Cancer Treatment Reviews 61 (2017) 23–34

Contents lists available at ScienceDirect

Cancer Treatment Reviews

journal homepage: www.elsevierhealth.com/journals/ctrv

General and Supportive Care

Early identification and intervention matters: A comprehensive review

of current evidence and recommendations for the monitoring of bone
health in patients with cancer
Thomas Brodowicz a, Peyman Hadji b,c, Daniela Niepel d, Ingo Diel e,⇑
a
Department of Medicine I and Comprehensive Cancer Center, Clinical Division of Oncology, Medical University of Vienna, General Hospital, Währinger Gürtel 18–20,
1090 Vienna, Austria
b
Department of Bone Oncology, Endocrinology and Reproductive Medicine, Northwest Hospital, Steinbacher Hohl 2–26, 60488 Frankfurt, Germany
c
Philipps-University of Marburg, Biegenstraße 10, 35037 Marburg, Germany
d
Amgen (GmbH) Europe, Dammstrasse 23, 6300 Zug, Switzerland
e
Center for Comprehensive Gynecology, Augustaanlage 7–11, 68165 Mannheim, Germany

a r t i c l e i n f o a b s t r a c t

Article history: Bone metastases are common in patients with advanced solid tumors, and many individuals experience
Received 16 June 2017 debilitating skeletal-related events (SREs; e.g. pathologic fracture, hypercalcemia, radiotherapy or sur-
Received in revised form 26 September gery to bone, and spinal cord compression). These events substantially affect disease outcomes, including
2017
survival and quality of life, and healthcare systems. Plain radiography is the most widely used imaging
Accepted 27 September 2017
modality for the detection of bone metastases; skeletal scintigraphy, computed tomography, positron
emission tomography and magnetic resonance imaging offer greater sensitivity but their use in routine
practice is restricted by high costs and limited availability. Biomarkers of bone turnover may also have
Keywords:
Skeletal-related events
a role in the early detection of bone metastases and can provide valuable prognostic information on dis-
Bone metastases ease progression. SREs can be delayed or prevented using agents such as the receptor activator of nuclear
Advanced cancer factor kappa B ligand (RANKL) inhibitor, denosumab, and bisphosphonates. Painful bone metastases can
Denosumab be treated with radiofrequency ablation, radiotherapy, or radionuclides such as radium-223 dichloride,
Bisphosphonates which has been shown to delay the onset of SREs in men with castration-resistant prostate cancer.
Imaging Close monitoring of bone health in patients with advanced cancer may lead to early identification of indi-
viduals with bone metastases who could benefit from early intervention to prevent SREs. This review
examines current guideline recommendations for assessing and monitoring bone health in patients with
advanced cancer, use of biomarkers and treatment of patients with bone metastases. The emerging evi-
dence for the potential survival benefit conferred by early intervention with denosumab and bisphospho-
nates is also discussed, together with best practice recommendations.
Ó 2017 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction pathologic fracture, spinal cord compression and hypercalcemia,

Bone metastases are common in patients with advanced solid
tumors [1]. Cancers particularly associated with bone metastases
include those of the prostate and breast (65–75% of patients) [1],
and those affecting the lung (30–40%) [1] and kidney (20–32%)
[1,2]. A substantial proportion of patients with advanced cancer
and bone metastases will develop skeletal complications known
collectively as skeletal-related events (SREs); these include
⇑ Corresponding author.
E-mail addresses: thomas.brodowicz@meduniwien.ac.at (T. Brodowicz), Hadji.
Peyman@khnw.de (P. Hadji), dniepel@amgen.com (D. Niepel), diel@cgg-mannheim.
de (I. Diel).
as well as radiation or surgery to bone, which are surrogate mark-
ers for skeletal pain and fractures [3]. On average, patients with
untreated bone metastases experience an SRE every 3–6 months
[3], placing a considerable burden on both patients and healthcare
systems [4]. A pooled analysis of data from phase 3 trials found
that moderate/severe pain and strong opioid analgesic use
generally increased in the 6 months preceding an SRE and
remained elevated once the SRE had occurred [5]; pain interfered
with daily living and reduced emotional wellbeing [5]. Further-
more, SREs have been associated with decreased survival [6,7].
Early detection of bone metastases is therefore important to enable
optimal management of patients with bone complications
secondary to cancer.

