Effects of Denosumab in Patients With Bone MetastasesWith 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

1CHU Brugmann, Universite Libre de Bruxelles, Brussels, Belgium2Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania3University of Washington Cancer Care Alliance, Seattle, Washington4Medical University of Vienna, Vienna, Austria5Amgen, Inc., San Francisco, California6Amgen, Inc., Thousand Oaks, California7Department of Medicine, Institut Gustave Roussy and University of Paris XI, Villejuif, France

ABSTRACTBone 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 humanmonoclonal 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 every4 weeks (30/120/180mg) or every 12 weeks (60/180mg). 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 hadmarked 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 andMineral Research.

KEY WORDS: CLINICAL TRIALS; BISPHOSPHONATES; NOVEL ENTITIES; OSTEOCLASTS; BONE TURNOVER MARKERS

Introduction

To maintain skeletal integrity and prevent skeletal complica-tions such as pathologic fracture, severe bone pain requiringradiotherapy or surgery, spinal cord compression, and hyper-

calcemia 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 osteoclast-

mediated 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

CLINICAL TRIALS JJBMR

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 phos-

phatase (TRAP-5b), a measure of viable osteoclasts that cause

bone resorption; and bone-specific alkaline phosphatase

(BSAP), procollagen-1 N-terminal peptide (P1NP), and osteo-

calcin, 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

180mg) or denosumab every 12 weeks (60 or 180mg)].

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 (500mg) and vitamin D

(400 IU).Initial and periodic study assessments included amedical history

and physical examination, recording of vital signs, electrocardio-

grams, radiographic evaluations of the spine, and laboratory

assessments, including hematology, serum chemistry, and

measurement of bone turnovermarkers. Concurrent antineoplastic

or hormonal therapy was permitted during study treatment at the

investigators discretion as long as no changes in regimens or

agents were plannedwithin 4weeks 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< 50nM BCE/mM creatinine at weeks 13 and

25 in the patients previously treatedwith IV BPs.(17) The cutoff value

for uNTX< 50nM BCE/mM creatinine was selected based on

previously published data suggesting that uNTX> 50nM 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 catego-

rical 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 Patients previously treated with IV BPs

IV BP

(n 43)All denosumab

(n 212)IV BP

(n 37)All denosumab

(n 74)Sex, n (%)

Women 43 (100) 212 (100) 18 (49) 38 (51)

Men 0 (0) 0 (0) 19 (51) 36 (49)

Age, mean, years (SD) 52 (11) 58 (11) 62 (12) 63 (12)

ECOG status, n (%)

0 19 (44) 135 (64) 9 (24) 15 (20)

1 20 (47) 70 (33) 23 (62) 36 (49)

2 4 (9) 6 (3) 5 (14) 21 (28)

3 0 (0) 1 (1) 0 (0) 0 (0)

Unknown 0 (0) 0 (0) 0 (0) 2 (3)

Tumor type, n (%)

Breast cancer 43 (100) 212 (100) 16 (43) 30 (40)

Prostate cancer 0 (0) 0 (0) 17 (46) 33 (45)

Multiple myeloma 0 (0) 0 (0) 3 (8) 6 (8)

Other solid tumor 0 (0) 0 (0) 1 (3) 5 (7)

Time since original diagnosis, years,

median (min, max)

3.1 (0.0, 15.6) 3.3 (0.0, 32.8) 3.1 (0.2, 13.2) 3.7 (0.1, 21.0)

Time since bone metastases, months,

median (min, max)

2.1 (0.3, 26.9) 1.9 (0.1, 206.2) 10.8 (0.0, 103.2) 7.2 (0.0, 237.6)

Bone metastases > 2, n (%) 34 (79) 156 (74) 34 (92) 68 (92)

Previous SREs 1 15 (35) 72 (34) 16 (43) 47 (64)Estimated GFR (mL/min/1.73 m2), median

(min, max)

98.7 (51.1, 160.2) 88.8 (29.0, 200.9) 101.1 (48.5, 182.8) 86.1 (30.8, 275.0)

Baseline uNTX/Cr (nM/mM), median (Q1, Q3) 49.1 (22.7, 111.7) 46.1 (25.3, 103.3) 103.2 (58.0, 145.7) 107.1 (48.6, 211.2)

Baseline sCTX (ng/mL), median (Q1, Q3) 0.6 (0.4, 0.7) 0. 6 (0.3, 0.8) 0.8 (0.4, 1.3) 0.8 (0.5, 1.5)

Breast cancer patients receiving hormone

therapy, n (%)

23 (54) 122 (58) 13 (81) 23 (77)

Prostate cancer patients receiving hormone

therapy, n (%)

14 (82) 25 (76)

IV BP, intravenous bisphosphonate; SD, standard deviation; ECOG, Eastern Cooperative Oncology Group; GFR, glomerular filtration rate; SREs, skeletal-

related events; uNTX, urinary N-telopeptide; Cr, creatinine; Q1, first quartile; Q3, third quartile; sCTX, serum C-telopeptide.

442 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.

