JBMR

CLINICAL TRIALS

Effects of Denosumab in Patients With Bone Metastases

With and Without Previous Bisphosphonate Exposure
Jean-Jacques Body , 1 Allan Lipton , 2 Julie Gralow , 3 Guenther G Steger , 4 Guozhi Gao , 5
Howard Yeh , 6 and Karim Fizazi7
1

CHU Brugmann, Universite Libre de Bruxelles, Brussels, Belgium

Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania
3
University of Washington Cancer Care Alliance, Seattle, Washington
4
Medical University of Vienna, Vienna, Austria
5
Amgen, Inc., San Francisco, California
6
Amgen, Inc., Thousand Oaks, California
7
Department of Medicine, Institut Gustave Roussy and University of Paris XI, Villejuif, France
2

ABSTRACT
Bone metastases place patients at increased risk of skeletal-related events (SREs), including pathologic fractures, spinal cord
compression, severe pain requiring radiotherapy or surgery, and hypercalcemia, because of increased osteoclast-mediated bone
resorption. Denosumab, a fully human monoclonal antibody, decreases bone resorption by inhibiting RANKL, which mediates osteoclast
activity. We compared the effects of denosumab in two phase 2 studies in patients with bone metastases naive to intravenous
bisphosphonate therapy (IV BP; n 255) and those with elevated levels of the bone resorption marker urinary N-telopeptide (uNTX)
despite ongoing IV BP treatment (n 111). Patients were randomized to receive IV BP every 4 weeks or subcutaneous denosumab every
4 weeks (30/120/180 mg) or every 12 weeks (60/180 mg). Patients treated with denosumab experienced a rapid and sustained reduction
in bone turnover regardless of prior IV BP exposure. After 25 weeks, the median uNTX reduction was 75% (IV BP-naive) and 80% (prior IV
BP) after denosumab treatment and 71% (IV BP-naive) and 56% (prior IV BP) in the IV BP arms. Denosumab patients with prior IV BP
exposure had marked suppression of the osteoclast marker TRAP-5b (median reduction: denosumab 73%, IV BP 11%). SRE incidence was
low across both studies. In patients previously treated with BPs, the rate of first on-study SRE was lower in the denosumab groups (8%)
than the IV BP group (17%). Denosumab appeared to be well tolerated in both studies. Denosumab suppresses bone resorption markers
independently of prior BP treatment, even in patients who appear to respond poorly to BPs. 2010 American Society for Bone and
Mineral Research.
KEY WORDS: CLINICAL TRIALS; BISPHOSPHONATES; NOVEL ENTITIES; OSTEOCLASTS; BONE TURNOVER MARKERS

Introduction

o maintain skeletal integrity and prevent skeletal complications such as pathologic fracture, severe bone pain requiring
radiotherapy or surgery, spinal cord compression, and hypercalcemia in patients with bone metastases, treatment with
intravenous bisphosphonates (IV BPs) is the current standard of
care.(13) In phase 3 clinical trials of patients with breast cancer,
prostate cancer, and other solid tumors,(46) 3843% of patients
experienced a skeletal-related event (SRE) while receiving
zoledronic acid, suggesting an unmet medical need and
demonstrating the necessity for more effective therapy.

In bone metastases, a continuous cycle of tumor growth and

osteolysis is marked by the activity of the receptor activator of
NF-kB ligand (RANKL), which mediates the formation, function,
and survival of osteoclasts.(79) Denosumab is a fully human
monoclonal antibody that specifically binds and neutralizes
RANKL, inhibiting osteoclastogenesis and decreasing osteoclastmediated bone destruction.(10) Denosumab provides a potential
option for the prevention of bone destruction caused by bone
metastases or multiple myeloma or for the prevention and
treatment of osteoporosis. A single subcutaneous (SC) dose of
denosumab suppressed bone turnover for up to 6 months in
postmenopausal women with low bone mass and for up to

