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The new england journal of medicine

review article

mechanisms of disease

Mechanisms of Bone Metastasis

G. David Roodman, M.D., Ph.D.

b one metastases are a frequent complication of cancer, occur-

ring 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
From the Department of Medicine, Divi-
sion 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,
annually in the United States.2 Furthermore, once tumors metastasize to bone, they are School of Medicine/Hematology, Kaufmann
usually incurable: only 20 percent of patients with breast cancer are still alive five years Medical Bldg., Suite 601, 3471 5th Ave.,
after the discovery of bone metastasis.3 The consequences of bone metastasis are often Pittsburgh, PA 15213, or at roodmangd@
msx.upmc. edu.
devastating. Osteolytic metastases can cause severe pain, pathologic fractures, life-
threatening hypercalcemia, spinal cord compression, and other nerve-compression syn- N Engl J Med 2004;350:1655-64.
Copyright 2004 Massachusetts Medical Society.
dromes. 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.

types of bone metastasis

Metastases have been characterized as osteolytic or osteoblastic (Fig. 1). This classifi-
cation 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 con-
trast, 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. Further-
more, 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 pro-
duction 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, includ-
ing 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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vide fertile ground in which tumor cells can grow.

A This seed-and-soil hypothesis of the mechanism
of bone metastasis was first advanced by Stephan
Osteoclast Paget in 188911 and is supported by findings in ani-
mal models of bone metastasis.

control of normal
bone remodeling
The adult skeleton continually turns over and re-
models itself through the coordinated activity of os-
teoclasts and osteoblasts on trabecular surfaces and
the haversian system. In normal bone, there is a bal-
anced remodeling sequence: first, osteoclasts re-
sorb bone, and then osteoblasts form bone at the
same site.

Osteoclasts arise from precursor cells in the mono-
cytemacrophage 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 ac-
C tivity of osteoclasts. The bone microenvironment
plays a critical role in the formation of osteoclasts
through the production of macrophage colony-
stimulating 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 necro-
sis factors, is expressed on the surface of osteo-
blasts and stromal cells and is released by activated
T cells.13 Most osteotropic factors, such as parathy-
roid hormone, 1,25-dihydroxyvitamin D3, and pros-
taglandins, induce the formation of osteoclasts by
increasing the expression of RANKL on marrow
Figure 1. Osteoclasts and Osteoblasts in Normal Bone
and Bone Metastasis. stromal cells and osteoblasts rather than by act-
Panel A shows osteoclasts and osteoblasts in normal ing directly on osteoclast precursors15,16 (Fig. 3).
bone (toluidine blue, 100). The large osteoclast is ac- RANKL binds the RANK receptor on osteoclast pre-
tively resorbing bone. Osteoblasts are small, cuboid cells cursors and induces the formation of osteoclasts by
that actively lay down bone matrix. Panel B shows osteo- signaling through the nuclear factor-kB and Jun
lytic bone metastasis (hematoxylin and eosin, 200). Re-
N-terminal kinase pathways. A soluble form of
nal carcinoma cells are invading the bone marrow, and
osteoclasts (arrows) are actively resorbing bone adjacent RANKL produced by activated T cells has been de-
to the tumor cells. Panel C shows osteoblastic metastasis tected in the joint fluid of animals with adjuvant ar-
(hematoxylin and eosin, 200). Thickened trabeculae and thritis.17
large numbers of osteoblasts are next to the bone sur- The importance of RANKL in the formation of
face, and there are tumor cells from adenocarcinoma of
osteoclasts has been demonstrated clearly by the
the lung between the two large trabeculae. Panel A was
provided by Dr. Hua Zhang, Helen Hayes Hospital, New technique of homologous recombination in which
York, and Panels B and C were provided by Dr. Brendan the RANKL or RANK gene has been deleted in mice
Boyce, University of Rochester, Rochester, New York. (knockout mice). These animals lack osteoclasts,
and as a result, severe osteopetrosis develops.18,19