https://doi.org/10.1016/j.ctrv.2017.09.008
0305-7372/Ó 2017 The Author(s). Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
24 T. Brodowicz et al. / Cancer Treatment Reviews 61 (2017) 23–34
The risk of SREs can be reduced through the use of agents such
as the receptor activator of nuclear factor kappa B (RANK) ligand
(RANKL) inhibitor denosumab (120 mg administered by subcuta-
neous injection every 4 weeks) [8] and bisphosphonates, such as
zoledronic acid (4 mg administered by intravenous infusion every
3–4 weeks) [9]. Pamidronate, ibandronate and clodronate are also
indicated for the prevention of SREs but only for patients with
breast cancer (pamidronate and clodronate are also indicated for
patients with multiple myeloma) [10–12]. Studies have shown that
tumor-specific androgen pathway inhibitors, such as abiraterone
acetate and enzalutamide, also have beneficial effects on bone in
patients with prostate cancer, although this effect is likely to be
due to their role in controlling the underlying disease rather than
a direct effect on bone [13–15]. However, some patients in these
studies received concomitant bisphosphonates. In addition,
radium-223 dichloride (radium-223) has been shown to improve
overall survival (OS) significantly compared with placebo in men
with castration-resistant prostate cancer and bone metastases
[16].
Early identification of patients with bone metastases is critical if
the treatment options are to be best used to shift the balance from
palliative treatment towards prevention of SREs, thus maintaining
patients’ quality of life. However, numerous factors hinder the
detection of bone metastases in patients with advanced cancer,
including a lack of established screening programs and differences
across patient groups in terms of who seeks medical advice. For
example, men are less likely than women to visit their doctor if
they experience pain [17], which may delay the identification of
symptomatic bone metastases in these patients. With the excep-
tion of breast cancer, general screening for bone metastases for
all patients with solid tumors is not recommended (Table 1). For
example, bone imaging is recommended in patients with non-
small-cell lung cancer (NSCLC) or renal cell carcinoma only if
symptoms suggest the presence of bone metastases [18,19]. In con-
trast, it is recommended that all patients with locally advanced
breast cancer undergo bone imaging, regardless of whether symp-
toms of bone metastases are present [20,21]. The European School
of Oncology (ESO)–European Society for Medical Oncology (ESMO)
joint guidelines for advanced breast cancer recommend bone
imaging as part of a full staging workup for patients with advanced
breast cancer, preferably with computed tomography (CT) or posi-
tron emission tomography (PET) coupled with CT (PET/CT) [20].
The guidelines also recommend that patients are managed by a
multidisciplinary team that includes imaging experts [20].
In the case of prostate cancer, European guidelines recommend
that only patients with intermediate- or high-risk disease should
be assessed using advanced imaging techniques [22,23]. The risk
of bone metastases in these patients may be assessed on the basis
of prostate-specific antigen (PSA) level, disease stage and Gleason
score (all at diagnosis) [24]. Guidance from the European Associa-
tion of Urology (EAU) and ESMO defines the following categories of
disease risk: intermediate risk – PSA level 10–20 ng/mL or Gleason
score of 7 or stage cT2b disease; high risk – PSA level greater
than 20 ng/mL or Gleason score of more than 7 or stage cT2c dis-
ease or higher [22,23].
Many imaging techniques are available for the detection of
bone metastases, although cost, availability and expertise may vary
across regions, meaning that patients may not have access to reg-
ular highly sensitive screening. New technologies for the detection
of bone metastases are being developed, such as biomarkers of
bone turnover, but these are not yet recommended in clinical prac-
tice. In this review, we discuss imaging and other techniques for
the early identification of bone metastases, and recommendations
for the early treatment of bone metastases immediately following
diagnosis.
Imaging modalities and assessment of bone metastases
The different imaging methods have advantages and disadvan-
tages in clinical practice (Table 2) [25–28]. Plain radiography
detects increased blood flow and reactive bone formation at the
site of metastases but has low sensitivity and specificity. Bone
scintigraphy is more sensitive than plain radiography for detecting
skeletal pathology but has low specificity [29]. These techniques
are relatively inexpensive and are available at most hospitals;
however, the low sensitivity and specificity necessitate confirma-
tion using other imaging modalities in patients with equivocal
findings of bone metastases or a small number of hot spots [27].
Magnetic resonance imaging (MRI) is more sensitive than bone
scintigraphy [28] and is the preferred method for early detection
of spinal cord metastases. CT can readily distinguish osteolytic,
sclerotic and soft tissue lesions, and is therefore useful during
localization for biopsy and to detect bone metastases that extend
into soft tissue [27]. Given the strengths and weaknesses of indi-
vidual imaging modalities, there is increasing interest in hybrid
techniques such as single-photon emission CT/CT, PET/CT and
PET/MRI, which combine anatomical and functional information.
It must be noted, however, that hybrid methods involving CT
increase a patient’s exposure to radiation [28]; the risk–benefit
profile should therefore be considered for each patient.
Imaging is usually recommended by European guidelines only
as part of disease staging, and only if there are signs or symptoms
of bone metastases. Bone scintigraphy is the preferred method for
detecting bone metastases (Table 1 and Fig. 1) [18–23] and recom-
mendations for use of other imaging techniques vary among guide-
lines. PET is recommended as an alternative to bone scintigraphy in
some guidelines [19,20,23] whereas other guidelines suggest that
it should be used only if bone scintigraphy is inconclusive [21] or
that it should not be used in routine practice [18,22]. MRI and CT
are recommended for clinical staging in patients with high- or
intermediate-risk prostate cancer [22,23], and PET/CT is recom-
mended for screening for bone metastases in patients with
advanced NSCLC or breast cancer [19,20]. PET/CT may also be used
in place of CT and bone scintigraphy in some patients with primary
breast cancer (those with large tumors, aggressive biology, and
signs or symptoms of metastases) [21]. The guidelines for renal cell
carcinoma recommend bone scintigraphy only in patients with
suspected bone metastases, and advanced imaging techniques
such as MRI or CT should be used only during staging [18]. Bio-
chemical methods for detecting bone metastases are mentioned
in the ESMO clinical practice guidelines for metastatic NSCLC,
although the precise tests are not specified [19]. The only other
guideline that recommends biochemical tests for metastases is
the EAU guideline on prostate cancer, which lists bone-specific
alkaline phosphatase (B-ALP) and PSA as indicators for bone metas-
tases [22].
In line with the recommendations in European guidelines, ran-
domized phase 3 trials in patients with breast or prostate cancer
generally used bone scintigraphy and CT/MRI to identify bone
metastases and SREs (spinal cord compression and pathologic frac-
ture), although other methods, such as radiographic bone survey or
clinical assessment of symptomatic SREs, have occasionally been
used. Bone turnover markers were assessed in only five of the iden-
tified phase 3 clinical trials (Table 3) [13–15,30–39].
With regard to follow-up, the guidelines differ in their recom-
mendations on how often tumors should be re-staged and whether
this should include skeletal assessment. There is a lack of guidance
on regular assessment for bone metastases. The EAU recommends
that, for patients with prostate cancer who have received treat-
ment with curative intent, PSA levels should be assessed 3, 6 and
12 months after treatment, then every 6 months for 3 years, and
 T. Brodowicz et al. / Cancer Treatment Reviews 61 (2017) 23–34 25

Table 1
European guideline recommendations for the assessment for bone metastases at diagnosis of different tumor types.

Tumor type Agency Summary of guidance

Prostate EAU [22]  Bone scintigraphy or radiography is recommended during routine disease staging, except in low-risk disease
– Low-risk disease: no routine bone scintigraphy; additional imaging only required if it changes patient management
– Intermediate-risk disease: bone scintigraphy and cross-sectional imaging
– High-risk disease (localized/locally advanced): CT/MRI and bone scintigraphy
 Bone scintigraphy or radiography should be performed in all patients with signs and symptoms of bone metastases
 PET should not be used for upfront staging
 18F-PET, PET/CT or diffusion-weighted whole-body or axial MRI are more sensitive than bone scintigraphy and targeted radiogra-
phy, but bone scintigraphy is preferred owing to lower cost and greater availability
 Elevated B-ALP and PSA are indicators of bone metastases
Prostate ESMO [23]  Imaging techniques recommended for patients with intermediate- or high-risk disease:
– Bone scintigraphy and thoraco-abdominal CT
– Whole-body MRI
– Choline PET/CT
Breast ESMO [21]  Asymptomatic distant metastases are rare in patients with primary breast cancer; tests for metastases are recommended only for
(primary) patients with locally advanced or symptomatic disease
 Bone scintigraphy, CT and abdominal ultrasonography can be considered for patients with:
– Clinically positive axillary nodes
– Tumors  5 cm along longest axis
– Aggressive tumor biology
– Clinical signs or symptoms, or laboratory values suggesting the presence of metastases
 Dual imaging methods combining functional and anatomical information, such as 18FDG–PET/CT, may be used when conventional
methods are inconclusive
 PET/CT should not be used for staging loco-regional disease but can be used to stage high-risk, locally advanced or inflammatory
disease because these patients are at a high risk of metastases
Breast ESO–ESMO  Patients with locally advanced breast cancer have a significant risk of metastatic disease; a full staging workup, including bone
(advanced) [20] imaging, is highly recommended
 Thoracic and abdominal CT are preferred to thoracic radiography
 PET/CT, if available, may be used instead of (not in addition to) CT and bone scintigraphy
 Given the high risk of concomitant distant metastases, patients with chest wall or regional (nodal) recurrence should undergo full
re-staging, including bone imaging
NSCLC ESMO [19]  Standard staging includes routine bone biochemistry tests (not specified) and CT of the chest and upper abdomen
(metastatic)  If bone metastases are suspected, recommended bone imaging techniques are:
– PET ± CT
– Bone scintigraphy
– 18FDG–PET
 MRI can be used to document localized bone metastases
 PET/CT and 18FDG–PET are more sensitive than bone scintigraphy
Renal cell ESMO [18]  Contrast-enhanced chest, abdominal and pelvic CT is mandatory
carcinoma  Bone scintigraphy is not recommended unless indicated by signs and symptoms of bone metastases
 Bone scan is not recommended unless indicated by clinical or laboratory signs or symptoms
 18FDG–PET is not recommended for diagnosis or staging

