Skeletal Integrity in Oncology: What Physicians Need to Know This program is supported by an educational donation from Matthew R. Smith, MD, PhD Associate

Skeletal Integrity in Oncology: What Physicians Need to Know

This program is supported by an educational donation from

Matthew R. Smith, MD, PhDAssociate Professor of MedicineHarvard Medical SchoolProgram Director, Genitourinary Oncology Massachusetts General Hospital Cancer CenterBoston, Massachusetts

clinicaloptions.com/oncologySkeletal Integrity in Oncology

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Program Faculty

Program DirectorMatthew R. Smith, MD, PhDAssociate Professor of MedicineHarvard Medical SchoolProgram Director, Genitourinary OncologyMassachusetts General Hospital Cancer CenterBoston, Massachusetts

Co-ChairsAllan Lipton, MDProfessor of Medicine and OncologyMilton S. Hershey Medical CenterPenn State Cancer InstituteHershey, Pennsylvania

G. David Roodman, MD, PhD Professor of Medicine, Vice Chair for ResearchDepartment of Medicine/Hematology-OncologyUniversity of Pittsburgh School of MedicineDirector, Myeloma ProgramDepartment of Medicine/Hematology-OncologyUniversity of Pittsburgh Cancer InstituteVA Pittsburgh Healthcare SystemPittsburgh, Pennsylvania


Program Faculty

James Berenson, MDPresident and Chief Executive OfficerMedical and Scientific DirectorInstitute for Myeloma and Bone Cancer ResearchWest Hollywood, California

Adam M. Brufsky, MD, PhDAssociate Professor of Medicine Hematology/OncologyUniversity of Pittsburgh School of Medicine Associate Director for Clinical Investigations University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania

Michael A. Carducci, MDProfessor of Oncology and UrologyDepartment of OncologyKimmel Cancer Center at Johns Hopkins Baltimore, Maryland

Celestia S. Higano, MD, FACPProfessor Departments of Medicine and UrologyUniversity of Washington Seattle, Washington

Paul H. Lange, MD, FACSProfessor and Chairman of the Department of UrologyUniversity of WashingtonSeattle, Washington


Program Faculty

Benjamin Leder, MD Associate Professor of MedicineHarvard Medical SchoolMassachusetts General HospitalBoston, Massachusetts

Noopur Raje, MD Director, Center for Multiple Myeloma Massachusetts General Hospital Cancer CenterBoston, Massachusetts

Alison T. Stopeck, MDAssociate Professor of Medicine Arizona Cancer Center University of ArizonaTucson, Arizona

Katherine N. Weilbaecher, MDAssociate Professor in Medicine and Cell BiologyDivision of OncologyWashington University School of Medicine St Louis, Missouri

Maurizio Zangari, MDProfessor of MedicineDepartment of HematologyUniversity of UtahSalt Lake City, Utah


Table of Contents

Disruption of Bone Homeostasis in Patients With Cancer

Bone-Targeted Therapy for Cancer-Related or Cancer Treatment–Induced Bone Complications

– Bone Health Checklist for Oncologists

Mitigating Bone Complications in Multiple Myeloma

Strategies to Prevent and Manage Bone Compromise in Breast Cancer

Strategies for Bone-Directed Therapy in Prostate Cancer

Disruption of Bone Homeostasis in Patients With Cancer


Normal Bone Remodeling Is a Coupled and Balanced Process

Osteoclastic bone resorption

Osteoblasts mediate new bone formation

Hattner R, et al. Nature. 1965:206:489-490.


Osteoporosis

Imbalance in Bone Homeostasis

Breast cancer,myeloma

Prostatecancer


Regulatory Influences: Systemic Hormones PTH, PTHrP

1,25-(OH)2 vitamin D3

Calcitonin

Gonadal steroids (estrogen, androgen)

GH

IGF-1


Hormonal Mediation of Bone Homeostasis

Hormonal influence in bone remodeling integral to bone health, especially trabecular bone

Process dynamic and continuous throughout life span

Balance and integration with other influences critical

Surge of gonadal hormones at puberty necessary for maximal skeletal maturity and strength

Natural hormonal waning with age decreases bone strength

Process predictable regardless of other influences


Effects of Gonadal Steroid Deprivation

Loss of gonadal hormones increases bone resorption

– Life span and activity of osteoblasts decreased, resulting in less new bone deposition