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mechanisms of disease

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, prosta-
glandins, and colony-stimulating factors (CSFs), which
induce the formation of osteoclasts. Accessory cells such
as T cells can produce cytokines that can inhibit the for-
mation of osteoclasts, such as interleukin-4, interleukin-
18, 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 en-
hance the proliferation and differentiation of osteoblasts
(Panel B). These include parathyroid hormone, prosta-
glandins, and cytokines as well as growth factors such as
platelet-derived growth factor (PDGF) produced by lym-
phocytes. 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 osteo-
blasts 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, in-
hibits the differentiation and resorption of osteo-
clasts in vitro and in vivo.
The ratio of RANKL to osteoprotegerin regulates
the formation and activity of osteoclasts. Overpro-
duction of osteoprotegerin in transgenic mice caus-
es severe osteopetrosis, whereas the absence of os-
teoprotegerin results in marked osteopenia.21,22
The importance of RANKL in bone destruction has
led to the development of recombinant osteopro-
tegerin and antibodies against RANKL as potential
treatments for bone metastasis.
Osteoclasts resorb bone by secreting proteases
that dissolve the matrix and producing acid that re-
leases bone mineral into the extracellular space un-
der 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 osteo-
blasts, including platelet-derived growth factor, fi-
broblast 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 mul-
tiple myeloma, osteoclasts accumulate only at bone-
resorbing surfaces adjacent to myeloma cells; their
levels are not increased in areas uninvolved with tu-
Figure 3. Receptor Activator of Nuclear Factor-kB Ligand (RANKL)
and Osteoclast Formation.
mor.34 In addition to the increase in bone resorp-
RANKL is a potent inducer of osteoclast formation. Osteotropic factors, 1,25-
tion, bone formation is suppressed so that bone
dihydroxyvitamin D3, parathyroid hormone (PTH), prostaglandin E-2, and inter- lesions in patients with myeloma become purely
leukin-1, induce the formation of osteoclasts by up-regulating the expression lytic.35
of RANKL on the surface of marrow stromal cells and immature osteoblasts. Several osteoclastogenic factors have been impli-
RANKL then binds its receptor, RANK, on the surface of osteoclast precursors cated in the increased activity of osteoclasts in my-
and signals through the nuclear factor-kB (NF-kB)and Jun N-terminal kinase eloma.36 The leading candidates are interleukin-1,
(JNK) pathways to induce the formation of osteoclasts and promote osteo- interleukin-6, macrophage inflammatory protein
clast survival. In addition to RANK, a decoy receptor, osteoprotegerin, inhibits
1a, and RANKL. Interleukin-1 is a potent stimulant
RANKL binding to RANK. RANKL can also occur in a soluble form produced
of osteoclast formation,37 but levels of interleukin-1
by T cells in inflammatory states. The ratio of RANKL to osteoprotegerin de-
termines the level of osteoclastogenesis. produced by myeloma cells are extremely low.38 Sati
et al.39 and Soutar et al.40 did not detect signifi-
cantly increased levels of interleukin-1b in myelo-
ma samples, suggesting that interleukin-1 may not
fect the adherence of osteoclasts to bone or inhibit be a major mediator of myeloma bone disease.
proteases produced by osteoclasts, such as cathep- Interleukin-6 is a growth factor or at least blocks
sin K, are under development and may be useful for apoptosis of myeloma cells.41 It is present in mar-
treating bone metastases. row plasma samples from patients with myeloma.42
Interleukin-6 is a potent stimulator of osteoclast
osteoblasts formation43 and can enhance the effects of para-
Osteoblasts are the bone-forming cells. They arise thyroid hormonerelated peptide on the formation
from mesenchymal stem cells, which form osteo- of osteoclasts in vivo.44 Interleukin-6 levels in the
blasts, adipocytes, and muscle cells.25 A transcrip- marrow have not consistently been correlated with
tion factor that is critical for the differentiation of the presence of bone lesions, however.45,46 When
osteoblasts is Runx-2, or core-binding factor a1 myeloma cells adhere to marrow stromal cells, the
(CBFA1). CBFA1 drives the expression of most production of interleukin-6 by marrow stromal cells
genes associated with osteoblast differentiation.26 increases.47 Thus, interleukin-6 appears to have an
Bone does not develop in mice that lack the CBFA1 important role in enhancing the growth or prolong-
gene.27,28 The differentiation of osteoblasts is less ing the survival of myeloma cells, but its role in my-
well understood than the differentiation of osteo- eloma bone disease remains to be determined.
clasts. It is clear that there is an early osteoblast RANKL is a major mediator of myeloma bone
precursor that produces alkaline phosphatase and disease. Several studies have suggested that myelo-
a more differentiated precursor that produces in- ma cells produce RANKL,48,49 but it is unclear
creasing amounts of osteocalcin and calcified ma- whether the amount of RANKL produced by my-
trix.29 Osteoblasts eventually become osteocytes. eloma cells is sufficient to induce the formation of
Bone morphometric proteins are critical factors that osteoclasts. Instead, it may simply prevent apopto-
stimulate the growth and differentiation of osteo- sis of osteoclasts. RANKL is produced by marrow