Abbreviations: B-ALP, bone-specific alkaline phosphatase; CT, computed tomography; EAU, European Association of Urology; ESMO, European Society for Medical Oncology;
ESO, European School of Oncology; F, fluorine; FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; NSCLC, non-small-cell lung cancer; PET, positron emission
tomography; PSA, prostate-specific antigen.

annually thereafter [22]. Routine bone imaging is not recom-
mended if there are no signs of biochemical relapse, except in indi-
viduals with bone pain or other symptoms of disease progression,
for whom re-staging should be considered [22]. The ESMO clinical
practice guidelines for prostate cancer suggest that regular imag-
ing should be undertaken to monitor response to treatment,
although conventional imaging such as CT and bone scintigraphy
are not suitable for assessing response or progression in patients
with metastatic bone disease, and alternative techniques should
be used, such as whole-body MRI [23]. Bone health is an under-
recognized issue in men, who can also experience a steady loss
of bone mineral density (BMD) with aging, which increases their
risk of pathologic fracture [40]. Many men receive androgen-
deprivation therapy (ADT) and are therefore at particularly high
risk of pathologic fracture, so should receive regular BMD monitor-
ing [23,40].
Follow-up recommendations for patients with advanced breast
cancer lack clarity. The ESO–ESMO guidelines recommend radio-
logical assessments in patients with persistent and localized pain
due to bone metastases, in order to identify any impending (or
actual) pathologic fracture. In addition, full re-staging (including
bone imaging) is recommended in patients with chest wall or
nodal recurrence [20]. No other recommendations are provided
on the frequency of disease staging or skeletal assessment [20]. A
large proportion of women with breast cancer are aged 50 years
or older [41] and are therefore likely to be peri- or post-
menopausal. This puts them at risk of low BMD, which is exacer-
bated by the endocrine therapies often used to treat breast
cancer (e.g. aromatase inhibitors and gonadotropin-releasing hor-
mone analogs), and they are therefore vulnerable to pathologic
fracture [40,42]. A position paper on the treatment of elderly
patients with cancer from the International Society of Geriatric
Oncology recommends that patients with breast cancer have their
BMD monitored every 1–2 years [40]. For patients receiving endo-
crine treatment for breast cancer, the ESMO clinical practice guide-
lines recommend regular follow-up: every 3–4 months for the first
2 years following treatment, then every 6 months in years 3–5, and
annually thereafter [21]. It is important to note that fracture risk is
high even in individuals with normal BMD. In the placebo arm of
the ABCSG–18 (‘Adjuvant denosumab in breast cancer’) trial in
postmenopausal women with early stage breast cancer, the inci-
dence of pathologic fracture was 10% in individuals with normal
BMD and 11% in those with low BMD [43].
For patients who have undergone surgery for localized renal cell
carcinoma, CT assessment every 3–6 months for 2 years is recom-
mended in those with high-risk disease, and annually for those
with low-risk disease [18]. The ESMO clinical practice guidelines
for metastatic NSCLC recommend follow-up every 6–12 weeks
after first-line treatment but do not state what this should
entail [19].
26 T. Brodowicz et al. / Cancer Treatment Reviews 61 (2017) 23–34

Table 2
Advantages and disadvantages of imaging modalities for the detection of bone metastases [25–28].

Imaging modality Advantages Disadvantages

Plain radiography  Widely available and inexpensive  Insensitive for detection of metastases
Radionuclide bone  Relatively inexpensive  Low specificity for bone metastases
scintigraphy  Evaluates whole skeletal system  Cannot directly detect osteolytic metastases
 Provides information on osteoblastic activity and skeletal vascularity
 More sensitive than plain radiography
CT  Higher resolution than plain radiography and provides three-dimensional  Low specificity for bone metastases
anatomical information
 Modality of choice for evaluating cortical bone (e.g. the ribs)
 Excellent soft tissue and contrast resolution; soft tissue extension of bone
metastases is easily visualized
 Useful to localize lesions for biopsy
MRI  Higher resolution than plain radiography and additional three-dimensional  Not suitable for evaluating cortical bone
anatomical information  Cost-effectiveness of newer MRI modalities (e.g. whole-
 Highly sensitive (95%) for detection of bone metastases body or axial MRI) unclear
 Multi-planar images permit imaging of the entire spine in the sagittal plane
 Excellent for demonstrating bone marrow infiltration
 Preferred imaging method for spinal cord compression and subsequent plan-
ning of surgery or radiation therapy
 Superior to 11C-choline PET/CT for detecting bone metastases
SPECT  Superior sensitivity and specificity to bone scintigraphy  Cannot generate absolute quantification values
 Axial slices provide better localization of radionuclide uptake than bone  Whole-body scanning not possible in a reasonable time
scintigraphy frame
 Less widely available and more costly than other imag-
ing modalities
18
FDG–PET  Superior sensitivity to bone scintigraphy  Role in routine practice unclear
 Allows visualization of functional aspects  Less widely available and more costly than other imag-
ing modalities
11
C-choline PET/CT  Higher specificity than bone scintigraphy and MRI, with fewer indeterminate  May not provide greater sensitivity than bone
lesions scintigraphy
 Cost-effectiveness unclear
 Less widely available and more costly than other imag-
ing modalities

Abbreviations: C, carbon; CT, computed tomography; FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon
emission computed tomography.

