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Practice Essentials

Metastatic bone disease occurs when cancer spreads from a primary organ site to bone. The spine
is the most common location of metastatic disease. See the image below.

Lateral radiograph shows sclerotic metastasis of the

L2 vertebra in a 54-year-old man with prostatic carcinoma.
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Pain is an important symptom of musculoskeletal metastases, but it is nonspecific. The pain
pattern can be helpful if, in addition to being activity related, it is present at rest and at night,
especially in patients older than 50 years. However, this pain pattern can be present in patients
with osteomyelitis and Paget disease, and in these instances, it is also nonspecific.
Laboratory tests that can be used to aid in the diagnosis of metastatic bone disease include the
 Serum alkaline phosphatase: Indirect reflection of bone destruction
 Serum protein electrophoresis
 Urinalysis, urine protein electrophoresis
 N-telopeptide of type II collagen: Marker of bone resorption but not widely used
Imaging studies
The following radiologic studies may be used to evaluate metastatic bone disease:
 Radiography: For the basic assessment of the extent of a tumor and the degree of cortical
erosion; can also be used for skeletal survey in patients with multiple myeloma
 Computed tomography scanning: Most sensitive imaging modality to detect bone
destruction, providing the best assessment of the extent of cortical destruction
 Magnetic resonance imaging: Most sensitive study for the assessment of the anatomic
(intramedullary and extraosseous) extent of a lesion
 Bone scanning: Very sensitive study for the detection of occult lesions and the assessment
of the biologic activity of lesions
 Angiography: Depicts devascularization of vascular metastases; may also be used to assess
pain palliation in patients with nonresectable metastases
Biopsies should be obtained from any soft-tissue mass or, if no soft-tissue mass is present, from
the most accessible bone in a mechanically safe area (eg, metaphysis vs diaphysis, acetabulum vs
subtrochanteric femur).
In selected patients with metastatic disease of the spine, the following diagnostic procedures may
be performed:
 Percutaneous core needle biopsy
 Open biopsy
See Workup for more detail.
The life span of patients with metastatic bone disease is limited; thus, the goal of management
needs to be centered on returning as much function as possible as rapidly as possible. Patients
with metastatic bone disease are generally treated with surgery or radiation therapy.
Radiation therapy
Radiation therapy remains a primary therapeutic modality for the treatment of spinal metastasis,
because nearly 95% of patients who are ambulatory at the start of radiation therapy remain so.
Consequently, the possibility of regaining cord function once it is lost as a result of spinal
metastasis is dismal. Therefore, such loss needs to be avoided by early diagnosis, treatment, and,
if indicated, surgical intervention.
The goals of surgical intervention for spinal surgery in patients with metastatic bone disease
includes decreasing or eliminating pain, decompressing neural elements to protect cord function,
and mechanically stabilizing the spine. [1, 2] Anterior or posterolateral decompression, combined
with anteroposterior reconstruction, may be used in the following:
 Diagnostic spinal surgery
 Cervical spinal surgery
 Thoracic and lumbar spinal surgery
Vertebroplasty, in which polymethylmethacrylate is percutaneously introduced, may be a
minimally invasive treatment alternative for patients with one- or two-level vertebral body
compression fractures. [3]
For the management of long bone metastatic disease accompanied by an impending or completed
fracture, open internal fixation is usually the preferred method of treatment. Stabilization with a