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mechanisms of disease

stromal cells in myeloma. In the microenviron- cocultures of two interleukin-6dependent myelo-

ment of bone in myeloma, RANKL production is ma cell lines with osteoblast-like human osteosar-
increased and osteoprotegerin is markedly de- coma cells reduced the amounts of osteocalcin pro-
creased.50 Blocking the binding of RANKL to the duced by the cells,61 the identity of the factor or
RANK receptor with a soluble form of the RANK factors responsible is unknown.
receptor or osteoprotegerin inhibits bone destruc- Recently, Tian and coworkers,62 using gene-
tion in a mouse model of myeloma.51,52 All these microarray analysis and immunohistochemical
data suggest that RANKL is a major mediator of analysis, found that myeloma cells expressed dick-
myeloma bone disease. kopf 1 (DKK1), a Wnt-signaling antagonist, and
Macrophage inflammatory protein 1a also ap- that the presence of high levels of DKK1 correlated
pears to be a key regulator of bone destruction in with focal bone lesions in patients with myeloma.
myeloma.53,54 Macrophage inflammatory protein They further demonstrated that bone marrow serum
1a is a potent inducer of osteoclast formation in vi- from these patients that contained more than 12 ng
tro, independently of RANKL, and enhances both of DKK1 per milliliter inhibited osteoblastic differ-
RANKL-stimulated and interleukin-6stimulated entiation in a murine myoblast cell line. These data
osteoclast formation.55 In approximately 70 percent suggest that DKK1 may be involved in the inhibition
of patients, myeloma cells produce macrophage in- of osteoblast differentiation in myeloma. It is likely
flammatory protein 1a, and the level of this protein that more than one factor is involved in the sup-
is elevated in bone marrow plasma.53 Macrophage pression of osteoblast activity in myeloma; this sit-
inflammatory protein 1a levels correlate strongly uation is analogous to the multiplicity of factors that
with the presence of osteolytic lesions; moreover, increase osteoclast activity.
DNA microanalysis of myeloma cells has shown
that the expression of the macrophage inflamma-
tory protein 1a gene is markedly increased and cor- osteolytic metastasis
from breast cancer
relates with bone disease.56 Furthermore, blocking the vicious circle
expression of the gene for macrophage inflamma-
tory protein 1a or the activity of macrophage in- Tumor cells in breast cancer produce factors that
flammatory protein 1a in murine models of myelo- directly or indirectly induce the formation of osteo-
ma decreases both bone destruction and myeloma clasts. In turn, bone resorption by osteoclasts releas-
tumor burden.57,58 Macrophage inflammatory pro- es growth factors from the bone matrix that stim-
tein 1a also enhances adhesive interactions between ulate tumor growth and bone destruction.63 This
myeloma cells and stromal cells by up-regulating reciprocal interaction between breast-cancer cells
the expression of b1 integrins on myeloma cells.57 and the bone microenvironment results in a vicious
Adhesive interactions between marrow stromal cells circle that increases both bone destruction and the
and myeloma cells increase the production of inter- tumor burden (Fig. 4).
leukin-6, RANKL, and macrophage inflammatory Bone is an abundant source of inactive growth
protein 1a, further increasing bone destruction. factors, which are activated during the bone-resorp-
tive process10 and which can then stimulate the
growth of breast-cancer cells. Parathyroid hor-
osteoblast dysfunction
in myeloma monerelated peptide is probably the factor pro-
duced by breast-cancer cells and most solid tumors
Bone lesions in myeloma are purely lytic there is that stimulates the formation of osteoclasts.64,65
no osteoblastic response. This phenomenon ex- Both parathyroid hormonerelated peptide and
plains the clinical observation that in about half the parathyroid hormone bind the same receptor
cases of myeloma, bone scans are normal in the (PTHR1) and induce the expression of RANKL on
presence of severe osteolytic bone destruction.59 marrow stromal cells. Parathyroid hormone is the
The basis of the decreased osteoblastic response in main peptide regulator of calcium homeostasis, and
myeloma is unknown. Myeloma cells can produce parathyroid hormonerelated peptide has biologic
tumor necrosis factor a, which inhibits osteoblastic effects on bone similar to those of parathyroid hor-
growth and differentiation.60 However, tumor ne- mone.66 In the amino acid sequences of parathy-
crosis factor a has not been implicated in the sup- roid hormone and parathyroid hormonerelated
pression of bone formation in myeloma. Although peptide, 8 of the first 13 amino acids are identical,