– Osteoclastic activity is less suppressed, increasing rate of resorption

Resulting imbalance promotes osteoporosis/osteopenia


Osteoporosis From Hormonal Deprivation

Normally seen in both aging men and women

Fractures in spine most prevalent

Trabecular bone at highest risk

Deprivation accelerated by systematic cancer therapy

Especially problematic with use of antihormonal cancer agents (prostate and breast cancer)


Pathogenesis of Osteolytic Bone Metastases

Tumor-derived osteoclast activating factors

– Parathyroid hormone–related protein

– Interleukin-6, -8, -11

– Tumor necrosis factor

– Macrophage colony-stimulating factor

Bone-derived tumor growth factors

– Transforming growth factor

– Insulin-like growth factors

– Fibroblast growth factors

– Platelet-derived growth factor

– Bone morphogenic proteins

Bone

Tumor Cells in Bone

Osteoclast

(+) (+)

Derived from Roodman GD. N Engl J Med. 2004;350:1655-1664.


SREs Reflect Morbidity From Bone Metastases Pathological fractures

– Nonvertebral

– Vertebral compression

Spinal cord compression/collapse

Radiation therapy

Surgery to bone

Hypercalcemia

SREs

Bone-Directed Therapy for Cancer-Related or

Cancer Treatment–InducedBone Complications


A Bone Health Checklist for Oncologists

Cancer-Related Osteoporosis Risk Factors

Androgen deprivation therapy

Aromatase inhibitor therapy

Premature menopause

Osteoporosis Risk Factors

Older than 65 yrs of age

Low BMI

Previous nontraumatic fracture

Currently smoking

Parental hip fracture

Tests

DEXA every 2 yrs

25(OH)D level (target > 40 ng/mL)

Serum calcium level

Treat any of the following

Hip or vertebral fracture

T-score ≤ -2.5

T-score -1 to -2.5 with 10-yr probability of hip fracture ≥ 3% or major osteoporotic fracture ≥ 20%


Available at: http://www.sheffield.ac.uk/FRAX/. Image used with permission of the WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield. FRAX is registered to Professor JA Kanis, University of Sheffield.

The FRAX Index: Assessing Fracture Risk

http://www.sheffield.ac.uk/FRAX/


Bisphosphonates Inhibitors of bone loss Potency varies greatly depending on

R1 and R2 side chains

Relative

R1 R2

Potency

Etidronate OH – CH3 1

Clodronate Cl – Cl 10

Tiludronate H – S – – Cl 10

Pamidronate OH –(CH2)2 – NH2 100

Alendronate OH –(CH2)3 – NH2 1000

Risedronate H –CH2 – N

5000

Ibandronate OH (CH2)2-N-(CH2)4-CH3 10,000

CH3

Zoledronic acid OH –N N 100,000

OH R1

OH R2 OH

P C P O

OH

O

No N

N


Effect of Bisphosphonates on Vicious Cycle of Bone Destruction

Decrease activity of osteoclasts

– Reduction in release of peptides

– Slowed tumor-cell growth

– Reduced production of PTHrP and other factors

– Decrease in bone resorption

PTHrP

Tumor Cells

IL-6

IL-8

PGE2

TNF-

CSF-1

BMP

PDGF

FGFs

IGFs

TGF-β

Osteoclast

Bone

Adapted from Mundy GR, et al. N Engl J Med. 1998;339:398-400.


Use of IV Bisphosphonates

Treatment of osteoporosis

Treatment of hypercalcemia

Prevent or decrease onset of fractures

Provide pain relief in bone metastasis

Improve quality of life

Antitumor effects

Doggrell SA. Expert Rev Anticancer Ther. 2009;9:1211-1218. Winter MC, et al. Curr Opin Oncol. 2009;21:499-506.


IV Bisphosphonates: Adverse Effects

Bone pain: responsive to NSAIDs

Nausea (minor)

Flulike symptoms

Anemia

Hypocalcemia

Papapetrou PD. Hormones (Athens). 2009;8:96-110.