Received in original form January 7, 2009; revised form May 21, 2009; accepted July 30, 2009. Published online August 3, 2009.
Address correspondence to: Jean-Jacques Body, MD, PhD, CHU Brugmann (Universite Libre de Bruxelles), 4 Place Van Gehuchten, 1020 Brussels, Belgium.
E-mail: Jean-jacques.body@chu-brugmann.be
Prior abstract presentation: Some of the information presented in this article was reported at the American Society of Clinical Oncology Congress, Chicago, IL, USA,
May 30June 3, 2008 and at the European Society for Medical Oncology Congress, Stockholm, Sweden, September 1216, 2008.
Journal of Bone and Mineral Research, Vol. 25, No. 3, March 2010, pp 440446
DOI: 10.1359/jbmr.090810
2010 American Society for Bone and Mineral Research

440

12 weeks in patients with multiple myeloma or breast

cancer,(10,11) including women with early-stage breast cancer
receiving aromatase inhibitors.(12)
In this report, we compare the efficacy and safety of
denosumab in reducing bone turnover in two clinical studies of
patients with bone metastases associated with various solid
tumors or multiple myeloma. In the first study, patients had no
previous exposure to IV BPs. In the second study, patients had
high levels of the bone turnover marker urinary N-telopeptide
(uNTX) despite ongoing treatment with IV BPs. Evidence of
bone turnover reduction is provided by decreased levels of
bone turnover markers: uNTX and serum C-telopeptide (sCTX),
which indicate bone resorption; tartrate-resistant acid phosphatase (TRAP-5b), a measure of viable osteoclasts that cause
bone resorption; and bone-specific alkaline phosphatase
(BSAP), procollagen-1 N-terminal peptide (P1NP), and osteocalcin, markers of bone formation. These bone turnover
markers have been used widely in clinical studies and are
recognized as reliable, accurate, and relevant for this
therapeutic indication.(1315) We also report safety outcomes
after up to 57 weeks.

Materials and Methods

Patients
Eligible patients were 18 years of age or older, with histologically
confirmed cancers, radiographic evidence of at least one bone
lesion, and an Eastern Cooperative Oncology Group (ECOG)
performance status of 2 or less. Study 20040113 (NCT00091832)
evaluated women with breast cancer and bone metastases who
had not been treated previously with IV BPs.(16) Study 20040114
(NCT00104650) included men and women with solid tumors and

bone metastases or multiple myeloma with evidence of high

levels of bone resorption (uNTX levels > 50 nM BCE/mM
creatinine) despite previous treatment with IV BPs for 8 weeks
or more.(17) In both studies, patients were excluded if they had
more than two prior SREs, osteonecrosis or osteomyelitis of the
jaw (current or past), planned oral surgery, radiotherapy to bone
less than 2 weeks before randomization, or evidence of
impending fracture in weight-bearing bones.
The studies were approved by the institutional review board or
ethics committee for each site. All patients provided written
informed consent.

Study designs and treatments

Both studies were randomized, active-controlled, multicenter
phase 2 trials comparing different doses of subcutaneous
denosumab with IV BPs (16,17) (Fig. 1). Patients were randomly
assigned to receive IV BP therapy every 4 weeks or the assigned
dose of denosumab [denosumab every 4 weeks (30, 120, or
180 mg) or denosumab every 12 weeks (60 or 180 mg)].
Randomization in both studies was stratified. In the study of
bisphosphonate-naive patients, patients were stratified by
type of antineoplastic therapy (i.e., hormonal therapy or
chemotherapy); in the study of previously treated patients,
stratification was by cancer type (i.e., prostate cancer, breast
cancer, multiple myeloma/other solid tumors) and baseline uNTX
(50 to 100 or >100 nmol/L/mM creatinine). IV BPs administered
were commercially available agents such as zoledronic acid,
ibandronate, or pamidronate, selected at the investigators
discretion and administered according to country-specific
labeling. Patients were treated for 25 weeks and were followed
for up to 32 weeks after the treatment phase was completed. In
study 20040114, patients had the option of entering a 2-year

Fig. 1. Study designs.

