasis. Tumor cells, in particular breast-cancer cells, secrete parathyroid hormonerelated peptide as the primary stimulator of osteoclastogenesis. In addition, tumor cells produce other factors that increase the formation of osteoclasts, including interleukin-6, prostaglandin E2 (PGE2), tumor necrosis factor, and macrophage colonystimulating factor (M-CSF). These factors increase the expression of receptor activator of nuclear factor-kB ligand (RANKL), which directly acts on osteoclast precursors to induce the formation of osteoclasts and bone resorption. The process of bone resorption releases factors such as transforming growth factor b (TGF-b), insulin-like growth factors (IGFs), fibroblast growth factors (FGFs), platelet-derived growth factor (PDGF), and bone morphogenetic proteins (BMPs), which increase the production of parathyroid hormonerelated peptide by tumor cells as well as growth factors that increase tumor growth. This symbiotic relationship between bone destruction and tumor growth further increases bone destruction and tumor growth.
of parathyroid hormonerelated peptide.64 The peptide induces the formation of osteoclasts and bone resorption, which releases transforming growth factor b. Transforming growth factor b, in turn, further increases production of the peptide by the breast-cancer cells.68 An antibody against parathyroid hormonerelated peptide is being evaluated in patients with bone metastases from breast cancer. In the vicious circle of breast-cancer metastases (Fig. 4), bone destruction increases local calcium levels, which promotes tumor growth and the production of parathyroid hormonerelated peptide.69 Breast-cancer cells also produce, or induce, interleukin-6, prostaglandin E2, macrophage colony-stimulating factor, interleukin-1, and tumor necrosis factor a,70,71 which may also play an important role in the induction of osteoclast formation by breastcancer metastases. Prostaglandin E2 can increase the expression of RANKL and directly enhance the effects of RANKL on the formation of osteoclasts.71 Together, these data suggest that parathyroid hormonerelated peptide is a major mediator of osteolytic bone destruction by breast cancer and other solid tumors.
therapeutic implications of resorption and tumor growth

There is a close relationship between bone destruction and tumor growth. For example, treating myeloma in mice with agents that block bone resorption but have no direct effect on tumor growth not only inhibits the formation of osteoclasts but also decreases the tumor burden.51,52 However, definitive evidence that decreasing bone destruction decreases the tumor burden in patients with bone metastasis is lacking. Gordon and coworkers72 reported that a single infusion of a potent bisphosphonate that blocks bone resorption markedly increased apoptosis of myeloma cells in vivo in 10 of 16 patients with newly diagnosed myeloma. In a large, randomized, double-blind, placebo-controlled study73 of the bisphosphonate clodronate, Powles et al. found that administration of the drug was associated with a decrease in both the incidence of bone metastasis and the death rate in patients with breast cancer who were at high risk for bone metastasis. However, blocking bone destruction does not appear to affect the growth of tumors in soft tissues,73 indicating the unique characteristics of tumor growth in bone.
and both peptides have similar three-dimensional structures.66 The production of parathyroid hormonerelated peptide is increased in metastases of breast cancer to bone. Only 50 percent of primary breast cancers express parathyroid hormonerelated peptide, whereas 92 percent of metastases of breast cancer to bone produce the peptide.67 However, it is unclear whether this difference results from induction of the peptide in the bone microenvironment or whether tumors that produce the peptide are more likely to metastasize to bone. When breast-cancer cells from patients are injected into nude mice and metastasize to bone, they increase the production
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osteoblastic metastasis another vicious circle?

The mechanisms of osteoblastic metastasis and the factors involved are unknown. Endothelin-1 has been implicated in osteoblastic metastasis from breast cancer.74 It stimulates the formation of bone and the proliferation of osteoblasts in bone organ cultures,75 and serum endothelin-1 levels are increased in patients with osteoblastic metastasis from prostate cancer.76 Furthermore, in an animal model of osteoblastic metastasis, treatment with a selective endothelin-1Areceptor antagonist decreased both osteoblastic metastasis and the tumor burden.74 The antagonist had no effect on the growth of the tumor at orthotopic sites. These results suggest that blocking osteoblast-inducing activity by tumors may decrease tumor growth and osteoblast activity and suggest that a vicious circle may also be involved in osteoblastic metastasis in which tumors induce osteoblast activity and thus the subsequent release from the osteoblasts of growth factors that increase tumor growth. In addition to endothelin-1, platelet-derived growth factor,77 a polypeptide produced by osteoblasts in the bone microenvironment, urokinase,78,79 and prostate-specific antigen (PSA)80 may also be involved.
