Bone metastases are a late event in tumor progression, contributing to

morbidity and mortality and decreasing patient quality of life. Bone metastases occur late in
tumor progression, toward the end of a multi-stage process. Bone is the preferred site for
breast and prostate cancer metastases; many other cancers, including lung and renal
tumors and melanomas also colonize the skeleton. At least 80 %
of patients with advanced breast and prostate cancers have bone metastases, and
survival from time of fi rst diagnosis of skeletal involvement in prostate cancer patients,
for example, is approximately 40 months [ 3 ].
Bone metastases are almost invariably found in the red marrow due to the high
blood fl ow in these areas. The bones involved most frequently are therefore those
with a high proportion of red marrow; more than 80 % of bone metastases are found
in the axial skeleton. Earliest bones affected by metastases include the spine,
pelvis and ribs, while the skull, humeri, femora, scapulae and sternum tend to
be involved later. In long bones proximal regions are generally involved before
distal regions. Lumbar and thoracic vertebrae are more often affected than cervical
vertebrae and vertebral bodies are more commonly involved than pedicles.
Metastases to bone of the hands and feet are rare and when they do occur are more
frequently due to a lung primary. Bone metastases are usually widespread and
multiple at the time of fi rst clinical manifestation, with the exception of renal cell
carcinoma or neuroblastoma, in which up to 10 % of patients may have a single
site of bone involvement.
Bone metastases can cause considerable morbidity for patients, with complications
including anaemia, increased susceptibility to infection, pathological skeletal
fractures, spinal instability, compression of the spinal cord and hypercalcaemia of
malignancy. The presence of bone metastases can also result in impaired mobility
and decreased physical functioning, as well as psychological distress, all of which
impact on the patients overall quality of life.
The most common symptom of bone metastases is pain. Cancer-induced bone pain
is frequently accompanied by radiological evidence of cancer-induced bone destruction.
Bone pain often results in hospital attendance and can considerably compromise
social functioning, quality of life and overall survival. Although most patients with
bone metastases will ultimately die from their disease, some patients will survive for
many years, often times with bone as their sole site of metastatic disease. For those
with a long life expectancy following diagnosis of metastatic bone disease, effective
pain control is highly important in order to maintain functioning and quality of life.
Bone pain is the most common presenting symptom of metastatic bone disease and
represents the most common cause of cancer-related pain [ 5 , 6 ]. However, not all
bone metastases are painful. Cancer-induced bone pain is reported to be present in
up to 2845 % of patients with bone metastases [ 7 9 ], but between 30 % and 50 %
of patients have asymptomatic bone metastases found during tagging studies for
primary tumours [ 10 ]. Pain from bone metastases frequently increases in magnitude
over the course of the disease. Words such as annoying, gnawing, aching and nagging
are commonly used to describe cancer-induced bone pain [ 11 ].
The relationship between bone invasion and bone pain is unclear [ 12 ]. Signifi cant
patient-to-patient variability exists in the type, severity and evolution of bone cancer
pain. Patients can have multiple bone lesions without related bone pain or patients
can have considerable pain without evidence of bone metastases [ 12 ]. In animal
models of bone cancer, pain-related behaviour is often present before any signifi cant
bone destruction occurs [ 13 ]. There may also be distortion between the perceived
location of the pain and the sites of the known bone lesions [ 12 ]. Thus the location

of bone metastases and the degree of bone destruction may not necessarily correlate
with the severity of the pain. Nor does the presence of bone pain correlate with
the type of primary tumour and location of the tumour, with the size and number of
metastases, or with the age and gender of patients [ 14 ]. Pain produced by metastatic
bone lesions is often disproportionate to their size or to the degree of bone involvement.
Bone pain may undergo fl uctuations in intensity without apparent change in
the nature or behaviour of the underlying metastases [ 15 ].