Acute Phase Reaction

Fever, myalgias, arthralgias

Occurs within 12-48 hrs of treatment

More common during first dose

Less severe with subsequent treatment

Managed conservatively


Renal Function: Use of Bisphosphonates

Changes in kidney function are related to Cmax

– Rate of infusion is the key factor in prevention of kidney problems

– Rates faster than 0.3-0.7 mg/min are associated with problems

Importantly, rate of infusion has no impact on prevention of skeletal complications

– Efficacy related to AUC (how much remains in patient)

Zoledronic acid and pamidronate affect different parts of the kidney

– Zoledronic acid: tubular

– Pamidronate: glomerular

Reduce the risk of renal dysfunction

– Monitor serum creatinine before each infusion

– Make sure patient is hydrated at time of treatment


Incidental finding of osteonecrosis in a patient complaining of a dislodged dental restoration. The patient underwent dental extraction in the region of the exposed bone 1 yr before presentation. She has no symptoms.

ONJ


ONJ: Clinical Features and Working Diagnosis Clinical features of suspected ONJ

– Exposed bone in maxillofacial area that occurs in association with dental surgery or occurs spontaneously, with no evidence of healing

Working diagnosis of ONJ

– No evidence of healing after 6 wks of appropriate evaluation and dental care

– No evidence of metastatic disease in the jaw or osteoradionecrosis

Weitzman R, et al. Crit Rev Oncol Hematol. 2007;62:148-152.


Frequency of ONJ in Malignant Bone DiseaseStudy Study

TypePts Treated With BP, n

Pts With Suspect or Proven ONJ, n

Frequency, %

Hoff et al, MDACCASCO 2006[1]

Chart review 4019 34 0.8

Durie et al[2] Web-based survey 1203 152 12.6

Pozzi et al, Italian Multicenter study[3] Chart review 888 16 1.8

Badros et al[4] Chart review/ observational 340 11 3.2

Tosi et al, analysis of Bologna 2002 trial[5]

Retrospective review of trial database 259 6 2.7

Zervas et al[6] Observational 254 28 11.0

Dimopoulos et al[7] Chart review 202 15 7.4

Cafro et al[8] Chart review 118 14 11.9

Berenson et al[9] Chart review 300 14 4.7

1. Hoff AO, et al. ASCO 2006. Abstract 8528. 2. Durie GM, et al. N Engl J Med. 2005;353:99-102. 3. Pozzi S, et al. ASH 2005. Abstract 5057. 4. Badros A, et al. J Clin Oncol. 2006;24:945-952. 5. Tosi P, et al. ASH 2005. Abstract 3461. 6. Zervas K, et al. Br J Haematol. 2006;134:620-623. 7. Dimopoulos M, et al. Haematologica. 2006;91:968-971. 8. Cafro A, et al. ASH 2005. Abstract 5152. 9. Berenson J, et al. Clin Lymphoma Myeloma. 2009;9:311-315.


Relative Risk Factors for ONJ

Cancer

Radiation therapy

Corticosteroids

Poor dental hygiene

Poor diet

Dental work

Trauma

Ethanol or tobacco use

Coagulopathy

Chemotherapy

Infection

Bisphosphonates


Managing ONJ

Make a diagnosis

– Get someone to evaluate who knows the entity

Assess its severity

– It takes on a wide spectrum

Maintain excellent dental hygiene and regular exams

Keep surgical intervention to a minimum

There is no standard treatment

– Antibacterial and antifungal rinses (chlorhexidine gluconate and nystatin)

– Systemic oral antibacterial, antiviral, and antifungal treatment


Preventive Dental Measures Reduce Incidence of ONJ > 50%

PRE, preimplementation of preventive measures; POST, postimplementation of preventive measures.

0.014

0.029

0

0.01

0.02

0.03

0.04

PRE Group POST Group

Inci

den

ce R

ate

(Cas

es/Y

r)

Ripamonti CI, et al. Ann Oncol. 2009;20:137-145.

A retrospective study in cancer patients receiving BPs


The Central Role of the Osteoclast in Osteolytic Bone Destruction

Growthfactors

Osteoclast differentiation

Osteolysis

Direct effects on osteoclast differentiation

Tumor cells

Bone loss

Activeosteoclast

Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.


Factors Increasing Osteoclast Activity in Bone Metastasis

RANKL

OPG

MIP-1 alpha

1,25(OH)2D3

PTHrP


Normal RANKL/OPG

Prevents Promotes

Osteoclastic Activity

RANKLOPG

Hofbauer LC, et al. JAMA. 2004;292:490-495.


The RANK/RANKL/OPG Pathway in Osteolytic Bone Disease

Prevents Promotes

Increased osteoclastic activity and

decreased OPG

OPG RANKL

Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.