locked intramedullary device followed by radiation therapy to the entire bone as soon as the
surgical wounds have healed is preferred. [4]
Devices and/or procedures used in the surgical fixation of long bones include the following:
 Standard or cemented stems
 Dynamic hip screws or plates
 Intramedullary fixation devices
 Total hip arthroplasty
Medications used in the treatment of metastatic bone disease include the following:
 Monoclonal antibody antineoplastic agents (eg, denosumab)
 Calcium metabolism modifiers/bisphosphonates (eg, pamidronate, zoledronate, and
The orthopedic surgeon has two major tasks to perform when treating patients who develop bone
metastases. [1] The first task is to biopsy a bony lesion of unknown origin, which may be found
during evaluation/staging studies or as a result of a patient's symptoms. (See Workup.)
The orthopedic surgeon's second task is to manage the stabilization of impending or already
completed pathologic fractures of bones in a critical area, such as an upper or lower extremity,
the pelvis, or the spine. In one study of patients with breast carcinoma, 19% of the patients
developed a pathologic fracture or hypercalcemia as the first sign that the carcinoma had spread
to bone. Moreover, 10% of the patients suffered spinal cord compression, and 9% of them
experienced bone marrow failure. (See Prognosis and Treatment.)
In patients with bone metastases, it is important to develop strategies that emphasize
maintenance of function, including ambulation, for the remainder of these patients’ lives and to
intervene when possible before a fracture occurs. The morbidity and mortality rates associated
with metastatic bone disease are greater when intervention is delayed.
(See Prognosis and Treatment.)
In females, the breasts and lungs are the most common primary disease sites; approximately 80%
of cancers that spread to bone arise in these locations. [5, 6, 7, 8,9] In males, cancers of
the prostate and lungs make up 80% of the carcinomas that metastasize to bone. [10] The
remaining 20% of primary disease sites in patients of both sexes are the kidney, gut, and thyroid,
as well as sites of unknown origin. (See Pathophysiology and Etiology)
Pathophysiology and Etiology
Previously, the two main theories of how tumor cells metastasize and grow in bones were Paget's
fertile soil hypothesis and Ewing's circulation theory. However, a substantial amount of work has
more clearly defined the metastatic process to bone. Bone metastases occur in a predictable
distribution. In order of frequency, the most common locations include the following:
 Spine
 Pelvis
 Ribs
 Proximal limb girdles
The red marrow theory, combined with knowledge about the cytokine stimulation of metastases,
provides an excellent explanation of how this distribution occurs.
Metastases distal to the knee and elbow are extremely uncommon, but approximately 50% of
these acral metastases are secondary to primary lung tumors. Carcinomas, such as those of the
breast and prostate, rarely exhibit such a distinct pattern.
Metastasis and bone destruction
In 1995, Mundy and Yoneda described the cellular events necessary for the success of the
metastatic process, including the attachment of tumor cells to the basement membrane, the
production of proteolytic enzymes by tumor cells (such as metalloproteinases, which are
enzymes that disrupt basement membranes), and the migration of tumor cells through the
basement membranes into surrounding tissue, especially the arteriolar network. [11]
Cells from the primary site must, through the process of neovascularization or through migration
to the nearest blood vessel, attach to the basement membrane of the vessel wall and produce
proteolytic enzymes that disrupt the basement membrane.
The cells then migrate through the basement membrane and float away in the bloodstream to a
distant site. The process through which these tumor cells are attracted to a specific site in the