Types of Cancer-Induced Bone Pain

1. Nociceptive Pain
Nociceptive pain results from direct injury to somatic structures (somatic pain) or
injury to visceral structures (visceral pain). Nociceptive bone pain is caused by stimulation of
nociceptors in the endosteum by chemical mediators, including prostaglandins, leukotrienes,
substance P, interleukin-1 and -6, endothelins and tumour necrosis factor A. The neural
pathways involved in somatic pain are intact and the pain is typically well localized. A
pathological fracture of a bone in a patient with bone metastases may also cause pain that
is nociceptive in nature.
2. Neuropathic Pain
Neuropathic pain has been characterized as pain directly attributable to injury of
a neural structure, possessing burning, stabbing, shooting or electric shock
characteristics [ 16 ]. Neuropathic bone pain may result from involvement of the
spinal cord, nerve roots or peripheral nerves and from direct infi ltration or chemical
irritation of nerves by tumours. Sensory and sympathetic neurons are present
within the bone marrow, mineralized bone and periosteum and all these compartments
can be affected by the presence of tumor cells, as well as by the occurrence of
ischaemia and fractures. Bone metastases may also be associated with neuropathic
pain mechanisms resulting from pressure on neural structures and/or maladaptive
plasticity of the nervous system [ 17 ]. The neuropathic component of bone pain
can also be due to pre-existing cancer-induced damage to sensory nerves such
as infi ltration or compression, as well as subsequent interventions such as chemotherapy
(e.g. platinum compounds (cisplatin, carboplatin, oxaliplatin), taxanes
(docetaxel, paclitaxel), vincristine, thalidomide and bortezomib) that may result
in neuropathy. A recent prospective cross-sectional study of patients with symptomatic
bone metastases showed that 17 % of patients had bone pain with distinguishable
neuropathic pain features and these patients reported greater pain intensity [ 18 ].
The typical burning or tingling nature of the pain, the radiation of pain along
a nerve distribution and the presence of sensory or motor defi cits are indicators
of mixed bone/neuropathic pain syndromes [ 19 ].
Typically the pain associated with spinal cord compression is neuropathic in
nature. The most common primary tumours associated with this type of complication
are breast and lung cancer. Pain in spinal cord compression is often localized to
the area overlying the tumour, increases with activities such as straining, coughing
and sneezing, and is made worse by straight leg raising. Pain often considerably
pre-dates neurological changes. Radicular pain may also be present which may
radiate down the legs or around the chest or upper abdomen. Depending on the
level of spinal involvement, pain can be unilateral or bilateral. Metastases in
the thoracic spine can often result in bilateral pain, while cervical or lumbosacral
metastases frequently result in unilateral pain. While pressure on the spinal cord
frequently results in pain, it can also lead to numbness, weakness, diffi culty urinating
and may even lead to paralysis if not addressed as an urgent matter.
Medical treatment of neuropathic pain is often not satisfactory, with pain
control very diffi cult to achieve for a large number of patients with this condition.

It has been reported in both clinical and preclinical studies that morphine
is typically less effi cacious in blocking neuropathic pain than in blocking infl ammatory
pain [ 20 23 ].
3. Infl ammatory Pain
It has been suggested that infl ammatory factors secreted by cancer cells are
involved in the pathophysiology of cancer bone pain [ 24 ]. Infl ammatory-induced
changes are caused by direct tissue damage resulting from tumour growth as
well as by the release of pain mediators by the cancer cells themselves. Tumour
cells release pro-nociceptive compounds, including prostaglandins, nerve growth
factor and endothelins, which can contribute to pain [ 25 , 26 ].
4. Muscular Pain
Reactive muscle cramps and spasm often occur in muscles in close proximity to
painful bone lesions. Spasms of the surrounding musculature most commonly
occur with bone metastases of the proximal extremities and spine and may cause
pain that is poorly responsive to opioids and anti-infl ammatory medications, and
may require specifi c treatment with anti-spasmotic agents [ 27 ].
5. Cancer Bone Pain as a Complex Pain Entity
For many years the question has been raised whether cancer-induced bone pain
is truly a subtype of infl ammatory pain or neuropathic pain or whether it represents
a unique type of pain state. Bone pain is increasingly considered to be a mixedmechanism
pain, rather than a single neuropathic, visceral or infl ammatory pain
state. According to this model, cancer bone pain is a complex syndrome with
involvement of infl ammatory, neuropathic and ischaemic mechanisms.
Animal models of malignant bone disease have enabled the effects of cancerinduced
bone pain on the nervous system to be studied. It has been demonstrated
that such animal models of cancer bone disease share key features with cancerinduced
bone pain in humans, with progressive bone destruction accompanying
progressive limping and guarding and leading to pathological fractures [ 28 30 ].
Thus, these models seem to be appropriate for the study of pain states that
are analogous to human cancer-induced bone pain. Through the use of animal
models, it has been suggested that cancer-induced bone pain is different from
other pain states, including infl ammatory and neuropathic pain. For example,
specifi c dorsal horn neuronal responses have been shown in cancer-induced bone
pain that are not present in infl ammatory or neuropathic states [ 31 ].
The complex nature of cancer bone pain suggests that the approach to its
management must also be unique. The relative degree of opioid resistance in
cancer-induced bone pain compared to other types of pain states highlights the
difference between cancer-induced bone pain and other pain states.