prostate cancer, although there is usually no histologic evidence of increased numbers of osteoclasts. In prostate cancer, levels of bone-resorption markers are higher in patients with bone metastasis than in patients without bone metastasis and reflect the extent of bone metastasis more accurately than does the PSA level.82 Recent clinical trials have suggested that blocking osteoclastic bone resorption decreases related skeletal events in patients with prostate cancer.6 However, in a murine model of prostate cancer, the inhibition of osteoclast activity did not inhibit the development of osteoblastic metastasis.83 Thus, it is unclear whether bone destruction precedes the development of osteoblastic metastasis or is a consequence of the increased bone formation. Yi et al. have shown in an animal model of osteoblastic metastasis that an initial phase of bone destruction is followed by extensive formation of bone.77 Their data suggest that bone resorption precedes bone formation in the development of osteoblastic metastases and that osteoclast activation plays an important role in the development of osteoblastic metastases.
biochemical markers of bone turnover for the detection of bone metastasis

The value of biochemical markers of bone turnover as a means of monitoring patients with bone metastases is still under investigation. Levels of bone-specific alkaline phosphatase, osteocalcin, and type I procollagen C-propeptide in serum are indicators of osteoblast activity, whereas serum levels of C-terminal telopeptide of type I collagen and tartrate-resistant acid phosphatase and urinary levels of type I collagen cross-linked N-telopeptides are markers of osteoclast activity. All these markers have been used to assess the response to therapy or for the detection of bone metastases,84-86 but results have been variable. Urinary type I collagen cross-linked N-telopeptides and C-terminal telopeptide of type I collagen appear to be the most useful.84 In summary, bone metastases are among the most debilitating problems in patients with cancer. The molecular mechanisms responsible for both osteolytic and osteoblastic metastases are just being identified. The use of gene arrays and proteomics and the availability of appropriate animal models of bone metastasis have permitted the identification
osteoblastic metastasis in prostate cancer

Overproduction of urokinase-type plasminogen activator (u-PA) by prostate-cancer cells increases bone metastasis,78 and cells transfected with an anti-sense DNA to u-PA had one third as many metastases as did cells transfected with an empty vector. Human PC3 prostate-cancer cells produce a factor that is homologous to u-PA.79 Prostate-cancer cells also release PSA, a kallikrein serine protease. PSA can cleave parathyroid hormonerelated peptide at the N-terminal, which could block tumorinduced bone resorption. It may also activate osteoblastic growth factors released in the bone microenvironment during the development of bone metastases, such as insulin-like growth factors I and II or transforming growth factor b.80 These data suggest that a vicious circle may also be responsible for osteoblastic metastasis. Bone metastases in prostate cancer are predominantly osteoblastic, with increased numbers of irregular bone trabeculae.81 However, markers of bone resorption are also increased in metastatic
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of factors produced by the tumor cells themselves or by the microenvironment in response to the tumor that mediate the process of bone destruction. These types of studies should result in the development of therapeutic agents to treat and possibly prevent this devastating complication of cancer.
references
1. Coleman RE, Rubens RD. The clinical
Supported by research funds from the Multiple Myeloma Research Foundation; a Department of Veterans Affairs Merit Review Award; and grants (AR41336 and AG13625) from the National Institutes of Health. I am indebted to members of the General Clinical Research Center, University of Pittsburgh Medical Center, for their assistance in the care of my patients.