DENOSUMAB IN PATIENTS WITH BONE METASTASES

Journal of Bone and Mineral Research

441

ongoing extension study. All patients were instructed to

take daily supplements of calcium (500 mg) and vitamin D
(
400 IU).
Initial and periodic study assessments included a medical history
and physical examination, recording of vital signs, electrocardiograms, radiographic evaluations of the spine, and laboratory
assessments, including hematology, serum chemistry, and
measurement of bone turnover markers. Concurrent antineoplastic
or hormonal therapy was permitted during study treatment at the
investigators discretion as long as no changes in regimens or
agents were planned within 4 weeks before or after randomization.

Endpoints
Key efficacy endpoints analyzed for this report include the median
percentage change from baseline in uNTX corrected for creatinine
(uNTX/Cr) at 25 weeks, the median percentage change from
baseline in other bone turnover markers (sCTX, BSAP, TRAP-5b,
P1NP, and osteocalcin), the proportion of patients experiencing
SREs after 25 weeks, and the time to the first SRE. SREs were

defined as pathologic fracture, either vertebral or nonvertebral;

spinal cord compression; surgery to bone; or radiation to bone,
including the use of radioisotopes.
Endpoints reported previously include the time to a reduction of
uNTX > 65% at weeks 13 and 25 in the IV BP-naive patients(16,18)
and the time to uNTX < 50 nM BCE/mM creatinine at weeks 13 and
25 in the patients previously treated with IV BPs.(17) The cutoff value
for uNTX < 50 nM BCE/mM creatinine was selected based on
previously published data suggesting that uNTX > 50 nM BCE/mM
creatinine increased the risk for SREs, cancer progression, and
death.(14) Safety endpoints included the incidence of adverse
events (AEs), changes in laboratory values (including calcium levels
and renal function), and the formation of antibodies.

Statistical analysis
Summary statistics were calculated for continuous and categorical variables. Kaplan-Meier analyses were conducted for the
times to the occurrence of the first SRE.

Table 1. Baseline Demographics and Disease Characteristics of Study Populations

IV BP-naive patients
IV BP
(n 43)
Sex, n (%)
Women
Men
Age, mean, years (SD)
ECOG status, n (%)
0
1
2
3
Unknown
Tumor type, n (%)
Breast cancer
Prostate cancer
Multiple myeloma
Other solid tumor
Time since original diagnosis, years,
median (min, max)
Time since bone metastases, months,
median (min, max)
Bone metastases > 2, n (%)
Previous SREs
1
Estimated GFR (mL/min/1.73 m2), median
(min, max)
Baseline uNTX/Cr (nM/mM), median (Q1, Q3)
Baseline sCTX (ng/mL), median (Q1, Q3)
Breast cancer patients receiving hormone
therapy, n (%)
Prostate cancer patients receiving hormone
therapy, n (%)

All denosumab
(n 212)

Patients previously treated with IV BPs

IV BP
(n 37)

All denosumab
(n 74)

43 (100)
0 (0)
52 (11)

212 (100)
0 (0)
58 (11)

18 (49)
19 (51)
62 (12)

38 (51)
36 (49)
63 (12)

19 (44)
20 (47)
4 (9)
0 (0)
0 (0)

135 (64)
70 (33)
6 (3)
1 (1)
0 (0)

9 (24)
23 (62)
5 (14)
0 (0)
0 (0)

15 (20)
36 (49)
21 (28)
0 (0)
2 (3)

43 (100)
0 (0)
0 (0)
0 (0)
3.1 (0.0, 15.6)

212 (100)
0 (0)
0 (0)
0 (0)
3.3 (0.0, 32.8)

16 (43)
17 (46)
3 (8)
1 (3)
3.1 (0.2, 13.2)

30 (40)
33 (45)
6 (8)
5 (7)
3.7 (0.1, 21.0)

2.1 (0.3, 26.9)

1.9 (0.1, 206.2)

10.8 (0.0, 103.2)

7.2 (0.0, 237.6)

34 (79)
15 (35)
98.7 (51.1, 160.2)

156 (74)
72 (34)
88.8 (29.0, 200.9)

34 (92)
16 (43)
101.1 (48.5, 182.8)

68 (92)
47 (64)
86.1 (30.8, 275.0)