Clinical practice patterns may vary between countries as a con-
sequence of differing national guideline recommendations and
other factors, such as local institutional practices. A patient chart
survey in five European countries showed that individuals in Ger-
many were more likely to have asymptomatic bone lesions
detected during routine imaging than were patients in the other
countries [44]. There is a need for clear and consistent guidelines
regarding regular assessment of bone metastases in individuals
with cancer. Current guidelines generally do not recommend rou-
tine bone surveys in asymptomatic patients. However, recent
real-world evidence from patients with advanced breast cancer
has shown that over half (58%) of bone metastases were identified
while they were asymptomatic [45]. Data from another real-world
study indicate that only 38% of patients with advanced solid
tumors and bone metastases had their bone metastases identified
during routine staging [44]. Early detection of bone metastases
alone does not improve survival [46]; it is early intervention that
results in better outcomes for patients [47,48].
Biomarkers of bone health and tumor-specific factors
Emerging evidence indicates that bone markers measured in
urine or plasma could be used to aid the early identification of
patients with asymptomatic bone metastases and those at risk of
bone lesion progression [49]. Several markers of bone turnover
have been identified as potential predictive biomarkers for bone
metastases, and the laboratory tests for these markers are gener-
ally inexpensive [50]. In the United Kingdom, for example, the cost
of measuring bone turnover markers in patients with osteoporosis
is approximately one-third of the cost of a dual-energy X-ray
absorptiometry scan [51]. A consensus paper from the Belgian
Bone Club recommends that bone turnover markers are used as a
cost-conscious option to monitor bone dynamics [52].
Several factors must be considered when using biomarkers to
aid the identification of bone metastases and those patients at risk
of SREs. It is essential that biomarker assessments are performed
consistently at the same time of day for each individual, because
serum levels of bone markers vary according to circadian rhythms,
with levels generally peaking in the morning [53]. Endocrine treat-
ments for breast cancer [54] and alterations in bone turnover
resulting from the menopause [55] can affect levels of bone
biomarkers in the absence of bone metastases. Similarly, ADT for
the treatment of patients with prostate cancer can also result in
aberrations in bone biomarkers in metastases-free individuals
[56]. Additionally, it has been shown that, in patients with solid
tumors, denosumab and bisphosphonates may alter the levels of
certain biomarkers despite the presence of bone metastases [50];
therefore, care should be taken when interpreting such results.
One such bone marker is alkaline phosphatase (ALP), a
membrane-associated enzyme found at high concentrations in
osteoblasts as well as in the liver, intestines and placenta. It can
be used to assess the presence of bone metastases, particularly in
patients with prostate cancer [57]. Several isoforms of ALP are
secreted by various organs into the blood, and B-ALP is a sensitive
predictive marker of bone turnover and bone metastases in
patients with advanced solid tumors [58]. Both total ALP and B-
ALP are significantly elevated in patients with prostate cancer
and bone metastases compared with patients without bone metas-
tases and healthy controls [59], and predict poor prognosis in
patients with bone metastases secondary to solid tumors [60,61].
An analysis of data from three identically designed blinded phase 3
trials that compared denosumab and zoledronic acid showed that
high B-ALP levels were associated with an increased risk of disease
 T. Brodowicz et al. / Cancer Treatment Reviews 61 (2017) 23–34 27

Newly diagnosed Locally advanced Advanced

Recommended imaging modalities • High risk:b bone • Radiography or bone

• Low risk: bone scintigraphy. scintigraphy + CT/MRI scintigraphy for all patients
Additional imaging recommended only • Upfront staging PET with signs or symptoms of
Prostate cancer

if the results will impact on patient should not be used bone metastases
management • Elevated B-ALP and PSA • Elevated B-ALP and PSA are
• Intermediate risk:a bone scintigraphy are indicators of bone indicators of bone metastases
+ cross-sectional imaging metastases • Patient education on signs
• BMD assessment for patients • BMD assessment for and symptoms of SREs
receiving ADT patients receiving ADT
Other assessments Denosumabc
• 18-fluoride PET Low-dose Zoledronic acidc
• PET/CT bisphosphonates Ra-223
• Diffusion-weighted MRI Low-dose denosumab
(whole body or axial)

Recommended imaging modalities • Bone scintigraphy NA

• Bone scintigraphy recommended • CT
Breast cancer (primary)d

only if disease is locally advanced • Abdominal ultrasound

or there are signs or symptoms of • Dual imaging
bone metastases (e.g. FDG–PET/CT)
• FDG–PET/CT for high-risk disease when conventional
Other assessments imaging is inconclusive
• Physical examination and in high-risk disease

Low-dose Low-dose
bisphosphonates bisphosphonates
for patients with Low-dose denosumab
low-estrogen status

NA • Bone scintigraphy • Radiological assessment

Breast cancer (advanced)

• CT for patients with persistent

• PET/CT or localized pain
• Radiological assessment • BMD assessment for
for patients with persistent patients receiving AIs
or localized pain • Full re-staging for patients
• BMD assessment for with chest wall or nodal
patients receiving AIs recurrence

Low-dose Denosumab
bisphosphonates Bisphosphonates
Low-dose denosumab

Recommended imaging modalities • None For suspected bone

• CT (chest and upper abdomen) metastases:
• Bone scintigraphy • PET ± CT and
bone scintigraphy
NSCLC

Other assessments • FDG–PET

• Routine bone biochemical tests • MRI for localized
(not specified) bone metastases

Denosumab
Zoledronic acid
Renal cell carcinoma

Recommended imaging modalities • CT to investigate • CT to investigate

• CT of chest, abdomen and pelvis distant metastases distant metastases
• Bone scintigraphy not recommended • MRI may also be used • MRI may also be used
unless there are signs or symptoms
of bone metastases Denosumabe
• FDG–PET is not recommended for Zoledronic acid
routine diagnosis/staging

Fig. 1. European guideline recommendations for the assessment of bone metastases and use of bone-protective agents at different disease stages [18–21,29]. aPSA level 10–
20 ng/mL or Gleason score 7 or stage cT2b or higher. bPSA level >20 ng/mL or Gleason score >7, or locally advanced disease with any PSA level and stage cT3–4 or lymph-
node-positive disease. c Calcium and vitamin D supplementation recommended. dAsymptomatic distant metastases are rare in primary breast cancer. eApproved but not
recommended by the guideline. Abbreviations: ADT, androgen-deprivation therapy; AI, aromatase inhibitor; B-ALP, bone-specific alkaline phosphatase; BMD, bone mineral
density; CT, computed tomography; FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; NA, not applicable; NSCLC, non-small-cell lung cancer; PET, positron
emission tomography; PSA, prostate-specific antigen; Ra-223, radium-223 dichloride; SRE, skeletal-related event.
28 T. Brodowicz et al. / Cancer Treatment Reviews 61 (2017) 23–34

Table 3
Methodologies used in phase 3 trials to identify bone metastases and SREs in patients with breast or prostate cancer.