course of bone metastases from breast cancer. Br J Cancer 1987;55:61-6. 2. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584-93. 3. Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001;27: 165-76. 4. Coleman RE, Seaman JJ. The role of zoledronic acid in cancer: clinical studies in the treatment and prevention of bone metastases. Semin Oncol 2001;28:Suppl 6: 11-6. 5. Charhon SA, Chapuy MC, Delvin EE, Valentin-Opran A, Edouard CM, Meunier PJ. Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma special reference to osteomalacia. Cancer 1983;51:918-24. 6. Oades GM, Coxon J, Colston KW. The potential role of bisphosphonates in prostate cancer. Prostate Cancer Prostatic Dis 2002;5:264-72. 7. Kahn D, Weiner GJ, Ben-Haim S, et al. Positron emission tomographic measurement of bone marrow blood flow to the pelvis and lumbar vertebrae in young normal adults. Blood 1994;83:958-63. [Erratum, Blood 1994;84:3602.] 8. van der Pluijm G, Sijmons B, Vloedgraven H, Deckers M, Papapoulos S, Lowik C. Monitoring metastatic behavior of human tumor cells in mice with speciesspecific polymerase chain reaction: elevated expression of angiogenesis and bone resorption stimulators by breast cancer in bone metastases. J Bone Miner Res 2001;16:107791. 9. Hauschka PV, Mavrakos AE, Iafrati MD, Doleman SE, Klagsbrun M. Growth factors in bone matrix: isolation of multiple types by affinity chromatography on heparinSepharose. J Biol Chem 1986;261:1266574. 10. Pfeilschifter J, Mundy GR. Modulation of type b transforming growth factor activity in bone cultures by osteotropic hormones. Proc Natl Acad Sci U S A 1987;84:2024-8. 11. Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889;1:571-3. 12. Roodman GD. Cell biology of the osteoclast. Exp Hematol 1999;27:1229-41. 13. Kodama H, Nose M, Niida S, Yamasaki A. Essential role of macrophage colonystimulating factor in the osteoclast differen-
tiation supported by stromal cells. J Exp Med 1991;173:1291-4. 14. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165-76. 15. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 1998;95:3597-602. 16. Hofbauer LC, Heufelder AE. Osteoprotegerin and its cognate ligand: a new paradigm of osteoclastogenesis. Eur J Endocrinol 1998;139:152-4. 17. Kong YY, Feige U, Sarosi I, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999;402: 304-9. 18. Tsukii K, Shima N, Mochizuki S, et al. Osteoclast differentiation factor mediates an essential signal for bone resorption induced by 1 alpha,25-dihydroxyvitamin D3, prostaglandin E2, or parathyroid hormone in the microenvironment of bone. Biochem Biophys Res Commun 1998;246:337-41. 19. Dougall WC, Glaccum M, Charrier K, et al. RANK is essential for osteoclast and lymph node development. Genes Dev 1999; 13:2412-24. 20. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309-19. 21. Min H, Morony S, Sarosi I, et al. Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med 2000;192:463-74. 22. Mizuno A, Amizuka N, Irie K, et al. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 1998;247:610-5. 23. Blair HC, Teitelbaum SL, Ghiselli R, Gluck S. Osteoclastic bone resorption by a polarized vacuolar proton pump. Science 1989;245:855-7. 24. Horton MA, Dorey EL, Nesbitt SA, et al. Modulation of vitronectin receptor-mediated osteoclast adhesion by Arg-Gly-Asp peptide analogs: a structure-function analysis. J Bone Miner Res 1993;8:239-47. 25. Aubin JE. Bone stem cells. J Cell Biochem Suppl 1998;30-31:73-82.
26. Yang X, Karsenty G. Transcription fac-
tors in bone: developmental and pathological aspects. Trends Mol Med 2002;8:340-5. 27. Otto F, Thornell AP, Crompton T, et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 1997;89:765-71. 28. Komori T, Yagi H, Nomura S, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997;89: 755-64. 29. Stein GS, Lian JB. Molecular mechanisms mediating proliferation/differentiation interrelationships during progressive development of the osteoblast phenotype. Endocr Rev 1993;14:424-42. 30. Wozney JM. Overview of bone morphogenetic proteins. Spine 2002;27:Suppl 1:S2S8. 31. Mundy GR, Chen D, Zhao M, Dallas S, Xu C, Harris S. Growth regulatory factors and bone. Rev Endocr Metab Disord 2001;2: 105-15. 32. Taube T, Elomaa I, Blomqvist C, Beneton MNC, Kanis JA. Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer. Bone 1994; 15:161-66. 33. Boyde A, Maconnachie E, Reid SA, Delling G, Mundy GR. Scanning electron microscopy in bone pathology: review of methods, potential and applications. Scan Electron Microsc 1986;4:1537-54. 34. Bataille R, Chappard D, Basle M. Excessive bone resorption in human plasmacytomas: direct induction by tumour cells in vivo. Br J Haematol 1995;90:721-4. 35. Taube T, Beneton MN, McCloskey EV, Rogers S, Greaves M, Kanis JA. Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption. Eur J Haematol 1992;49: 192-8. 36. Roodman GD. Biology of osteoclast activation in cancer. J Clin Oncol 2001;19: 3562-71. 37. Pfeilschifter J, Chenu C, Bird A, Mundy GR, Roodman GD. Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclastlike cells in vitro. J Bone Miner Res 1989;4:113-8. 38. Lust JA, Donovan KA. The role of interleukin-1 beta in the pathogenesis of multiple myeloma. Hematol Oncol Clin North Am 1999;13:1117-25. 39. Sati HI, Greaves M, Apperley JF, Russell