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of parathyroid hormonerelated peptide.64 The pep-

tide 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 parathy-
roid 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 pro-
duction of parathyroid hormonerelated peptide.69
Breast-cancer cells also produce, or induce, interleu-
kin-6, prostaglandin E2, macrophage colony-stim-
ulating factor, interleukin-1, and tumor necrosis
factor a,70,71 which may also play an important role
in the induction of osteoclast formation by breast-
cancer metastases. Prostaglandin E2 can increase
the expression of RANKL and directly enhance the
Figure 4. The Vicious Circle of Osteolytic Metastasis.
effects of RANKL on the formation of osteoclasts.71
Tumor cells, in particular breast-cancer cells, secrete
parathyroid hormonerelated peptide as the primary Together, these data suggest that parathyroid hor-
stimulator of osteoclastogenesis. In addition, tumor monerelated peptide is a major mediator of os-
cells produce other factors that increase the formation teolytic bone destruction by breast cancer and other
of osteoclasts, including interleukin-6, prostaglandin E2 solid tumors.
(PGE2), tumor necrosis factor, and macrophage colony-
stimulating factor (M-CSF). These factors increase the
expression of receptor activator of nuclear factor-kB lig-
and (RANKL), which directly acts on osteoclast precur-
therapeutic implications
sors to induce the formation of osteoclasts and bone
of resorption and tumor
resorption. The process of bone resorption releases fac- growth
tors such as transforming growth factor b (TGF-b), insu-
lin-like growth factors (IGFs), fibroblast growth factors There is a close relationship between bone destruc-
(FGFs), platelet-derived growth factor (PDGF), and bone tion and tumor growth. For example, treating my-
morphogenetic proteins (BMPs), which increase the eloma in mice with agents that block bone resorp-
production of parathyroid hormonerelated peptide by tion but have no direct effect on tumor growth not
tumor cells as well as growth factors that increase tumor
growth. This symbiotic relationship between bone de- only inhibits the formation of osteoclasts but also
struction and tumor growth further increases bone decreases the tumor burden.51,52 However, defini-
destruction and tumor growth. tive evidence that decreasing bone destruction de-
creases the tumor burden in patients with bone
metastasis is lacking. Gordon and coworkers72 re-
and both peptides have similar three-dimensional ported that a single infusion of a potent bisphos-
structures.66 phonate that blocks bone resorption markedly in-
The production of parathyroid hormonerelated creased apoptosis of myeloma cells in vivo in 10
peptide is increased in metastases of breast cancer of 16 patients with newly diagnosed myeloma. In
to bone. Only 50 percent of primary breast can- a large, randomized, double-blind, placebo-con-
cers express parathyroid hormonerelated peptide, trolled study73 of the bisphosphonate clodronate,
whereas 92 percent of metastases of breast cancer Powles et al. found that administration of the drug
to bone produce the peptide.67 However, it is un- was associated with a decrease in both the incidence
clear whether this difference results from induction of bone metastasis and the death rate in patients
of the peptide in the bone microenvironment or with breast cancer who were at high risk for bone
whether tumors that produce the peptide are more metastasis. However, blocking bone destruction
likely to metastasize to bone. When breast-cancer does not appear to affect the growth of tumors in
cells from patients are injected into nude mice and soft tissues,73 indicating the unique characteristics
metastasize to bone, they increase the production of tumor growth in bone.