Results

Demographics and baseline characteristics

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 BP-

naive 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

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 three-

quarters 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

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

Total DenosumabIV Bisphosphonates

Med

ian

Perc

enga

te C

hang

e in

uNT

X/Cr

(Q1,

Q3)

-100

- 80

- 60

- 40

-20

0

20

40

60

80

Study Week2 5 9 13 17 21 25

Med

ian

Perc

enga

te C

hang

e in

uNT

X/Cr

(Q1,

Q3)

M

edia

n Pe

rcen

gate

Cha

nge

in u

NTX/

Cr (Q

1, Q

3)

-100

- 80

- 60

- 40

-20

0

20

40

60

80

2 5 9 13 17 21 25Study Week

A. IV-BP Naive Patients (Breast Cancer)

B. Patients Previously Treated With IV BPs (All Tumor Types)

00

-100

-80

-60

-40

-20

0

20

40

60

80

Study Week

C. Patients Previously Treated with IV BPs (Breast Cancer Subset)

D. Patients Previously Treated with IV BPs (Prostate Cancer Subset)

2 5 9 13 17 21 250

Study Week

-100

-80

-60

-40

-20

0

20

40

60

80

2 5 9 13 17 21 250

Med

ian

Perc

enga

te C

hang

e in

uNT

X/Cr

(Q1,

Q3)

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 themedian 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

of changes in serum calcium was similar in both treatment

groups in both studies. The median changes in serum calcium

did not exceed 0.05mmol/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.

Discussion

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

sCTX

N = 34 N = 176

N = 34 N = 167

-100

-80

-60

-40

-20

0

20

Med

ian

perc

enta

ge c

hang

e (Q

1, Q

3)

N = 33 N = 165

BSAP

N = 50

N = 23

N = 50

TRAP-5b

IV Bisphosphonates

Denosumab (all doses)

N = 23 N = 51

N = 23

Osteocalcin

N = 51

N = 23

N = 167

N = 34

P1NP

N = 34 N = 175 N = 51

N = 23

-100

-80

-60

-40

-20

0

20

IV BP-Nave Patients

Patients Previously Treated with IV BPs

IV BP-Nave Patients

Patients Previously Treated with IV BPs

sCTX: serum C-telopeptideTRAP-5b: tartrate-resistant alkaline phosphataseBSAP: bone-specific alkaline phosphataseP1NP: procollagen 1 N-terminal peptide

-100

-80

-60

-40

-20

0

20

Med

ian

perc

enta

ge c

hang

e (Q

1, Q

3)

-100

-80

-60

-40

-20

0

20

Med

ian

perc

enta

ge c

hang

e (Q

1, Q

3)

-100

-80

-60

-40

-20

0

20

Med

ian

perc

enta

ge c

hang

e (Q

1, Q

3)

Med

ian

perc

enta

ge c

hang

e (Q

1, Q

3)

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

444 Journal of Bone and Mineral Research BODY ET AL.

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 continu-

ing 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

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 TRAP-

5b, 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

Table 2. Summary of Adverse Events Through Week 57

IV BP-naive patients

Patients Previously Treated

with IV BPs

IV BP

(n 43)All denosumab

(n 211)IV BP

(n 35)All denosumab

(n 73)Number of patients reporting any AEs, n (%) 41 (95) 200 (95) 34 (97) 70 (96)

AEs of CTCAE grades 3, 4, or 5, n (%) 20 (47) 93 (44) 25 (71) 40 (55)

Number of patients reporting serious AEs 15 (35) 75 (36) 19 (54) 37 (51)

Treatment-related AEs, n (%) 13 (30) 45 (21) 3 (9) 19 (26)

Treatment-related serious AEs, n (%) 0 (0) 0 (0)a 0 (0) 1 (1)

Withdrawals from study because of AEs, n (%) 1 (2) 5 (2) 3 (9) 4 (6)

Deaths, n (%) 8 (19) 32 (15) 12 (34) 23 (32)

Treatment-related deaths 0 (0) 0 (0) 0 (0) 0 (0)

Adverse events reported by 10% or more of patients

receiving denosumab in either study

Nausea 10 (23) 47 (22) 7 (20) 17 (23)

Vomiting 8 (19) 36 (17) 6 (17) 7 (10)

Diarrhea 7 (16) 35 (17) 4 (11) 10 (14)

Asthenia 12 (28) 34 (16) 7 (20) 15 (20)

Back pain 4 (9) 30 (14) 5 (14) 8 (11)

Headache 8 (19) 28 (13) 1 (3) 5 (7)

Fatigue 5 (12) 28 (13) 4 (11) 8 (11)

Bone pain 8 (19) 26 (12) 12 (34) 21 (29)

Constipation 7 (16) 26 (12) 6 (17) 16 (22)

Anemia 2 (5) 23 (11) 8 (23) 17 (23)

Arthralgia 13 (30) 24 (11) 1 (3) 6 (8)

Pain in extremity 8 (19) 21 (10) 3 (9) 7 (10)

Pyrexia 9 (21) 18 (9) 1 (3) 7 (10)

Cough 7 (16) 18 (9) 4 (11) 5 (7)

Peripheral edema 6 (14) 14 (7) 1 (3) 11 (15)

Dyspnea 5 (12) 12 (6) 4 (11) 7 (10)

Paresthesia 4 (9) 11 (5) 3 (9) 10 (14)

Thrombocytopenia 0 (0) 5 (2) 2 (6) 9 (12)

aOne 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, CommonTerminology Criteria for Adverse Events.

DENOSUMAB IN PATIENTS WITH BONE METASTASES 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 denosu-

mab in patients with solid tumors and multiple myeloma are

ongoing.

Disclosures

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., AstraZe-

neca, Sanofi-Aventis, Novartis, Ipsen-Beaufour, Pharmion, Bristol

Myers Squibb, and Takeda. KF also has received research funding

from Amgen, Inc.

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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