body is not completely clear, though type I collagen, a byproduct of bone resorption, has been
shown to be a chemotactic factor that attracts tumor cells to bone.
If they survive the journey to the distant site, the tumor cells attach to the basement membrane of
the vessel wall using proteolytic enzymes (integrins/cadherins). After disrupting the receptor site
basement membrane, they migrate into the substance of the distal host tissue. Producing
chemotactic factors, as well as RANK ligand (a transmembrane or soluble protein essential for
the formation, function, and survival of osteoclasts), these cells stimulate osteoclast activity,
causing bone resorption and leading to the formation of pockets or holes in the bone in which the
tumor cells grow.
Another important substance that stimulates bone resorption is parathyroid hormone ̶ related
peptide (PTHrP). This substance is expressed by breast carcinoma cells, as well as by oat cell
tumors of the lung, and is a potent stimulant of osteoclasts. Guise et al reported elevated PTHrP
levels in the bone marrow plasma (as compared with serum plasma levels) in rats with
tumors. [12]
An interesting concept, reported by Mundy and Yoneda, is that myeloma cells are especially
adapted to producing bone destruction through direct stimulation of osteoclasts. [11] During the
resorption process, the osteoclasts release interleukin (IL)-6, which is a major regulatory factor
in the growth of myeloma cells. Additional myeloma cells further stimulate increased
osteoclastic production in a continuous feedback mechanism. This enhances survival of the
tumor cells and further destruction of the bone. [11]
United States statistics
Approximately 1.2 million patients present with cancer each year in the United States. Of these,
approximately 600,000 persons have metastases to bone. In contrast, 2,700 patients per year
develop primary bone sarcoma.
Age-related demographics
The age range of patients with sarcoma is different from that of individuals with carcinoma of
bone; most metastatic bone lesions occur in adults older than 50 years, while most sarcomas
occur in adolescents or young adults (<30 years). Therefore, a bone-occupying mass in an adult
is much more likely to be a focus of metastatic carcinoma than to be a primary sarcoma of bone.
However, in a patient with a bone lesion with no documentation of metastatic disease, caution is
warranted to ensure the correct diagnosis.
In general, once skeletal metastases are present, patient survival is dramatically shortened. For
example, the 5-year overall survival rate for people with prostate cancer is 93%, but once
skeletal metastases are present, the average survival time is only 29 months. However, patients
are surviving and remaining active for longer periods as treatment protocols improve. These
factors make the orthopedic surgeon's task in prophylactic or reconstructive surgery more
challenging. [13]
In addition, perioperative complications occur more frequently among patients with skeletal
metastases; the perioperative mortality rate in this population is approximately 8%, and the
perioperative infection rate is approximately 4% (although the infection rate is higher at
previously irradiated sites).
Most patients with metastatic bone disease survive for 6-48 months. In general, patients with
breast and prostate carcinoma live longer than those with lung carcinoma. [14, 15] Patients with
renal cell or thyroid carcinoma have a variable life expectancy.
Kirkinis et al studied 462 patients presenting with metastatic bone disease to the extremities or
pelvis who underwent orthopedic treatment. [16] Overall surival rates were 45% at 1 year, 29% at
2 years, and 13% at 5 years. Preoperative hemoglobin was found to be an independent predictor
of better survival; lung histotype, age, pathologic fracture, and previous combined therapy were
negative predictors of survival.