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RG, Croucher PI. Expression of interleukin1beta and tumour necrosis factor-alpha in plasma cells from patients with multiple myeloma. Br J Haematol 1999;104:350-7. 40. Soutar RL, Dillon JM, Brown D, Ralston SH. Cytokine expression in multiple myeloma and monoclonal gammopathy: analysis by reverse transcription/polymerase chain reaction and quantitative PCR. Leuk Lymphoma 1996;24:111-20. 41. Cheung WC, Van Ness B. Distinct IL-6 signal transduction leads to growth arrest and death in B cells or growth promotion and cell survival in myeloma cells. Leukemia 2002;16:1182-8. 42. Bataille R, Chappard D, Klein B. Mechanisms of bone lesions in multiple myeloma. Hematol Oncol Clin North Am 1992;6:28595. 43. Kurihara N, Bertolini D, Suda T, Akiyama Y, Roodman GD. IL-6 stimulates osteoclast-like multinucleated cell formation in long term human marrow cultures by inducing IL-1 release. J Immunol 1990;144: 4226-30. 44. de la Mata J, Uy HL, Guise TA, et al. Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo. J Clin Invest 1995;95:2846-52. 45. Iwasaki T, Hamano T, Ogata A, Kakishita E. Clinical significance of interleukin-6 gene expression in the bone marrow of patients with multiple myeloma. Int J Hematol 1999; 70:163-8. 46. Ballester OF, Moscinski LC, Lyman GH, et al. High levels of interleukin-6 are associated with low tumor burden and low growth fraction in multiple myeloma. Blood 1994; 83:1903-8. 47. Teoh G, Anderson KC. Interaction of tumor and host cells with adhesion and extracellular matrix molecules in the development of multiple myeloma. Hematol Oncol Clin North Am 1997;11:27-42. 48. Sezer O, Heider U, Jakob C, Eucker J, Possinger K. Human bone marrow myeloma cells express RANKL. J Clin Oncol 2002;20: 353-4. 49. Sezer O, Heider U, Jakob C, et al. Immunocytochemistry reveals RANKL expression of myeloma cells. Blood 2002;99:4646-7. 50. Pearse RN, Sordillo EM, Yaccoby S, et al. Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to stimulate bone destruction and promote tumor progression. Proc Natl Acad Sci U S A 2001;98: 11581-6. 51. Oyajobi BO, Mundy GR. Receptor activator of NF-kappaB ligand, macrophage inflammatory protein-1alpha, and the proteasome: novel therapeutic targets in myeloma. Cancer 2003;97:Suppl:813-7. 52. Croucher PI, Shipman CM, Lippitt J, et al. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood 2001;98:3534-40. 53. Choi SJ, Cruz JC, Craig F, et al. Macro-
phage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood 2000;96:671-5. 54. Uneda S, Hata H, Matsuno F, et al. Macrophage inflammatory protein-1 alpha is produced by human multiple myeloma (MM) cells and its expression correlates with bone lesions in patients with MM. Br J Haematol 2003;120:53-5. 55. Han JH, Choi SJ, Kurihara N, Koide M, Oba Y, Roodman GD. Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Blood 2001;97:3349-53. 56. Magrangeas F, Nasser V, Avet-Loiseau H, et al. Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease. Blood 2003;101:4998-5006. 57. Choi SJ, Oba Y, Gazitt Y, et al. Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease. J Clin Invest 2001;108:1833-41. 58. Oyajobi BO, Franchin G, Williams PJ, et al. Dual effects of macrophage inflammatory protein-1alpha on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease. Blood 2003;102: 311-9. 59. Leonard RC, Owen JP, Proctor SJ, Hamilton PJ. Multiple myeloma: radiology or bone scanning? Clin Radiol 1981;32:2915. 60. Pavalko FM, Gerard RL, Ponik SM, Gallagher PJ, Jin Y, Norvell SM. Fluid shear stress inhibits TNF-alpha-induced apoptosis in osteoblasts: a role for fluid shear stress-induced activation of PI3-kinase and inhibition of caspase-3. J Cell Physiol 2003; 194:194-205. 61. Barille S, Collette M, Bataille R, Amiot M. Myeloma cells upregulate interleukin-6 secretion in osteoblastic cells through cellto-cell contact but downregulate osteocalcin. Blood 1995;86:3151-9. 62. Tian E, Zhan F, Walker R, et al. The role of the Wnt/b-catenin signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003;349:2483-94. 63. Chirgwin JM, Guise TA. Molecular mechanisms of tumor-bone interactions in osteolytic metastases. Crit Rev Eukaryot Gene Expr 2000;10:159-78. 64. Guise TA, Yin JJ, Taylor SD, et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest 1996;98:1544-9. 65. Shen X, Falzon M. PTH-related protein modulates PC-3 prostate cancer cell adhesion and integrin subunit profile. Mol Cell Endocrinol 2003;199:165-77. 66. Karaplis AC, Goltzman D. PTH and PTHrP effects on the skeleton. Rev Endocr Metab Disord 2000;1:331-41.