Malignant Bone Pain Presentations

Cancer-induced bone pain is not considered to exist as a single entity, but rather
consists of a triad of continuous pain, spontaneous pain and incident pain [ 32 , 33 ].
Continuous pain, also called background pain, is present constantly, whereas
spontaneous and incident pain are both subtypes of breakthrough pain, which occur
episodically and sometimes unpredictably.
1. Continuous Bone Pain
Continuous bone pain is described as a constant dull ache that increases in intensity
as disease advances [ 5 ]. Continuous background pain is the most frequent
presentation of bone pain and can be pinpointed by the patient with relative ease.
This type of pain has a gradual onset over a period of weeks or months, and may
come and go at fi rst. It tends to becomes more progressive and more severe

in intensity over time. Bone pain can be hard for patients to differentiate from
ordinary low back pain or from arthritis. If the lesion is in weight-bearing bone,
the pain may worsen on weight-bearing and these lesions may cause pain early
in the course of the disease, whereas bones such as the ribs or sternum may
remain asymptomatic until later in the disease, often until the development of
pathological fractures. Typically this type of pain is well-localized to one or
more specifi c bone areas. It can be dull in character and/or can have a deep sensation
that burns or aches. It may also be accompanied by episodes of stabbing discomfort
[ 19 ]. Continuous bone pain often increases with pressure on areas of involvement,
which may account for it worsening at night when the patient is lying
down. While not diagnostic of bone metastases, pain at night and pain incompletely
relieved by rest are typical symptoms of bone metastases. Because of the
higher prevalence of axial skeleton metastases, continuous bone pain is more
likely to involve the pelvis, rib cage or lumbar, dorsal and cervical spine. Pain
from bone lesions in the extremity tends to be well-defi ned, as opposed to lesions
in the pelvis and spine which may produce vague, diffuse symptoms.
2. Breakthrough Pain
Breakthrough pain is a transitory exacerbation of pain experienced by the patient
who has relatively stable and adequately controlled baseline pain. Types of
breakthrough pain include incident pain and spontaneous pain. In an exploratory
study of cancer-induced bone pain involving cancer patients, 41 of 55 patients
had breakthrough pain, with 20 of 41 patients describing breakthrough pain of
rapid onset (less than 5 min) and of short duration (less than 15 min) [ 11 ].
Patients with breakthrough pain also had greater interference with quality of life,
including negative impact on mood, relationships, sleep, walking, work and
enjoyment of life, than those without breakthrough pain [ 11 ].
Incident bone pain is defi ned as an intermittent episode of severe pain that is
induced by normally non-noxious movement or mechanical loading of the
tumor-bearing bone(s). Bone metastases are the most frequent cause of incident
pain. Patients who experience incident pain often have mild or indeed no pain at
rest. Incident-related bone pain is often repetitive and unpredictable and can
occur many times during the day. Incident bone pain is diffi cult to treat and has
been suggested to predict worse pain control [ 34 ]. Bone pain caused by cancer
exacerbated by movement or posture can be more diffi cult to control than
continuous bone pain [ 34 , 35 ].
Spontaneous bone pain (also known as idiopathic bone pain) occurs with no
identifi able cause and can last longer than incident pain. It therefore represents
one of the more challenging aspects of cancer pain management [ 27 ].
The clinical characteristics of cancer-induced bone pain make optimal
management diffi cult, and a large portion of patients report poor pain control
[ 36 , 37 ]. Bone pain is thought to respond less well to opioid analgesics due to its
temporal characteristics. Because these episodes of bone pain are relatively short
lasting, the doses of opioids used to control the pain may result in troublesome
adverse effects when the patient is at rest. More recently rapid-onset opioids
have emerged, with fast onset and offset of action which have helped in the management
of sudden-onset and short-lived movement-related pain.