49.1 (22.7, 111.7)

0.6 (0.4, 0.7)
23 (54)

46.1 (25.3, 103.3)

0. 6 (0.3, 0.8)
122 (58)

103.2 (58.0, 145.7)

0.8 (0.4, 1.3)
13 (81)

107.1 (48.6, 211.2)

0.8 (0.5, 1.5)
23 (77)

14 (82)

25 (76)

IV BP, intravenous bisphosphonate; SD, standard deviation; ECOG, Eastern Cooperative Oncology Group; GFR, glomerular filtration rate; SREs, skeletalrelated events; uNTX, urinary N-telopeptide; Cr, creatinine; Q1, first quartile; Q3, third quartile; sCTX, serum C-telopeptide.

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Journal of Bone and Mineral Research

BODY ET AL.

Analyses of efficacy endpoints included only data from the

25-week treatment phase. Safety analyses included data from
both the 25-week treatment phase and the 32-week
off-treatment follow-up phase for a total of 57 weeks. For
patients from study 20040114 who enrolled in the extension
study, data were censored at the time they entered the
extension.

commonly used BP (by 91% of patients in the BP-naive study and

81% of patients in the previous-BP study). Approximately half the
patients in the study of BP-naive patients and more than threequarters of breast and prostate cancer patients in the study of
patients previously treated with IV BPs were receiving hormone
therapy at baseline (see Table 1).

Bone turnover

Results
Demographics and baseline characteristics

A. IV-BP Naive Patients

(Breast Cancer)

80

Median Percengate Change in uNTX/Cr (Q1, Q3)

Median Percengate Change in uNTX/Cr (Q1, Q3)

All the patients in the IV BP-naive study were women with breast
cancer and bone metastases. In the study of patients previously
treated with IV BPs, the population was evenly distributed
between men and women, with breast, prostate, and other solid
tumors and multiple myeloma similarly distributed between
treatment groups (Table 1). Prostate cancer was the most
common tumor type (45%) in this second study.
In the IV BP-naive study, patients generally were older in the
denosumab groups than in the IV BP group (mean age 58 versus
52 years). In the study of patients previously treated with IV BPs,
the study population tended to be older than those in the IV BPnaive study, with a mean age of 63 years (see Table 1). In both
studies, bone turnover marker levels were similar in the IV BP and
denosumab groups (see Table 1). Zoledronic acid was the most

60
40
20
0
-20
- 40
- 60
- 80
-100
0

13

17

Patients treated with denosumab experienced a rapid reduction

in bone turnover marker levels in both studies. In the study of IV
BP-naive patients, the median percent change in uNTX/Cr at
25 weeks was 75% for the denosumab groups and 71% for the
IV BP group (Fig. 2A). In the study of patients previously treated
with IV BPs, denosumab-treated patients experienced a median
reduction in uNTX/Cr of 80% compared with a reduction of 56%
for those in the IV BP group (see Fig. 2B). Results were similar for
the subsets of patients with breast and prostate cancer (see
Fig. 2C, D). Reductions in uNTX were greater in the IV BP
treatment group in the BP-naive study than in the study of
patients who had high levels of uNTX despite previous BP
therapy (see Fig. 2). Patients previously treated with IV BPs
reached a uNTX level of less than 50 nM BCE/mM creatinine in a
median 9 days for the denosumab groups and 65 days for the IV
BP group; among IV BP-naive patients, the median time to reach
uNTX less than 50 nM BCE/mM creatinine was 9 days for the

21

B. Patients Previously Treated With IV BPs

(All Tumor Types)

80
60
40
20
0
-20
- 40
- 60
- 80
-100

25

Study Week

Median Percengate Change in uNTX/Cr (Q1, Q3)

Median Percengate Change in uNTX/Cr (Q1, Q3)

17

21

25

Total Denosumab

IV Bisphosphonates

C. Patients Previously Treated with IV BPs

(Breast Cancer Subset)

80

13

Study Week

60
40
20
0
-20
-40
-60
-80

D. Patients Previously Treated with IV BPs

(Prostate Cancer Subset)

80
60
40
20
0
-20
-40
-60
-80

-100

-100
0

13

17

21

25

Study Week

13

17

21

25

Study Week

Fig. 2. Median reduction in uNTX/Cr from baseline through 25 weeks.