Denosumab: Inhibiting RANK in Bone Disease High affinity human monoclonal antibody that binds

RANKL

Administered via SC injection

Specific: does not bind to TNF-α, TNF-β, TRAIL, or CD40L

Inhibits formation and activation of osteoclasts

Mitigating Bone Complications in Multiple Myeloma


Bone Involvement in Different Tumor Types

DiseasePrevalence (US)(in Thousands)

Incidence of Bone Metastases in

Patients With Advanced Disease, %

Median Survival of Patients With Bone

Metastases, Mos

Myeloma 49.6[1] 84[2] 37-58[4]

Lung 327[1] 30-40[3] 8-10[5]

Breast 2051[1] 65-75[3] 19-25[6]

Prostate 1477[1] 65-75[3] 30-35[7]

1. National Cancer Institute. Available at: http://seer.cancer.gov/csr/1973-1999/prevalence.pdf. 2. Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33. 3. Coleman RE. Oncologist. 2004;9(suppl 4):14-27. 4. Palumbo A, et al. Blood. 2004;104:3052-3057. 5. Smith W, et al. Semin Oncol. 2004;31(suppl 4):11-15. 6. Lipton A. J Support Oncol. 2004;2:205-213. 7. Tu SM, et al. Cancer Treat Res. 2004;118:23-46.


Prevalence of Osteolytic Bone Destruction in Multiple Myeloma Frequency of skeletal abnormalities and bone pain detected by x-ray

(N = 824)

7168

63 60

LyticLesions

Bone Painat Diagnosis

Osteopenia PathologicFractures

Pat

ien

ts (

%)

0

10

20

30

40

50

60

70

80

90

100


Melton LJ 3rd, et al. J Bone Miner Res. 2005;20:487-493

Fracture Incidence Myeloma Patients

Retrospective cohort study of 168 patients with myeloma

~ 20% present with pathologic fracture at diagnosis

– 1-yr rate of pathologic fracture is 40%

– Even with disease control, rate of fracture continues to rise

– ~ 60% of patients will sustain a pathologic fracture during the course of their disease

Patients with fracture have 20% increased risk of death


Bone Is Removed by Osteoclast Activity and Replaced by Osteoblast Activity

Courtesy of Dr. G R Mundy, Vanderbilt University.


Bone Remodeling Is Uncoupled in MM

Hattner R, et al. Nature. 1965;206:489-490. Normal Myeloma


Malignant Disease and the Skeleton

Tumor

Bone formation:blastic metastases

Bone resorption:lytic metastases,hypercalcemia


Bone Cell Stimulation in Malignancy

Multiple Myeloma

Osteolytic Solid TumorsIncluding Breast Cancer

Osteoclasts Osteoblasts


Bone Scans in Myeloma Can Underestimate Bone Involvement


Current Treatment of MM Bone Disease

Surgical procedures

– Vertebroplasty

– Balloon kyphoplasty

Radiotherapy

Bisphosphonates

Novel agents

Treatment of myeloma


Surgical Treatment of Vertebral Compression Fractures in Cancer Patients Operative management

– Vertebral column reconstruction

– A or P decompression with internal fixation

– Oncology patients are generally poor candidates for open surgery due to soft bone/tumor mass and comorbidities

Minimally invasive procedures

– Vertebroplasty

– Balloon kyphoplasty


Tumor-Related VCFs: Vertebroplasty

Fourney DR, et al. J Neurosurg. 2003;98(1 suppl):21-30. Reproduced with permission from the American Association of Neurological Surgeons. http://www.aans.org/

http://www.aans.org/


Tumor-Related VCFs: Balloon Kyphoplasty

Introduction Allows precise, minimally

invasive access to the vertebral body

Provides working channel

Balloon inflation Reduces the fracture Compacts the bone May elevate endplates

Removal Leaves a defined cavity

and trabecular dam that can be filled with an approved bone void filler of the physician’s choice


PlaceboPamidronate

Berenson JR, et al. N Engl J Med. 1996;334:488-493. Berenson JR, et al. J Clin Oncol. 1998;16:593-602.

Pamidronate Decreases Skeletal-Related Events in Myeloma Patients

24

41 38

9 21

Pat

ien

ts (

%)

0

10

20

30

40

50

60

Mos

51

P < .001P = .015


Zoledronic Acid and Pamidronate in Multiple Myeloma

Patients with no SRE similar between pamidronate and zoledronic acid over the study period (13 wks)

Median time to first SRE ~ 1 yr for both pamidronate and zoledronic acid

Rosen LS, et al. Cancer J. 2001;7:377-387.