Mechanisms of Cancer-Induced Bone Pain

A variety of possible mechanisms by which bone metastases may cause pain have
been reported, but a limited amount of data supports these proposed mechanisms
and the exact mechanism by which a bone metastasis induces pain is not completely
understood. These mechanisms likely include local production of growth factors and
cytokines (either tumour-induced or tumour-produced), tumour induced osteolysis,

stimulation of ion channels on nerve cell endings and direct infi ltration [ 38 , 39 ].
Stretching of the periosteum by tumour expansion, mechanical stress of the weakened
bone, nerve entrapment by the tumour or direct destruction of the bone are all possible
mechanisms responsible for causing bone pain [ 5 ].
1. Alterations in Bone Turnover
Bone-resorbing osteoclasts and bone-synthesising osteoblasts are responsible
for the continuous restructuring and remodeling of the human skeleton. Bone is
constantly being remodelled in a dynamic process where osteoblasts are responsible
for bone formation and osteoclasts for its resorption. Normal bone undergoes
constant resorption and new bone formation. A balance between resorption and
formation maintains bone strength and structural integrity. Osteoblasts are mononucleate
cells derived from fi broblasts, while osteoclasts are terminally differentiated,
multi-nucleated monocyte lineage cells that resorb bone through maintaining an
extracellular microenvironment of acidic pH at the osteoclast- mineralized bone
interface [ 40 ]. The effects of osteoclasts and osteoblasts are normally balanced
to maintain a steady state of bone density.
When tumour cells metastasize to bone, there is a loss of mechanisms that
normally regulate the balance between osteoclast and osteoblast activity, and the
balance between resorption and new bone formation is altered. This may lead
to an abnormal state of increased bone destruction (osteolysis), increased bone
formation (osteosclerosis), or both [ 31 ].
It has been traditional to think of bone metastases as either osteolytic or osteoblastic,
with different factors being responsible for each. Increased bone destruction
is characteristic of osteolytic metastases and markedly increased bone formation
results in osteoblastic metastases. Osteolytic bone metastases are associated with
increased osteoclast activity and formation and are highly cellular.
Osteoblastic metastases are associated with excess new bone matrix formation by
osteoblasts
and are relatively acellular. The predominant types of metastases are osteolytic.
Purely osteolytic lesions are seen with cancers of the thyroid, uterus or gastrointestinal
tract. Purely osteoblastic lesions are commonly seen in patients with
prostate cancer.
This distinction between osteolytic and osteoblastic bone lesions is not
absolute however; many patients with bone metastases have both osteolytic and
osteoblastic lesions and individual metastatic lesions can contain osteolytic
and osteoblastic elements. Increased osteoclast activity may be seen with osteoblastic
lesions. Mixed lesions contain elements of osteolytic and osteoblastic
metastases and are seen commonly in cancers of the lung, breast, cervix, ovary
and testes. Thus, the concept that there are two distinct types of bone metastases
is somewhat simplistic and there may in fact be a spectrum of bone metastases;
predominantly osteoblastic metastases also have resorptive components and
predominantly osteolytic metastases also have a local bone formation response,
which may represent an attempt at bone repair [ 41 ]. Both osteolytic and osteoblastic
bone lesions may cause pain in patients with bone metastases.
Studies have suggested that osteoclasts play an important role in cancerinduced
bone loss and that they contribute to its aetiology [ 42 44 ]. Osteoclaststimulating
factors from the tumour, the tumour-associated stroma or the bone
stimulate osteoclast proliferation [ 45 50 ]. Osteoclasts have been shown to be
present in high numbers in animal models of bone cancer and these high numbers
may correlate with cancer-induced bone pain [ 28 , 51 ]. Osteoclast-mediated bone
remodeling results in the production of extracellular proteins, known to be potent
activators of nociceptors [ 52 ]. The acidic environment produced by osteoclasts
may contribute to cancer-induced bone pain through activation of acid- sensitive
nociceptors that innervate the marrow, mineralized bone and periosteum [ 53 ].