DENOSUMAB IN PATIENTS WITH BONE METASTASES

Journal of Bone and Mineral Research

443

denosumab groups and 8 days for the IV BP group. The receipt of

hormone therapy or chemotherapy at baseline had no
significant effect on changes in uNTX levels (data not shown).
Denosumab-induced suppression of bone turnover also was
demonstrated in the median reductions of serum levels of other
markers analyzed (Fig. 3). Among patients previously treated
with IV BPs, the difference in the median change of the osteoclast
marker TRAP-5b at week 25 was substantial between the
denosumab and IV BP treatment arms (73% for denosumab
versus 11% for IV BP).

Skeletal-related events (SREs)

The incidence of SREs was low in both treatment groups across
both studies. Among IV BP-naive patients, 12% of patients in the
denosumab groups and 16% of patients in the IV BP group
experienced a first on-study SRE over 25 weeks. Among patients
previously treated with IV BPs, the rate of first on-study SRE was
lower in the denosumab groups (8%) than the IV BP group (17%),
and IV BP-treated patients experienced SREs earlier than
denosumab-treated patients.(17) Among IV BP-naive patients,
the Kaplan-Meier curves of the time to first on-study SRE were
similar in both treatment groups.(17,18)

Safety
No unexpected changes in calcium, creatinine, liver enzymes, or
electrolytes were reported in either study, and the overall profile

Median percentage change (Q1, Q3)

Patients Previously
Treated with IV BPs
sCTX

N = 34 N = 176

N = 23

N = 51

-20
-40
-60
-80
-100

20
0

BSAP
N = 34 N = 167

N = 50

-20
-40
-60

N = 23

-80
-100

20
0

Elevated bone turnover markers are associated with disease

progression and poor prognosis in breast cancer, prostate
cancer, and other solid tumors with bone metastases. Inhibition
of osteoclast function, as measured by decreases in bone
resorption markers, results in fewer skeletal complications and a
more favorable prognosis.(1) In these two studies, denosumab
reduced levels of uNTX/Cr and other bone turnover markers such
IV BP-Nave
Patients
Median percentage change (Q1, Q3)

20

Discussion

Median percentage change (Q1, Q3)

Median percentage change (Q1, Q3)

Median percentage change (Q1, Q3)

IV BP-Nave
Patients

of changes in serum calcium was similar in both treatment

groups in both studies. The median changes in serum calcium
did not exceed 0.05 mmol/L in either group. Denosumab
treatment had no apparent effect on renal function in either
study.
The rates of AEs were similar between treatment groups in
both studies (Table 2), and the events reported were consistent
with a population of patients undergoing treatment for
advanced cancer. Rates of treatment-related events of
Common Terminology Criteria for Adverse Events (CTCAE)
grades 3, 4, or 5 were low and similar in both studies (see
Table 2). No treatment-related deaths were reported. Most
deaths were from disease progression, and rates of death were
similar between treatment groups in both studies. No cases of
osteonecrosis of the jaw and no neutralizing antibodies to
denosumab were reported during the 25-week treatment and
32-week follow-up periods.

Patients Previously
Treated with IV BPs

20

TRAP-5b

N = 33 N = 165

N = 50

-20

N = 23

-40
-60
-80
-100

20

Osteocalcin

N = 167

N = 51

-20
-40

N = 34

-60

N = 23

-80
-100

P1NP
N = 34 N = 175

N = 51

IV Bisphosphonates

-20

Denosumab (all doses)

-40
-60

N = 23
-80
-100

sCTX: serum C-telopeptide

TRAP-5b: tartrate-resistant alkaline phosphatase
BSAP: bone-specific alkaline phosphatase
P1NP: procollagen 1 N-terminal peptide

Fig. 3. Median percentage change in secondary bone turnover markers at 25 weeks.

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Journal of Bone and Mineral Research

BODY ET AL.