Background: Bone is a frequent site of metastases in advanced cancer and is associated with significant skeletal
morbidity. Current treatment options are aimed at preserving and improving functional independence and quality of life.
Materials and Methods: A review of current literature focusing on diagnostic tools and treatment approaches of bone
metastasis in advanced cancer was performed and conclusions were incorporated into diagnostic and treatment
algorithms. Results: Radiologic imaging has added valuable tools for screening and diagnostics of bone metastasis.
Clinical management of skeletal metastasis includes improved pain management, introduction of bone modifying agents
and advancements in surgical and radiation therapy. We propose three algorithms enhancing the sensitivity of diagnostics
and improving multidisciplinary management of vertebral and non-vertebral bone metastasis. Conclusion: Bone
metastases are an expression of a systemic disease. Treatment options include highly specialized modalities yet need to be
tailored to individual needs. Algorithms help standardize treatment procedures and can improve treatment outcome in a
multidisciplinary setting.

 Metastatic bone disease

 algorithm for diagnostic and treatment

 bone-targeted agents

 skeletal morbidity

 multidisciplinary management

 vertebral bone metastasis

 non-vertebral bone metastasis

 review

Structural integrity of the bone is meticulously regulated through the actions of osteoclasts and
osteoblasts. The dynamics of bone resorption and formation in this context are determined by the
stress and force bone is subjected to and orchestrated by cytokines and other factors. The healthy
skeletal structure is lost if this balance is disturbed by the detrimental effects of either bone
metastasis or cancer treatment (1). In cancer patients, the skeletal morbidity is conferred upon by the
burden of bone metastasis and by cancer treatment-induced bone loss (CTIBL). Cessation of
hormonal support, necessary for maintenance of healthy bone structure, is a common problem for
aging men and women. In this context of treatment, adjuvant use of aromatase inhibitors (AI) in
breast cancer and androgen deprivation therapy (ADT) in prostate cancer are associated with an
additional significant bone loss and an increased fracture rate (2-4). In fact, the Fracture Intervention
Trial (FIT) showed a significant increase in mortality risk in postmenopausal women with
osteoporosis-induced fractures (5). The lifetime risk of fracturing either the hip or spine averages
almost 40% in women and 12% in men over 50, reflecting the need for early detection and treatment
of these endocrine disturbances and the resulting osteoporosis (6, 7).
This increase in fracture rate and its consequences associated with use of an AI or ADT has not been
adequately addressed in the oncology setting in the past. Increased awareness and approval of the
osteoprotective agent denosumab, in this non-metastatic setting, has led to a significant reduction
in bone fractures in postmenopausal breast cancer patients treated in the adjuvant setting with an AI
and non-metastatic prostate cancer patients treated with ADT (8, 9). In addition to anti-hormonal
treatment, prolonged chemotherapy can also affect the endocrine output of reproductive hormones
critically necessary for maintaining healthy bone metabolism (10, 11).
Metastasis to the bone occurs in 70% of advanced breast, lung, kidney, thyroid and prostate cancer,
whereas patients with gastrointestinal cancers suffer from this form of metastasis in only 20% of
cases. Metastasis to the bone can present itself as either lytic, blastic or as mixed lesions (12). In
osteolytic bone lesions, bone resorption exceeds the rate of bone formation, whereas in osteoblastic
lesions the opposite is true. In both cases, a fragile bone structure is produced. Bone metastases
form breast cancer have been described as prototypic osteolytic lesions, whereas bone metastases
from prostate cancer as osteoblastic metastases. Histologically, however, accelerated osteolytic and
osteoblastic pathological processes can coexist in the same lesion, irrespective of the radiological
appearance (13).
Various biological factors endorse the bone as a common site of cancer metastasis. Besides a
favorable high blood flow to the red bone marrow, adhesive factors in the bone marrow stroma and
the special environment within the hematopoetic stem cell niche allow tumor cells to take up
residency and dormancy, thereby evading possible effects of systemic therapy (14).
About half the patients with these lesions suffer skeletal complications like pathological fractions,
spinal cord compression and eminent pain requiring radiation therapy or surgery. These four
complications are referred to as skeletal-related events (SRE) and confer morbidity and major loss of
quality of life upon patients with metastasis of the bone. Several studies have even shown a
reduction in overall survival (15-17). Pathological fractures and the necessity of radiation therapy are
the most common SREs, emphasizing the extent of bone damage and pain associated with
metastasis to the bone. Such pain-inducing complications further lead to immobility and loss of
functional independence (18). Under-treatment of bone pain occurs in up to 60% of patients with
advanced cancer and constitutes a major cause of psychological distress, manifesting itself in
depression and anxiety (19, 20).

Current management of bone metastases entails a multidisciplinary approach since cancer is an

expression of a systemic disease. Therefore, integrating various disciplines like orthopedic surgery,
radiation oncology and medical oncology into the big picture of an individual case can cause some
friction. The best course of action is not always straight forward since each specialty might look at
the problem at hand from a different angle. The best way to unite these different angles and views is
often through guidelines and algorithms, which can yield a foundation for decision making but can
also be tailored to individual needs, often the case in advanced cancer.

Through implementing evidence-based diagnostics and interventions the striving for improvement
in survival and prevention of SREs has the best chance to succeed. We, therefore, propose a clinical
algorithm for diagnostics and treatment of bone metastasis and integrate the current management
and research into it.