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mechanisms of disease

prostate cancer, although there is usually no histo-

osteoblastic metastasis
another vicious circle? logic evidence of increased numbers of osteoclasts.
In prostate cancer, levels of bone-resorption mark-
The mechanisms of osteoblastic metastasis and the ers are higher in patients with bone metastasis than
factors involved are unknown. Endothelin-1 has in patients without bone metastasis and reflect the
been implicated in osteoblastic metastasis from extent of bone metastasis more accurately than does
breast cancer.74 It stimulates the formation of bone the PSA level.82
and the proliferation of osteoblasts in bone organ Recent clinical trials have suggested that block-
cultures,75 and serum endothelin-1 levels are in- ing osteoclastic bone resorption decreases related
creased in patients with osteoblastic metastasis skeletal events in patients with prostate cancer.6
from prostate cancer.76 Furthermore, in an animal However, in a murine model of prostate cancer, the
model of osteoblastic metastasis, treatment with a inhibition of osteoclast activity did not inhibit the
selective endothelin-1Areceptor antagonist de- development of osteoblastic metastasis.83 Thus, it
creased both osteoblastic metastasis and the tu- is unclear whether bone destruction precedes the
mor burden.74 The antagonist had no effect on the development of osteoblastic metastasis or is a con-
growth of the tumor at orthotopic sites. These re- sequence of the increased bone formation. Yi et al.
sults suggest that blocking osteoblast-inducing ac- have shown in an animal model of osteoblastic me-
tivity by tumors may decrease tumor growth and tastasis that an initial phase of bone destruction is
osteoblast activity and suggest that a vicious circle followed by extensive formation of bone.77 Their
may also be involved in osteoblastic metastasis in data suggest that bone resorption precedes bone
which tumors induce osteoblast activity and thus formation in the development of osteoblastic me-
the subsequent release from the osteoblasts of tastases and that osteoclast activation plays an im-
growth factors that increase tumor growth. In ad- portant role in the development of osteoblastic me-
dition to endothelin-1, platelet-derived growth fac- tastases.
tor,77 a polypeptide produced by osteoblasts in the
bone microenvironment, urokinase,78,79 and pros-
tate-specific antigen (PSA)80 may also be involved. biochemical markers of bone
turnover for the detection
of bone metastasis
osteoblastic metastasis The value of biochemical markers of bone turnover
in prostate cancer
as a means of monitoring patients with bone metas-
Overproduction of urokinase-type plasminogen ac- tases is still under investigation. Levels of bone-spe-
tivator (u-PA) by prostate-cancer cells increases cific alkaline phosphatase, osteocalcin, and type I
bone metastasis,78 and cells transfected with an procollagen C-propeptide in serum are indicators of
anti-sense DNA to u-PA had one third as many me- osteoblast activity, whereas serum levels of C-termi-
tastases as did cells transfected with an empty vec- nal telopeptide of type I collagen and tartrate-resis-
tor. Human PC3 prostate-cancer cells produce a fac- tant acid phosphatase and urinary levels of type I
tor that is homologous to u-PA.79 Prostate-cancer collagen cross-linked N-telopeptides are markers
cells also release PSA, a kallikrein serine protease. of osteoclast activity. All these markers have been
PSA can cleave parathyroid hormonerelated pep- used to assess the response to therapy or for the de-
tide at the N-terminal, which could block tumor- tection of bone metastases,84-86 but results have
induced bone resorption. It may also activate os- been variable. Urinary type I collagen cross-linked
teoblastic growth factors released in the bone N-telopeptides and C-terminal telopeptide of type I
microenvironment during the development of bone collagen appear to be the most useful.84
metastases, such as insulin-like growth factors I and
II or transforming growth factor b.80 These data In summary, bone metastases are among the
suggest that a vicious circle may also be responsi- most debilitating problems in patients with cancer.
ble for osteoblastic metastasis. The molecular mechanisms responsible for both os-
Bone metastases in prostate cancer are pre- teolytic and osteoblastic metastases are just being
dominantly osteoblastic, with increased numbers identified. The use of gene arrays and proteomics
of irregular bone trabeculae.81 However, markers of and the availability of appropriate animal models of
bone resorption are also increased in metastatic bone metastasis have permitted the identification

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of factors produced by the tumor cells themselves Supported by research funds from the Multiple Myeloma Re-
search Foundation; a Department of Veterans Affairs Merit Review
or by the microenvironment in response to the tu- Award; and grants (AR41336 and AG13625) from the National In-
mor that mediate the process of bone destruction. stitutes of Health.
These types of studies should result in the develop- I am indebted to members of the General Clinical Research Cen-
ter, University of Pittsburgh Medical Center, for their assistance in
ment of therapeutic agents to treat and possibly the care of my patients.
prevent this devastating complication of cancer.

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