Trial name and Tumor type Treatment vs comparator Imaging methodology used Biomarker measurements taken
author
TRAPEZE; James et al. Prostate Docetaxel vs docetaxel plus  ‘Clinical assessment’ of symptomatic SREs  None
[34] strontium-89 or zoledronic acid,  No protocol-mandated radiological assessment
or both
PREVAIL; Loriot et al. Prostate Enzalutamide vs placebo  Assessment of SREs not specified  None
[35]
AFFIRM; Scher et al. Prostate Enzalutamide vs placebo  CT or MRI of soft tissue to assess progression  None
[14] and Fizazi  Radionuclide bone scan to assess bone lesions and
et al. [15] metastases
ALSYMPCA; Sartor Prostate Radium-223 vs placebo  Bone metastases confirmed using bone scintigraphy  None
et al. [37] and CT
 ‘Clinical assessment’ of symptomatic SREs
CALGB 90202 Prostate Zoledronic acid vs placebo  Bone metastases confirmed by bone scintigraphy,  None
(Alliance); Smith MRI, CT or plain radiography
et al. [38]  ‘Clinical assessment’ of symptomatic SREs and new
bone metastases (radiographic assessment was not
required)
COU-AA-301; Prostate Abiraterone acetate and  Bone scintigraphy scheduled throughout the study  None
Logothetis et al. prednisone vs placebo and  Radiographic assessment for pathologic fracture
[13] prednisone and spinal cord compression
Fizazi et al. [32] Prostate Denosumab vs zoledronic acid  Radiographic evidence of bone metastases required  Urinary type 1 collagen NTx
 Skeletal survey (including radiographic assess-  B-ALP
ment) to identify SREs and new bone metastases
Stopeck et al. [39] Breast Denosumab vs zoledronic acid  Bone metastases confirmed by radiography, CT or  Urinary type 1 collagen NTx
MRI  B-ALP
 Pathologic fracture assessed by radiography, CT or
MRI
ZICE; Barrett-Lee Breast Zoledronic acid vs ibandronate  Radiographic evidence of 1 bone metastasis  None
et al. [31] required
 Plain radiography to identify SREs
ZOOM; Amadori et al. Breast Zoledronic acid Q12W vs  Radiographic evidence of 1 bone metastasis  Type 1 collagen NTx
[30] zoledronic acid Q4W required
 Radiography or CT to identify pathologic fractures
BOLERO-2; Gnant Breast Everolimus vs placebo  Bone scintigraphy or skeletal survey to identify  Serum B-ALP
et al. [33] bone metastases  Serum P1NP
 Patients with bone metastases also assessed by  Serum type 1 collagen CTx
radiography, CT or MRI
Rosen et al. [36] Breast or Zoledronic acid vs pamidronate  Bone metastases confirmed by bone scintigraphya  Serum B-ALP and PTH
multiple and bone survey  Urinary pyridinoline,
myeloma  SREs identified by ‘clinical assessment’ deoxypyridinoline and type
1 collagen NTx

Abbreviations: B-ALP, bone-specific alkaline phosphatase; CT, computed tomography; CTx, C-terminal telopeptides; MRI, magnetic resonance imaging; NSCLC, non-small-cell
lung cancer; NTx, N-terminal telopeptides; P1NP, procollagen type 1 N-terminal propeptides; PTH, parathyroid hormone; Q, every; SRE, skeletal-related event; W, weeks.
a
In patients with breast cancer only.

progression at the primary site and in bone, as well as reduced OS
in both treatment arms [60]. In patients with prostate cancer and
bone metastases receiving zoledronic acid, early increases in serum
B-ALP levels have been shown to predict short SRE-free survival
and reduced OS [62]. Multivariate analysis of data from patients
with prostate cancer enrolled in a phase 3 trial identified ALP, B-
ALP and PSA as significant predictors of OS [63].
The predominant protein in bone is type 1 collagen, and numer-
ous studies have shown that markers of collagen breakdown are
correlated with the presence of bone metastases [64]. Serum type
1 collagen C-terminal telopeptides (CTx), B-ALP, osteocalcin and
procollagen type 1 N-terminal propeptides (P1NP) have been iden-
tified as sensitive predictors of bone metastases in patients with
advanced tumors [58]. Patients with bone metastases and high
levels of N-terminal telopeptides (NTx) have a significantly
increased relative risk of SREs, disease progression and death com-
pared with patients with low levels of NTx [65,66]. Other collagen
markers that may have diagnostic value include serum procollagen
type 1 C-terminal propeptides and type 1 collagen degradation
products; both have been found to be significantly elevated in
patients with prostate cancer and bone metastases compared with
those without bone metastases and healthy controls [59,67]. Sim-
ilarly, in patients with NSCLC, those with bone metastases had
higher levels of serum type 1 collagen CTx and P1NP than those
without bone metastases [68]. Early increases in levels of serum
type 1 collagen CTx after starting zoledronic acid treatment have
been shown to predict short SRE-free survival and reduced OS in
patients with prostate cancer and bone metastases [62]. P1NP
alone [69] and the combination of P1NP, B-ALP and tartrate-
resistant acid phosphatase 5b, have been shown to be significant
predictors of the development of bone metastases in patients with
early breast cancer [70].
The use of bone markers to guide treatment decisions has been
investigated in the BISMARK study (‘Cost-effective use of BISphos-
phonates in metastatic bone disease – a comparison of bone MAR-
Ker directed zoledronic acid therapy to a standard schedule’). In
this study, patients with bone metastases secondary to breast can-
cer received standard treatment with zoledronic acid (one infusion
every 3–4 weeks) or marker-directed treatment, in which the fre-
quency of treatment depended on levels of urinary type 1 collagen
NTx [71]. Unfortunately, the study was terminated early because of
slow recruitment; this meant that non-inferiority of marker-
directed treatment compared with standard treatment could not
be demonstrated. The authors suggested that basing zoledronic
acid dosing on levels of urinary type I collagen NTx alone was likely
to result in suboptimal treatment [71].
RANKL is a key mediator of osteoclast function and survival, and
has been linked to bone metastases. Elevated levels of RANKL have
 T. Brodowicz et al. / Cancer Treatment Reviews 61 (2017) 23–34 29