Previous SectionNext Section

Algorithm I: Presentation and Diagnostics

Metastases of the bone can be asymptomatic and detected incidentally during initial staging, at follow-up examination in
the adjuvant setting or at treatment re-evaluation restaging. However, in 75% of patients, metastatic bone disease presents
with pain, warranting further examination (21). We propose a diagnostic algorithm in Figure 1.
Bones, which must endure constant static force, such as the hips, femurs and vertebral column, become symptomatic early
on, whereas other non-weight bearing bones, such as ribs or skull, may only become symptomatic late in disease due to
pathologic fractures. Common sites of bone metastasis are the proximal femurs, pelvis, spine, ribs and skull. Rarely, acral
metastasis to the hands and feet occur, mostly associated with lung cancer (22, 23).
Besides pain and pathological fractures, hypercalcaemia is a hallmark of advanced cancer, occurring in only about 10% of
the patients with bone metastasis. However, hypercalcaemia is often of paraneoplastic origin through parathyroid
hormone-related protein without signs of metastasis to the bone (24). Spinal cord compression, through infiltrating
vertebral metastases or fractured osteolytic lesions, can cause debilitating pain and major neurological deficits.
Presentation of localized pain in the context of cancer usually warrants radiological imaging. Due to cost restraints, a plain
radiograph is usually the initial diagnostic step to evaluate bone pain. However, for bone metastasis to be recognized by
this method, osteolytic lesions must be at least 1 cm in diameter with a loss of bone mineral of 25-50% (25). Higher
resolution and additional three-dimensional anatomic information is achieved through computed tomography (CT) scans
and magnetic resonance imaging (MRI) imaging. CT shows its strength in visualizing the cortical integrity and helps
evaluate the extent of structural destruction, outperforming MRI in this aspect. With its high contrast resolution, CT easily
differentiates between osteolytic lesions, sclerotic lesions and soft tissue. This virtue is particularly useful, when localizing
lesions for biopsy (26).
With MRI very small skeletal metastasis can be detected. MRI is favored for detection of vertebral metastasis and
evaluating their association with the spinal cord. These advantages and the multi-planar imaging capability make MRI a
helpful imaging tool in preparation for surgical and radiation procedures (27, 28).
For initial staging of cancer disease or in the context of follow-up examinations in disease-free patients, nuclear bone
scintigraphic imaging with Technetium-99 (99mTc) is widely accepted since it evaluates the whole skeletal system and is
relatively inexpensive. 99mTc bone-scan cannot directly detect osteolytic metastasis since it is incorporated into sites with
elevated bone turnover rates and is, hence, a marker of osteoblastic activity (29). Osteolytic metastasis with minimal
osteoblastic bone formation can, thereby, produce false negative bone scans. If hotspots are detected, CT or MRI is needed
to clarify further anatomic detail. In disease-free patients and in the absence of other metastasis in the follow-up
examinations, a biopsy may be necessary to confirm metastatic disease. In addition, patients with oligo/singular bone
metastasis and in the absence of other/visceral metastasis need to be identified with a high sensitivity since potential
curative localized treatment options may be warranted. Novel imaging technologies with projected increased sensitivity
and specificity have not been adequately tested in prospective trials if they offer additional value in terms of impact on
skeletal morbidity and survival through earlier and more reliable detection of metastasis (30, 31).
Previous SectionNext Section
Algorithm II: Treatment of Vertebral Bone Metastases