With advanced disease, bone loses mechanical strength and is subject to further
osteolysis, pathological fractures, and microfractures.
2. Nerve Injury by Tumour Invasion
It has been suggested that nerve or nerve root injury by tumour invasion is involved
in the pathophysiology of cancer-induced bone pain [ 24 ]. Sensory and sympathetic
neurons are present within the bone marrow, mineralized bone, and periosteum
and all of these are susceptible to injury from the presence of tumour cells,
fractures and ischaemia. Sensory fi bers in any of these tissues may therefore play
a role in the generation and maintenance of bone pain [ 54 ]. For example, nerve
root infi ltration and nerve compression by osteolytic vertebrae may result in
neuropathic cancer bone pain, and infi ltration or compression of adjacent nerves
by tumour growth can also result in pain of a neuropathic nature. Tumour cells
present in bone also have the capacity to grow out from the bone and invade
surrounding tissues and nerves, further contributing to bone-related pain.
3. Stretching of Periosteum and Endosteum by Increasing Tumour Size
Nociceptive pain may also arise as a result of stretching of the periosteum resulting
from tumour infi ltration of the bone. Many nerves are found in the periosteum and other
nerves enter bones surrounding blood vessels [ 5 ]. Studies have shown
that the periosteum is densely innervated by both sensory and sympathetic
fi bres [ 55 57 ] and that it receives the greatest density of nerve fi bres per unit
area of all bone tissues. It has been proposed that bone pain arises predominantly,
if not exclusively from the periosteum [ 58 60 ]. However, stimulation of
nerve endings in the endosteum also results in the release of chemical agents
from the destroyed bone tissue, such as prostaglandins, bradykinin, substance P
and histamine. It has been suggested that the main mechanism of bone pain from
small metastases is from this stimulation of nerve endings in the endosteum by
chemical agents from the destroyed bone tissue [ 12 ].
4. Microfractures and Pathological Fractures
Bones involved with cancer are weakened and thus are at increased risk of
fracturing. Microfractures can occur in the bony trabeculae at the site of the
metastases resulting in bone distortion. Microfractures cause pain that result from
the destruction of bone, reducing its weight bearing capabilities. In the appendicular
skeleton, instability due to the presence of metastases results in symptoms with
use of the extremity or with weight bearing. A pathological fracture can result
when loads are applied that are greater than the support provided by the normal
bony trabeculae. Fractures can occur with a fall or injury, but can also occur
during everyday activities, resulting in sudden severe pain. Pathologic fractures
have been reported at some time in approximately 830 % of patients with bone
metastases [ 61 , 62 ].
Fractures are more likely to occur with osteolytic metastases and can occur in
ribs and vertebrae as well as in long bones. Long bone fractures occur in 1020 %
of patients [ 27 ]. The femur and humerus are the bones most commonly fractured
due to metastases. A long bone fracture or an epidural extension of tumour into
the spine causes the most disability.
Bone metastases of the axial skeleton develop a gradual weakening of the
trabeculae and loss of architecture which can result in mechanical pain and/or
pain at rest. Tumour growth may also cause weakness of the vertebrae, with
eventual collapse of the bone resulting in sudden pain in the middle of the back.
Painful vertebral compression fractures, pathologic or osteoporotic, are a source
of considerable morbidity in cancer patients. Most fractures occur in the
thoracolumbar region and adjacent-level fractures occur in approximately 18 %
of patients [ 63 ].