Table 2. Summary of Adverse Events Through Week 57

Patients Previously Treated
with IV BPs

IV BP-naive patients

Number of patients reporting any AEs, n (%)

AEs of CTCAE grades 3, 4, or 5, n (%)
Number of patients reporting serious AEs
Treatment-related AEs, n (%)
Treatment-related serious AEs, n (%)
Withdrawals from study because of AEs, n (%)
Deaths, n (%)
Treatment-related deaths
Adverse events reported by 10% or more of patients
receiving denosumab in either study
Nausea
Vomiting
Diarrhea
Asthenia
Back pain
Headache
Fatigue
Bone pain
Constipation
Anemia
Arthralgia
Pain in extremity
Pyrexia
Cough
Peripheral edema
Dyspnea
Paresthesia
Thrombocytopenia

IV BP
(n 43)

All denosumab
(n 211)

IV BP
(n 35)

All denosumab
(n 73)

41 (95)
20 (47)
15 (35)
13 (30)
0 (0)
1 (2)
8 (19)
0 (0)

200 (95)
93 (44)
75 (36)
45 (21)
0 (0)a
5 (2)
32 (15)
0 (0)

34 (97)
25 (71)
19 (54)
3 (9)
0 (0)
3 (9)
12 (34)
0 (0)

70 (96)
40 (55)
37 (51)
19 (26)
1 (1)
4 (6)
23 (32)
0 (0)

10 (23)
8 (19)
7 (16)
12 (28)
4 (9)
8 (19)
5 (12)
8 (19)
7 (16)
2 (5)
13 (30)
8 (19)
9 (21)
7 (16)
6 (14)
5 (12)
4 (9)
0 (0)

47 (22)
36 (17)
35 (17)
34 (16)
30 (14)
28 (13)
28 (13)
26 (12)
26 (12)
23 (11)
24 (11)
21 (10)
18 (9)
18 (9)
14 (7)
12 (6)
11 (5)
5 (2)

7 (20)
6 (17)
4 (11)
7 (20)
5 (14)
1 (3)
4 (11)
12 (34)
6 (17)
8 (23)
1 (3)
3 (9)
1 (3)
4 (11)
1 (3)
4 (11)
3 (9)
2 (6)

17 (23)
7 (10)
10 (14)
15 (20)
8 (11)
5 (7)
8 (11)
21 (29)
16 (22)
17 (23)
6 (8)
7 (10)
7 (10)
5 (7)
11 (15)
7 (10)
10 (14)
9 (12)

One serious treatment-related AE (pyrexia) was recorded in the 120-mg every 4 weeks denosumab group, but it was determined to be unrelated to
treatment after the study database was locked. IV BP, intravenous bisphosphonate; Q4W, every 4 weeks; Q12W, every 12 weeks; CTCAE, Common
Terminology Criteria for Adverse Events.

as sCTX and TRAP-5b consistently regardless of tumor types,

prior history of SRE, and prior IV BP exposure. Notably, among
patients whose uNTX levels remained high despite previous IV
BP therapy, denosumab rapidly decreased uNTX and other
markers of bone turnover, whereas continuation of BP treatment
led only to a progressive and lower decrease in uNTX levels. This
slower effect may be due in part to the interference of changing
antineoplastic treatments over time. The difference in TRAP-5b
levels between denosumab-treated patients and those continuing IV BPs is especially striking and suggests the persistence of
functioning osteoclasts despite BP treatment but whose activity
can be suppressed when treatment is switched to denosumab.
These results demonstrate the biologic activity of denosumab.
They also confirm a mechanism of action for denosumab that is
distinct from that of BPs. BPs are intercalated into bone and
inhibit the osteoclasts ability to resorb bone. Denosumab, by
inhibiting the interaction of RANK with its ligand, prevents the
formation, maturation, and survival of osteoclasts. In studies of
animal models treated with the RANKL inhibitor osteoprotegerin
(OPG), surviving osteoclasts were observed after BP treatment
DENOSUMAB IN PATIENTS WITH BONE METASTASES