4446

0

20

40

60

Pamidronate90 mg

Zoledronicacid 4 mg

All SREs

Pat

ien

ts W

ith

SR

E (

%) 8

0

100


Myeloma Bone DiseaseMyeloma cells

Tumor-derived osteoclast activating factors Macrophage

inflammatory protein IL-3

Tumor-derived osteoblast inhibitory factors DKK1, IL-3, sFRP2, IL-7

Bone

Osteoclast Osteoblasts

(-)

Stromal cells– RANKL– IL-6

Derived from Roodman GD. N Engl J Med. 2004;350:1655-1664.

(+) (+)


RANKL

OPG

Pearse RN, et al. Proc Natl Acad Sci U S A. 2001;98:11581-11586. Copyright 2001. National Academy of Sciences, U.S.A.

RANK Ligand Is Increased and OPG Is Decreased in Myeloma


Effect of Denosumab vs Pamidronate on Urinary NTX in Patients With Myeloma

90807060504030201000

10

20

40

60

Uri

ne

NT

X

(mm

ol B

CE

/mm

ol C

reat

inin

e) 50

30

DaysValues are expressed as absolute medians

Pamidronate 90 mgDenosumab 3.0 mg/kg

Denosumab 0.3 mg/kgDenosumab 0.1 mg/kg

Denosumab 1.0 mg/kg

Reproduced and adapted with permission from the American Association for Cancer Research: Body JJ, et al. Clin Cancer Res. 2006;12:1221-1228.


Phase II Study of Denosumab in Relapsed and Plateau-Phase MM Effective for myeloma bone disease

Median changes in bone resorption markers were -70% and -52% for relapsed and PP patients

Vij R, et al. Am J Hematol. 2009;84:650-656.


Denosumab vs Zoledronate

Phase III trial in 1776 patients with solid tumors (not breast or prostate) or myeloma

– Primary endpoint: median time to first SRE

Delay in time to first SRE or subsequent SRE was not statistically different

Serious adverse events were similar

ONJ infrequent and similar (10 vs 11 patients)

Henry D, et al. EJC Supplements. 2009;7(3):12. Abstract 20LBA.


DKK1 and sFRP-2 in Myeloma Bone Disease Inhibitors of the WNT signaling pathway

WNT signaling is a critical pathway for OBL differentiation

Secreted by myeloma cells

Marrow plasma from patients with high levels of DKK1 or sFRP-2 inhibit murine OBL differentiation

DKK1 gene expression levels correlated with extent of bone disease in MM patients

Tian E, et al. N Engl J Med. 2003;349:2483-2489. Oshima T, et al. Blood. 2005;106:3160-3165.


Anti-DKK1 Increases Bone Formation in the SCID-Rab MM Model

This research was originally published in Blood. Yaccoby S, et al. Blood. 2007;109:2106-2111.© The American Society of Hematology.

ControlAnti-DKK1

P < .001

BM

D (

% C

han

ge)

10

5

0

-5

-10

-15

-20

Control

Anti-DKK1

Pre-Rx Final

Boneresorption

Boneformation


Activin decreases bone mineral density and strength

Activin and Bone Growth

Reduced bone formation

Activin

Activin inhibits osteoblasts

Osteoblast

Activinreceptortype IIA

Activin

Activinreceptortype IIA

Activin stimulates osteoclasts

Increased bone resorption

Osteoclast


Activin A Levels Are Elevated in Patients With MM and Osteolytic Disease

Activin A levels are increased in bone marrow plasma of MM

patients

Activin A is produced by the microenvironment, notably BMSCs and osteoclasts

Average Levels of Activin A MM 0-1 OL: 28.62 ± 6.2 pg/mLMM > 1 OL: 112.07 ± 30.4 pg/mLnon-MM: 30.6 ± 7.9 pg/mL

Vallet S, et al. Proc Natl Acad Sci U S A. 2010;107:5124-5129. Copyright 2010 National Academy of Sciences, U.S.A.

*P < .05; †P < .01

NS150

100

50

0

pg

/mL

MM 0-1 OL

MM > 1 OL

Non MM

* *3500

2500

500

0

pg

/mL

OC

3000

2000

1500

1000

BMSC OB MM

Mean1300

Mean1884

NS

Mean299 Mean

8.2

†

†


Normal Mice Mice + Tumor Mice + Tumor

+ RAP-011

Chantry A, et al. Cancer Treat Rev. 2008;34: Supplement 1 pg 3. Reprinted with permission.