been found in biopsies from aggressive prostate, lung and kidney
tumors [72–74]. Furthermore, elevated serum RANKL has been
shown to be a significant risk factor for biochemical recurrence
in patients undergoing radical prostatectomy for localized prostate
cancer [75], and RANK-positive breast tumors have been associ-
ated with an increased risk of bone metastases [76]. Similar links
between high levels of RANK and reduced disease-free survival
and OS in patients with breast cancer were reported in the phase 3
GeparTrio study, even though high RANK levels were associated
with increased sensitivity to chemotherapy [77]. Breast tumors
that are positive for the chemokine receptor type 4, alone or in
combination with RANK, are more likely to metastasize to bone
than are tumors that are negative for these markers [76].
A diagnostic algorithm designed to consolidate current proce-
dures for the detection of bone metastases in practice was pub-
lished in 2016 [27]. Fig. 2 shows a modified version of this
algorithm to reflect potential strategies by which early detection
of bone pathology might be improved. New developments in
biomarkers and tumor-specific factors have the potential to con-
tribute to risk assessment, although further evidence is needed
on their prognostic value. Once established, however, it is possible
Reasons for suspecting
that biomarkers could in future replace, or complement, imaging
modalities as diagnostic tools. Biomarker assessment may be fas-
ter, less invasive and cheaper than imaging, which would reduce
the burden on healthcare systems. These assessments could be
performed more regularly than imaging and could help to identify
patients who may be at risk of developing bone metastases, or to
detect bone metastases at an early stage, before they become
established and symptomatic.
Treatment of patients with bone metastases
Early identification of bone metastases means that treatment
can be initiated to prevent or delay the development of SREs,
which can be debilitating and painful and have a significant impact
on patients’ lives [5,78–80]. SREs are also associated with substan-
tial healthcare resource utilization, including hospitalization and
surgery [81]. Therefore, prevention or delay of SREs will benefit
both patients and healthcare systems. Denosumab and bisphos-
phonates have been widely studied for the prevention of SREs in
patients with advanced cancer. In a long-term follow-up study,
zoledronic acid significantly delayed the median time to first SRE

Tumor- and patient-specific factors

Markers of bone turnover
PC: PSA level, Gleason score
B-ALP; CTx; osteocalcin; P1NP;
bone pathology

BC: lymph node involvement; CTIBL

NTx; P1CP; ICTP; TRACP5b; PC: ADT
tumor size; age at diagnosis;
RANKL; RANK BC: estrogen suppression
tumor subtype

Symptoms (e.g. pain)

Pathological laboratory Acute pain
parametersa
Metastases elsewhere

Bone scan Targeted imaging

(scintigraphy preferred) MRI/CT
Diagnostic measures

DXA
for BMD

+
Oligo/singular PET/CT
bone metastases and/or biopsy

– + +
Hybrid imaging
techniques
Biopsy SPECT/CT; PET/MRI

Follow-up – +
PET/CT

Therapy
Therapy

Therapy Low-dose BTAs;

Surgery; radiotherapy; radioablative therapy; calcium and vitamin D
analgesia; radionuclides; BTAs; cancer therapy supplementation