but not after treatment with OPG.(19,20) In bone biopsies from

patients who died with multiple bone metastases, surviving
osteoclasts were observed after BP treatment but not after
treatment with denosumab.(21) Because it effectively inhibits
osteoclast formation, maturation, and survival, denosumab may
be effective for patients in whom osteoclasts persist or are still
formed despite treatment with BPs. Persistent osteoclast activity
was confirmed in the patients previously treated with BP by the
fact that TRAP-5b levels did not decrease after further BP
treatment. The clinical implications of these findings may be
important but remain to be demonstrated.
Among IV BP-naive patients, the incidence of SREs was
similarly low after IV BP and denosumab treatment. Among
patients with prior exposure to IV BPs, the incidence of SREs was
lower in the denosumab group than in patients on continuing IV
BPs. The ability of denosumab to further suppress bone turnover
markers, particularly uNTX and the osteoclast biomarker TRAP5b, in patients already receiving IV BP but continuing to exhibit
evidence of a high bone resorption rate may account for the
lower rate of SREs in the second study. Because of the relatively
Journal of Bone and Mineral Research

445

small sizes of the populations, larger phase 3 studies are ongoing

to provide a more accurate estimate of the effect of denosumab
treatment on the risk of SREs.
The rates or types of AEs, deaths, and serious adverse events
appeared to be similar between groups in both studies, and no
additional adverse events surfaced related to switching from BP
to denosumab.
Growing evidence indicates that a bone-targeting strategy is
likely to be a valuable and promising approach in patients with
bone metastases.(22,23) Results of the current studies add to this
evidence, demonstrating that denosumab may provide an
important therapeutic advance in the prevention of skeletal
complications of bone metastases. Phase 3 studies of denosumab in patients with solid tumors and multiple myeloma are
ongoing.

7. Fuller K, Wong B, Fox S, Choi Y, Chambers TJ. TRANCE is necessary and

sufficient for osteoblast-mediated activation of bone resorption in
osteoclasts. J Exp Med 1998;188:9971001.
8. Lacey DL, Tan HL, Lu J, et al. Osteoprotegerin ligand modulates
murine osteoclast survival in vitro and in vivo. Am J Pathol
2000;157:435448.
9. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine
that regulates osteoclast differentiation and activation. Cell 1998;93:
165176.
10. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebocontrolled study of AMG 162, a fully human monoclonal antibody to
RANKL, in postmenopausal women. J Bone Miner Res 2004;19:1059
1066.
11. Body JJ, Facon T, Coleman RE, et al. A study of the biological receptor
activator of nuclear factor-kB ligand inhibitor, denosumab, in
patients with multiple myeloma or bone metastases from breast
cancer. Clin Cancer Res 2006;12:12211228.

Disclosures

12. Ellis GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in
patients receiving adjuvant aromatase inhibitors for nonmetastatic breast
cancer. J Clin Oncol 2008;26:48754882.

JJB has received consultancy and lecture fees from Amgen, Inc.,
and Novartis. AL has received consultancy fees and honoraria
from Amgen, Inc. AL also has received honoraria, consulting fees,
research funds, and payments for expert testimony from
Novartis, Inc. JG has received research funding from Amgen,
Inc., Novartis, Inc., and Roche. GGS has received honoraria from
Amgen, Inc. GG and HY are employees of Amgen, Inc., and have
received stocks/stock options from Amgen, Inc. KF has received
consultancy fees and/or honoraria from Amgen, Inc., AstraZeneca, Sanofi-Aventis, Novartis, Ipsen-Beaufour, Pharmion, Bristol
Myers Squibb, and Takeda. KF also has received research funding
from Amgen, Inc.

13. Brown JE, Cook RJ, Major P, et al. Bone turnover markers as predictors
of skeletal complications in prostate cancer, lung cancer, and other
solid tumors. J Natl Cancer Inst 2005;97:5969.

Acknowledgments
We acknowledge the medical writing assistance of Ting Chang
and Sue Hudson on behalf of Amgen, Inc. This study was
supported by Amgen, Inc., Thousand Oaks, CA, USA.

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