As the development of a fracture can have detrimental effects on quality of

life, as well as on survival, efforts have been made to predict sites of fracture.
Various characteristics have been suggested as important criteria for determining
a patients risk of fracture, with certain cancer types associated with an increased
risk. Only few cancer types, however, have been an object of detailed study of
fracture risk. Patients with multiple myeloma have been shown to have the
highest fracture incidence, followed by breast, prostate, and lung cancer [ 64 ].
Much research has focused on prostate cancer, where a decreased bone mineral
density and an increased risk of fractures, mainly linked to the use of anti-androgen therapy,
has been demonstrated [ 65 ]. Patients with breast cancer have a relatively
long survival, thus these patients are more likely to develop pathological
fractures. Women with low bone mineral density also have an increased risk of
breast cancer [ 66 ], and may therefore have an increased risk of fractures.
Aromatase inhibitors have been shown to be associated with a signifi cantly
higher risk of fractures than tamoxifen due to the lowering of estradiol levels,
whereas tamoxifen has partial estrogen agonistic properties [ 67 ]. Bone fractures
also represent a frequent complication of thyroid cancer and renal cell cancer
[ 68 70 ]. Renal cell metastases to bone can be unusually expansile and destructive,
which creates an increased risk of pathological fracture.
Other implicated characteristics for increased risk of fracture include: duration
of lesions, (the risk of pathologic fracture appears to increase with the duration
of metastatic disease [ 71 ], size of the lesion, location of the lesion (cortical involvement
in the subtrochanteric region of the femur increases the risk), type of treatment,
and osteolytic versus osteoblastic lesions. Breast cancer metastases that are purely
osteolytic are more likely to fracture than those that are osteoblastic or mixed
osteolytic and osteoblastic. Osteoblastic lesions in high-risk areas such as the
proximal femur have a high rate of fracture however.
Because fractures are associated with increased risk of death in patients with
malignant bone disease, prevention of fractures is an important goal of therapy.
5. Activation of Acid-Sensing Nociceptors by Tumour-induced Acidosis
As infl ammatory cells invade tumour stroma, they release proteins that generate
local acidosis. Areas of ischaemic necrosis and osteoclasts contribute to further
lowering pH. The large amount of apoptosis that occurs in the tumour environment
may also contribute to the acidotic environment.
Pain receptors expressing acid-sensing ion channels are sensitized and activated
by this decrease in pH. The low pH causes the acid-sensing ion channels on
nerve cell endings to be stimulated, resulting in activation of nociceptors. This
activation of acid-sensing receptors by tumour-induced acidosis in bone metastases
and tumour-induced release of proteins and acidosis may be particularly important
in the generation of cancer-induced bone pain [ 24 , 72 ]. Inhibiting acid-sensing
ion channels may therefore lead to a reduction in cancer-induced bone pain.
6. Nociceptor Sensitization
It is also reported that malignant bone pain may have distinct additional
mechanisms that contribute to pain, including CNS excitation and disinhibition
and nociceptor sensitization (increased responsiveness to noxious or non- noxious
stimuli), which may underlie more persistent, mechanically evoked pain. This
sensitization could originate in the periphery (peripheral sensitization) or in
central structures (central sensitization).
Central sensitization is responsible for tactile allodynia (pain in response to
light touching of the skin) and for the severe burning pain such as that seen from
mere blowing on the skin in patients with nerve damage. Central sensitization is
also responsible for the spread of pain beyond an area of tissue damage resulting
in tenderness in adjacent non-damaged tissue. It can also occur following orthopaedic

surgery which may contribute to pain on movement or touch [ 73 ].