Positive/negative Action Observation Potential strategy for improved

+/–
result of test identification of bone
pathology

Fig. 2. Diagnostic algorithm for bone pathology in patients with cancer, with potential strategies to improve early diagnosis. aLevels of alkaline phosphatase, lactate
dehydrogenase, hemoglobin, leukocytes, thrombocytes, calcium, etc. Abbreviations: ADT, androgen-deprivation therapy; B-ALP, bone-specific alkaline phosphatase; BC, breast
cancer; BMD, bone mineral density; BTA, bone-targeted agent; CT, computed tomography; CTIBL, cancer treatment-induced bone loss; CTx, C-terminal telopeptides; DXA,
dual-energy X-ray absorptiometry; ICTP, type 1 collagen degradation products; MRI, magnetic resonance imaging; NTx, N-terminal telopeptides; P1CP, procollagen type 1 C-
terminal propeptides; P1NP, procollagen type 1 N-terminal propeptides; PC, prostate cancer; PET, positron emission tomography; PSA, prostate-specific antigen; RANK,
receptor activator of nuclear factor kappa B; RANKL, receptor activator of nuclear factor kappa B ligand; SPECT, single-photon emission computed tomography; TRACP5b,
tartrate-resistant acid phosphatase 5b.
30 T. Brodowicz et al. / Cancer Treatment Reviews 61 (2017) 23–34
compared with placebo (236 vs 155 days; p = 0.009) and reduced
the proportion of patients who experienced an on-study SRE (21
months: 36% vs 46%; p = 0.023) [82]. Zoledronic acid is the bispho-
sphonate that features most prominently in clinical recommenda-
tions. Comparative studies have failed to identify an alternative
bisphosphonate that is more effective in delaying SREs [31,83],
and it is the only bisphosphonate that reduces the risk of SREs in
patients with prostate cancer and bone metastases [84]. In con-
trast, denosumab has shown superiority over zoledronic acid in
three identically designed phase 3 studies involving 5723 patients
with breast cancer, prostate cancer and other advanced solid
tumors: time to first on-study SRE was extended by a median of
8.2 months and the risk of a first on-study SRE was reduced by
17% (p < 0.001) [85].
Once a patient has experienced a SRE, they are at risk of subse-
quent SREs, which impose a further burden on patient quality of
life and put pressure on healthcare resources. Zoledronic acid sig-
nificantly reduces the risk of multiple SREs in patients with
advanced solid tumors and multiple myeloma [82,83]. Denosumab
significantly reduced the risk of multiple SREs in patients with
advanced solid tumors, and was superior to zoledronic acid at pre-
venting first and subsequent SREs in a pooled analysis of the three
phase 3 trials (p < 0.001) [85]. Bone metastases and SREs are also
linked to reduced survival. In a Danish study of 2427 women with
breast cancer, the risk of death in the year following a diagnosis of
bone metastases was double that in patients with localized disease
(hazard ratio [HR] 2.12; 95% confidence interval [CI] 1.71–2.62) [6].
Furthermore, 1–year survival increased with longer bone-
metastases-free intervals (1 to <3-year interval 39.9%; 5-year
interval 52.6%) [6]. SREs have also been shown to be associated
with significantly increased mortality in men with metastatic
castration-resistant prostate cancer (HR 1.67; 95% CI 1.22–2.30;
p = 0.001) [7].
Painful bone metastases can be palliated with radionuclides
(e.g. radium-223) [86], radiofrequency ablation [87], or radiother-
apy [88]; however, preventing or delaying the onset of pain is
preferable to treating pain itself. Tumor-specific treatments can
benefit bone through control of the underlying disease, and the
effects of denosumab, bisphosphonates and radionuclides on bone
have been shown to prevent SREs and delay the onset of pain; early
intervention is therefore important to minimize patient morbidity.
Another analysis of the pooled phase 3 data showed that deno-
sumab significantly delayed the onset of moderate-to-severe pain
by 1.8 months and the time to overall pain interference by 2.6
months (both p < 0.001) in patients with advanced solid tumors
[79]. These effects on pain delay and interference were also
observed in patients with no or mild pain at baseline, indicating
that early treatment is clinically meaningful. In the same analysis,
health-related quality of life was also improved in patients who
received denosumab relative to those who received zoledronic acid
[79].
Evidence is emerging of potential survival benefits with deno-
sumab and bisphosphonates in some patients with bone metas-
tases secondary to solid tumors. In exploratory analyses, patients
with elevated baseline levels of urinary type 1 collagen NTx had
a significantly reduced risk of death if they received zoledronic acid
rather than placebo (risk reduction: 31%; p = 0.0028) [89]. In the
same study, multivariate analyses indicated a survival benefit with
zoledronic acid in patients who had a history of SREs and in those
in whom time since diagnosis was shorter than the median [89]. In
an exploratory analysis of patients with metastatic lung cancer,
denosumab was associated with significantly improved median
OS compared with zoledronic acid (8.9–9.5 vs 7.7–8.0 months; p
= 0.01) [90]. An ongoing open-label, phase 3 trial (SPLENDOUR;
‘Survival improvement in lung cancer induced by denosumab
therapy’; NCT02129699) is investigating the effect on survival of
adding denosumab to first-line standard of care for patients with
advanced NSCLC. Radionuclides may also be valuable in the man-
agement of bone metastases and prevention of SREs, particularly
radium-233, which has been evaluated extensively in men with
prostate cancer, and may also confer a survival benefit [16,91].
However, radium-223 cannot be used in patients with visceral
metastases [92]; therefore, early identification of patients with
metastases only to bone may allow initiation of radium-223 treat-
ment while patients are still eligible to receive it.
While there is strong evidence to support early intervention in
patients with bone metastases, some data suggest that treatment
with bisphosphonates may not benefit all patient populations
equally. Exploratory interaction analyses of data from the PR05
trial of the use of sodium clodronate in men with bone metastases
secondary to prostate cancer suggest that early therapy may be
associated with a greater relative survival benefit in men with
poorer prognostic features, such as raised serum alkaline phos-
phatase and creatinine levels [93]. A raised alkaline phosphatase
level is likely to be associated with increased osteoblastic activity,
and early bisphosphonate treatment may modify osteoclast activa-
tion and bone lysis. In addition, a raised creatinine level may be
associated with decreased bisphosphonate excretion, and rela-
tively greater drug exposure and enhanced biological effect [93].
Moreover, the lack of a statistically significant benefit with early
bisphosphonate therapy on symptomatic bone progression-free
survival in patients with metastases [94] may suggest the involve-
ment of other mechanisms in the development (and survival) of
bone metastases in these patients, such as up-regulation of human
epidermal growth factor 2 and endothelial growth factor receptor,
in response to ADT [95]. Given its distinct mechanism of action and
pharmacology, bisphosphonate data cannot be used to infer
whether denosumab will benefit some patient groups more than
others.
European guidelines provide recommendations for the assess-
ment of bone metastases and use of bone-protective agents at dif-
ferent disease stages (Fig. 1). Some guidelines recommend that
treatment for the prevention of SREs is initiated as soon as bone
metastases have been identified, regardless of whether they are
symptomatic [20,29], whereas others recommend treatment only
for patients at high risk of SREs [23], pointing out that the risk–
benefit ratio should be taken into account when offering patients
denosumab or bisphosphonates [22]. The variation in guideline
recommendations leads to differences in clinical practice, and
many patients who might benefit from these agents are not receiv-
ing them. In a European patient chart survey, almost one-fifth of
patients with bone metastases would never receive bisphospho-
nates, even though most had a moderate-to-high risk of developing
a SRE [44]. Furthermore, bisphosphonate treatment was often
delayed, a common reason being safety concerns [44]. It has been
established that the long-term safety profiles of denosumab and
bisphosphonates are generally good, although a small proportion
of patients may experience osteonecrosis of the jaw (ONJ) [96],
so dental monitoring is required during treatment.
Early intervention may result in longer treatment exposure for
patients and an associated increase in the potential for adverse
events. However, this risk should be minimized and weighed
against the benefits of early intervention, such as preventing SREs
and reducing the burden of SREs on patients and healthcare sys-
tems. While a growing body of evidence suggest potential non-
inferiority between 12- and 4-weekly zoledronic acid regimens
with respect to SREs in patients with bone involvement
[30,97,98], optimal trade-offs must balance the risk of adverse
events against efficacy (as well as considering convenience and
cost), and will be informed and guided by emerging evidence and
patient preferences. Although rare, significant adverse events, such