67. Powell GJ, Southby J, Danks JA, et al. Localization of parathyroid hormonerelated protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res 1991;51:3059-61. 68. Yin JJ, Selander K, Chirgwin JM, et al. TGF-b signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 1999; 103:197-206. 69. Buchs N, Manen D, Bonjour JP, Rizzoli R. Calcium stimulates parathyroid hormone-related protein production in Leydig tumor cells through a putative cation-sensing mechanism. Eur J Endocrinol 2000;142: 500-5. 70. Grano M, Mori G, Minielli V, Cantatore FP, Colucci S, Zallone AZ. Breast cancer cell line MDA-231 stimulates osteoclastogenesis and bone resorption in human osteoclasts. Biochem Biophys Res Commun 2000;270:1097-100. 71. Wani MR, Fuller K, Kim NS, Choi Y, Chambers T. Prostaglandin E2 cooperates with TRANCE in osteoclast induction from hemopoietic precursors: synergistic activation of differentiation, cell spreading, and fusion. Endocrinology 1999;140:1927-35. 72. Gordon S, Helfrich MH, Sati HI, et al. Pamidronate causes apoptosis of plasma cells in vivo in patients with multiple myeloma. Br J Haematol 2002;119:475-83. 73. Powles T, Paterson S, Kanis JA, et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 2002;20: 3219-24. 74. Guise TA, Yin JJ, Mohammad KS. Role of endothelin-1 in osteoblastic bone metastases. Cancer 2003;97:Suppl:779-84. 75. Kasperk CH, Borcsok I, Schairer HU, et al. Endothelin-1 is a potent regulator of human bone cell metabolism in vitro. Calcif Tissue Int 1997;60:368-74. 76. Nelson JB, Hedican SP, George DJ, et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med 1995;1:944-9. 77. Yi B, Williams PJ, Niewolna M, Wang Y, Yoneda T. Tumor-derived platelet-derived growth factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer. Cancer Res 2002;62:917-23. 78. Achbarou A, Kaiser S, Tremblay G, et al. Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res 1994;54: 2372-7. 79. Rabbani SA, Desjardins J, Bell AW, et al. An amino-terminal fragment of urokinase isolated from a prostate cancer cell line (PC-3) is mitogenic for osteoclast-like cells. Biochem Biophys Res Commun 1990;173: 1058-64. 80. Cramer SD, Chen Z, Peehl DM. Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like
n engl j med 350;16
www.nejm.org
april 15, 2004
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domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts. J Urol 1996;156:526-31. 81. Roudier MP, Vesselle H, True LD, et al. Bone histology at autopsy and matched bone scintigraphy findings in patients with hormone refractory prostate cancer: the effect of bisphosphonate therapy on bone scintigraphy results. Clin Exp Metastasis 2003;20:171-80. 82. Maeda H, Koizumi M, Yoshimura K, Yamauchi T, Kawai T, Ogata E. Correlation between bone metabolic markers and bone
scan in prostatic cancer. J Urol 1997;157: 539-43. 83. Lee YP, Schwarz EM, Davies M, et al. Use of zoledronate to treat osteoblastic versus osteolytic lesions in a severe-combinedimmunodeficient mouse model. Cancer Res 2002;62:5564-70. 84. Costa L, Demers LM, Gouveia-Oliveira A, et al. Prospective evaluation of the peptide-bound collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status. J Clin Oncol 2002;20:850-6.
85. Wada N, Fujisaki M, Ishii S, Ikeda T,
Kitajima M. Evaluation of bone metabolic markers in breast cancer with bone metastasis. Breast Cancer 2001;8:131-7. 86. Tamada T, Sone T, Tomomitsu T, Jo Y, Tanaka H, Fukunaga M. Biochemical markers for the detection of bone metastasis in patients with prostate cancer: diagnostic efficacy and the effect of hormonal therapy. J Bone Miner Metab 2001;19:45-51.
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