When cancer metastasizes to the bone, the axial skeleton is preferred. Within the axial skeleton, the vertebral column is
most often affected. In more than 10% of cancer patients, these metastases are symptomatic (32).
When treating metastatic lesions to the bone, a multidisciplinary approach is necessary to gain local control over the
lesions by means of radiation therapy or surgery. We propose, therefore, algorithm II for treatment of vertebral bone
metastasis in Figure 2.
When tumor masses and pathological fractures of the vertebra cause compression of myeloradicular structures (i.e. nerve
roots, spinal cord) with neurological deficits or uncontrollable pain, immediate surgical intervention is warranted. To
provide temporary relief of symptoms related to pressure and edema secondary to tumor mass a therapy with
corticosteroids should be concurrently initiated (33). Different factors must be considered when choosing the
aggressiveness of the surgical intervention. Besides the preoperative neurological condition and the performance status,
the aggressiveness of the primary tumor and the life expectancy of the patient are the determining factors (34). In
advanced cancer diseases, a palliative decompression and stabilization, followed by radiation therapy, can improve the
quality of life. However, if a prolonged overall survival is estimated, due to a very slow growing tumor or a relatively
good prognosis, more aggressive interventions can be justified. Clearly, a sound interdisciplinary communication is
necessary in order to select patients appropriately.
Pain inflicted by vertebral body fractures can also be treated by vertebroplasty or kyphoplasty. Kyphoplasty has been
reported to cause less cement extravasation as the most common complication enabling a superior restoration of vertebral
body height. Both techniques appear to have a comparable effectiveness in achieving pain relief; however, differences in
functional outcome remain unclear (35).
Besides surgery, radiation therapy is an efficacious treatment method for local tumor control and for palliation of painful
bone metastasis. For pain control, high response rates of 85% have been reported with complete pain relief in about half of
the patients. Most responders showed fast symptom relief within the first 2 weeks (36). Radiation therapy promotes
ossification of osteolytic bone metastasis and can numb small nerve endings, thereby relieving pain and increasing
stability of the bone (37). For patients already treated with external-beam irradiation (EBRT), a re-treatment approach with
stereotactic body radiation therapy (SBRT) can be considered. SRBT minimizes radiation doses to the spinal cord by
precise radiation delivery to vertebral metastases, thereby allowing effective retirement in terms of pain and local tumor
control of previously radiated regions with EBRT (38).
If symptomatic metastasis to the bone is diffuse and of osteoblastic nature, therapeutic radioisotopes can be a treatment
choice. 153Samarium and 89strontium deliver a therapeutic dose of beta radiation simultaneously to multiple bone
sites. 223Radium has a strong affinity towards the bone and emits short-ranged high energy α-particles to cells (39). In a
Phase III Trail (ALSYMPCA) with patients with castrate-resistant prostate cancer and bone metastasis only, it proved its
efficacy, compared to best supportive care, by improving overall survival and the quality of life, in addition to reducing
skeletal morbidity. However, the patient population was heterogeneous, including patients who had previously received
docetaxel and patients deemed either unfit or unwilling to receive chemotherapy (40).
Previous SectionNext Section
Algorithm III: Treatment of Non-vertebral Bone Metastasis

The treatment goals and caveats of non-vertebral bone metastasis are similar to the previous said, with palliation of pain
and preservation and restoration of function being the primary focus. We, therefore, propose algorithm II for treatment of
non-vertebral bone metastasis in Figure 3.
Pathological fractures are clearly an indication for surgical intervention with internal fixation even in advanced disease.
An impending fracture of a long bone can warrant in selected patients with advanced disease a prophylactic fixation
followed by postoperative radiation therapy (41). We recommend a prophylactic radiation of asymptomatic non-vertebral
bone metastasis to increase local tumor control. If multiple symptomatic non-vertebral bone metastases are present, a
treatment with therapeutic radioisotopes can be considered.
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Figure 1.

Diagnostic algorithm for bone metastases. *AP, LDH, Hb, leucocytes, thrombocytes, calcium; ** algorithms for vertebral
and non-vertebral bone metastases. CT, computed tomography; Hb, haemoglobin; LDH, lactate dehydrogenase; OP,
surgical treatment; Ox, osteoprotective therapy; PET, positron emission tomography; Px, pain therapy; Rx, radiotherapy;
Tx, cancer treatment; MRI, magnetic resonance imaging.