as ONJ, should continue to be evaluated in clinical studies, and
 T. Brodowicz et al. / Cancer Treatment Reviews 61 (2017) 23–34
steps taken to prevent such complications and to diagnose and
treat them early in clinical practice [99]. It should be noted that,
given their distinct mechanisms of action, the non-inferiority evi-
dence for zoledronic acid cannot be extrapolated to denosumab;
trials evaluating the effect of denosumab administration frequency
on the prevention of symptomatic skeletal events are in progress
[100].
Interest in the adjuvant use of denosumab and bisphosphonates
in patients with non-metastatic cancer (and without cancer
treatment-induced bone loss) is also increasing in light of the
potential survival benefit that these agents may confer. Evidence
from patients with breast cancer suggests that adjuvant bisphos-
phonate therapy may improve survival [101] and other outcomes,
including the prevention of breast cancer recurrence in bone
[101,102], in selected populations, particularly postmenopausal
women. A meta-analysis has suggested that patients receiving
low- or high-dose bisphosphonate regimens (e.g. 6-monthly or
3–4-weekly zoledronic acid) experience similar benefits with
respect to bone recurrence [101]. Furthermore, low-dose zole-
dronic acid improved disease-free survival in patients with early
stage breast cancer receiving adjuvant endocrine therapy [103–
105]. Comparable results have been reported with low-dose deno-
sumab (60 mg every 6 months) [106]. Data on early intervention
with denosumab and bisphosphonates in other tumor types are
limited, but some benefit has been observed in patients with pros-
tate cancer. In a randomized, placebo-controlled phase 3 trial of
1432 men with non-metastatic castration-resistant prostate can-
cer, denosumab significantly improved bone-metastases-free sur-
vival by a median of 4.2 months compared with placebo (HR
0.85; 95% CI 0.73–0.98; p = 0.028) [107]. Median OS was, however,
similar in both treatment groups. Time to first bone metastases
was also significantly delayed in the denosumab group compared
with the placebo group (HR 0.84; 95% CI 0.71–0.98; p = 0.032)
[107]. Further investigations into the adjuvant use of denosumab
and bisphosphonates, and the potential antitumor effects of these
agents, are ongoing.
As with any targeted intervention, the risks associated with
denosumab and bisphosphonates can be minimized by identifying
patients most likely to benefit from early intervention and by lim-
iting exposure as far as possible. With respect to identifying
patients most likely to benefit, understanding which patients are
likely to develop bone metastases will help to inform treatment
decisions and potentially improve outcomes. Unfortunately, there
are currently no algorithms that reliably predict which patients
will develop bone metastases and would therefore benefit most
from the early use of denosumab and bisphosphonates in an adju-
vant setting. However, several general prognostic factors that
increase the risk of developing bone metastases in breast cancer
have been identified, including: tumor subcategory, age at diagno-
sis, histological subtype, grade, lymph node involvement and
tumor size [108,109]. In prostate cancer, PSA levels have been
found to correlate with the presence of bone metastases [110],
and PSA kinetics have been shown to be a useful indicator of bone
metastases during treatment [24]. With respect to limiting expo-
sure, it is currently unclear for how long patients may benefit from
treatment with denosumab and bisphosphonates during their clin-
ical course. It should be noted, however, that the doses of deno-
sumab and bisphosphonates used for the prevention of
osteoporosis and cancer treatment-induced bone loss [43,111]
are considerably lower than those used for the prevention of SREs
in metastatic bone disease [8,9]; and it should be possible to use
lower doses in the adjuvant setting and therefore reduce the risk
of complications such as ONJ.
The balance between adverse event risks and efficacy should
favor the early use of denosumab and bisphosphonates in an adju-
vant setting in patients considered to be at risk of bone metastasis
31
[101,107] or low BMD [43,111]. The prescription of these agents
should be considered in these settings, particularly when the risk
is high. Recently, Cancer Care Ontario and the American Society
of Clinical Oncology have published guidelines which recommend
that adjuvant low-dose zoledronic acid (4 mg every 6 months) or
clodronate (1600 mg a day) should be considered in post-
menopausal women with breast cancer who are candidates for sys-
temic therapy [112]. The guideline authors conclude that data for
denosumab are promising but currently insufficient to support a
recommendation for adjuvant use in breast cancer. However, the
authors also recognize the need for more research to compare
agents, dose regimens and treatment duration. These guidelines
do not cover the use of denosumab and bisphosphonates for the
prevention of pathologic fractures in patients at risk of cancer
treatment-induced bone loss, or in other cancers [112].
When prescribing denosumab and bisphosphonates, attention
should also be paid to renal function, in the case of bisphospho-
nates, and to risk factors for osteonecrosis and hypocalcemia, par-
ticularly in elderly populations [40]. Ultimately, treatment
decisions should be evidence based, and shared with patients
and guided by their personal preferences and individual clinical
circumstances.
Best practice recommendations and conclusions
Early detection of bone metastases is critical in order that treat-
ment is initiated early; this will help to improve outcomes in
patients with advanced cancer. Radiography is the most widely
used imaging technique for the detection of bone metastases,
reflecting its wide availability and low cost. Bone scintigraphy is,
however, the imaging modality of choice recommended by Euro-
pean guidelines. While CT, PET and MRI each offer advantages over
bone scintigraphy, their roles in routine practice are unclear given
high cost and limited availability. Guidelines differ in their recom-
mendations on how often disease stage should be re-assessed in
different tumor types, and whether patients should have regular
skeletal assessment.
Interest in biomarkers for monitoring bone health in patients
with cancer is growing in the medical community. Numerous bio-
chemical markers of bone turnover have been evaluated in patients
with and without bone metastases; serum and urinary levels of
type 1 collagen CTx and P1NP in particular provide good predictive
and prognostic power. Their use in combination with imaging
modalities may improve the early identification of patients at risk
of developing bone metastases, individuals who already have
asymptomatic bone metastases, and those who may be at immi-
nent risk of a SRE. Expression of RANKL also predicts outcomes in
several tumor types. Bone metastases can lead to SREs, which are
painful and debilitating, but the risk of such events can be reduced
with denosumab or bisphosphonates. However, in clinical practice
patients are often not prescribed these agents [44] or do not persist
with treatment [113]. Radium-223 may also be used to delay the
onset of symptoms of SREs in men with metastatic prostate cancer,
although it is not licensed for use in individuals with visceral
metastases [16,92]. Emerging and future evidence will further
inform administration regimens to optimize the benefit–risk
profile.
Common treatments for prostate and breast cancer, such as ADT
and aromatase inhibitors, may induce bone loss; therefore,
patients receiving such treatments should be closely monitored
for changes in BMD. The use of low-dose denosumab (60 mg as a
single injection every 6 months [114]) or bisphosphonates (annual
infusions or daily/weekly/monthly tablets, in line with license par-
ticulars) can be discussed with such patients, as this may reduce
the risk of pathologic fracture [21,29,40]. Close monitoring of bone
32 T. Brodowicz et al. / Cancer Treatment Reviews 61 (2017) 23–34
health in patients with cancer may lead to early identification and
treatment of bone loss and/or bone metastases, which may result
in improved outcomes for patients and a reduced burden on
healthcare systems.
Acknowledgement
Writing support was provided by Liz Hartfield PhD of Oxford
PharmaGenesis, Oxford, United Kingdom, and was funded by
Amgen (Europe) GmbH.
Role of the funding source
Amgen (Europe) GmbH set up the initial meeting in which the
manuscript concept was discussed, and provided funding for med-
ical writing support and manuscript submission.
Disclosure
Thomas Brodowicz has participated in advisory boards for, and
has received honoraria from, Amgen, Bayer, Eisai, Eli Lilly, Novartis,
PharmaMar and Roche.
Peyman Hadji has participated in advisory boards for, and has
received honoraria from, Amgen, Eli Lilly, Novartis, Pfizer, Roche
and UCB.
Daniela Niepel is an employee of Amgen.
Ingo Diel has acted as a consultant for Amgen and has received
honoraria from Amgen and Teva.
Author contributions
All authors contributed to the conception of the article, were
involved in drafting the article and revising it critically for impor-
tant intellectual content. All authors approved the final article and
agree to be accountable for all aspects of the work.
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