Besides effective systemic cancer treatments, bone-targeted agents like biphosphonates and the receptor activator of
nuclear factor-kB ligand (RANKL) antibody denosumab have changed the course of metastatic cancer to the bone by
reducing skeletal morbidity (42, 43).
Biphosphonates accumulate in the bone where they decrease bone resorption and increase mineralisation by inhibiting the
osteoclasts and inducing their apoptosis. Possible anti-tumor and anti-angiogenetic effects are still matter of current
research (44). Pamidronate and zoledronic acid have been approved in the US and Europe for the treatment of cancer-
related bone complications. Both biphosphonates have been shown to reduce skeletal morbidity by 30%, lower the
incidence of SREs and delay time to first SRE in patients with metastatic bone disease significantly (45). Zoledronic acid
has shown a greater risk reduction for development of skeletal complications than pamidronate in breast cancer by
multiple event analysis (46). More than half of the patients reported moderate pain improvement, lasting almost 12 weeks.
Besides being an additional treatment approach for pain relief, biphosphonates are part of the standard therapy for
hypercalcaemia (47).
Denosumab is a monoclonal antibody that inhibits osteoclast-mediated bone destruction by binding to RANKL (48).
Denosumab has shown superior efficacy compared to zoledronic acid in breast cancer and castration-resistant prostate
cancer regarding such clinical end-points as time to first SRE, prevention of subsequent SREs and overall risk (49-51).
In order to delay time to first SRE and reduce skeletal morbidity in patients, it is recommended to initiate treatment with
bone-targeted agents as soon as metastases of the bone are diagnosed, regardless if the metastases are symptomatic or not.
This incremental gain in time before first SRE translates into additional quality of life since the consequences of a SRE
can alter the course of the disease. The costs of consecutive treatments for early SREs are by far higher than the costs of
bone-targeted agents preventing or delaying first SREs (52, 53).
Previous SectionNext Section

There has been major progress in reducing skeletal morbidity in CTIBL and management of bone metastases in the last
years. In the advanced cancer setting, treatment of bone metastases aims at palliating pain, maintaining function and
preventing SREs. The development of new bone-targeted agents has significantly reduced skeletal morbidity and increased
quality of life for patients with metastatic disease involving the bone. It is recommended to apply these drugs early on at
diagnosis of bone metastases and not to wait until symptoms arise.
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Figure 2.

Treatment of vertebral bone metastases. OP, Surgical treatment; Ox, osteoprotective therapy; Px, pain therapy; Rx,
radiotherapy; Tx, cancer treatment; Rx/RN, radiotherapy and/or radionuclide therapy. Osteoprotective therapy:
denosumab or bisphosphonates (as approval), calcium and vitamin D supplementation (as prescribing information).

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Figure 3.

Treatment of non-vertebral bone metastases. OP, Surgical treatment; Ox, osteoprotective therapy; Px, pain therapy; Rx,
radiotherapy; Tx, cancer treatment; Rx/RN, radiotherapy and/or radionuclide therapy. Osteoprotective therapy:
denosumab or bisphosphonates (as approval), calcium and vitamin D supplementation (as prescribing information).

Specific local treatment modalities for bone metastasis have to be incorporated into comprehensive treatment approaches
reflecting the systemic nature of metastatic disease. Treatment algorithms can promote such integration of various
disciplines like orthopedic surgery, radiation oncology and medical oncology, in pursuit of tailoring optimal treatment
strategies to individual patient need.

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 This article is freely accessible online.

 Conflicts of Interest
Dr. Jehn has received consulting and speaker fees from Amgen and Merck. Prof. Diel has received consulting
and speaker fees from Amgen, Medtronic, Riemser and Teva. Dr. Overkamp has received consulting and
speaker fees from Amgen. Dr. Schaefer has received consulting and speaker fees from Amgen. Prof. Kurth has
received consulting and speaker fees from Amgen, Roche and Implantcast. Prof. Miller has received consulting
and speaker fees from Amgen and Novartis. Prof. Lüftner has received consulting and speaker fees from
 Received March 15, 2016.
 Revision received April 22, 2016.
 Accepted April 27, 2016.
 Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights
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