RAP-011 Prevents Development of Myeloma Bone Lesions


Novel Therapeutic Targets forMM Bone Disease Target Potential Therapy

RANKL Anti-RANKL

MIP-1a CCR1 antagonist

DKK1/sFRP-2 WNT agonist, anti-DKK1, bortezomib

Activin A ACE-011


Agents Used to Treat Multiple Myeloma Also Affect Bone

Thalidomide

Lenalidomide

Bortezomib


Giuliani N, et al. Blood. 2007;110:334-338.

Effect of Bortezomib on Bone Formation in MM Patients Analysis of in vivo effect of bortezomib in a cohort of MM

patients

– Significant increase in the number of osteoblastic cells x mm2 of bone tissue observed in MM patients responding to bortezomib treatment

– No significant increase in nonresponders

– Osteoblastic cells x mm2 of bone tissue in responder MM patients after therapy decreased compared with healthy bone from the control group

– Significant increase in the number of Runx-2/Cbfa1–positive osteoblastic cells in responder MM patients compared with nonresponders

Strategies to Prevent and Manage Bone Compromise

in Breast Cancer


Causes of Cancer Treatment–InducedBone Loss

Bone loss

GnRH agonists

Bilateral oophorectomy Bilateral orchiectomy

Chemotherapy-induced ovarian failure

Elevated bone turnover

Pfeilschifter J, et al. J Clin Oncol. 2000;18:1570-1593. Theriault RL. Oncology (Williston Park). 2004;18(5 suppl 3):11-15. Dempster DW. Osteoporos Int. 2003;14 suppl 5:S54-S56.

Diminished bone quality

Aromatase inhibitors

Glucocorticoids

Hypogonadism


Bone Loss With Cancer Therapies

1. Kanis JA. The European Foundation for Osteoporosis and Bone Disease. Osteoporos Int. 1997;7:390-406. 2. Eastell R, et al. J Bone Miner Res. 1990;5:1237-1241. 3. Maillefert JF, et al. J Urol. 1999;161:1219-1222. 4. Gnant M, et al. Lancet Oncol. 2008;9:840-849. 5. Shapiro CL, et al. J Clin Oncol. 2001;19:3306-3311.

Bo

ne

Lo

ss a

t 1

Yr

(%)

Naturally Occurring Bone Loss

CTIBL

0

2

4

6

8

10

Normal Men[1]

Postmenopausal Women[1]

Menopausal Women[1]

Al Therapy inPostmenopausal

Women[2]

ADT[3]

Al Therapy+ GnRH

Agonist inPremenopausal

Women[4]

Premature Menopause

Secondary toChemotherapy[5]

0.51.0

2.02.6

4.6

7.07.7


Tamoxifen

LetrozoleAnastrozole

Placebo

Fra

ctu

res

(%)

11.0

7.7

5.7

4.0

5.34.6

7.0

5.0

P < .0001

P < .001

0

2

4

6

8

10

12

14

P = .003

P = .25

Exemestane

ATAC[1]

(68 Mos)IES[2]

(58 Mos)BIG 1-98[3]

(26 Mos)MA.17[4]

(30 Mos)

Steroidal and Nonsteroidal AIs Increase Fracture Risk Compared With Tamoxifen

1. Howell A, et al. Lancet. 2005;365:60-62. 2. Coleman RE, et al. Lancet Oncol. 2007;8:119-127. 3. Thürlimann B, et al. N Engl J Med. 2005;353:2747-2757. 4. Goss PE, et al. J Natl Cancer Inst. 2005;97:1262-1271.


SABRE: Prevention of AI-Induced Bone Loss With Risedronate

*P values from paired t-test for open-label, noncomparative groups.†P values from ANCOVA in favor of anastrozole plus risedronate.

AnastrozoleAlone

Lower Risk (n = 26) Moderate Risk (n = 114)

Anastrozole+ Placebo

Anastrozole+ Risedronate

Anastrozole+ Risedronate

Higher Risk (n = 33)

Per

cen

t C

han

ge

in B

MD

F

rom

Ba

seli

ne

to 2

4 M

os

P = .0109* P = .5988*

P = .0006*

P = .0104*

P < .0001†

P < .0001†-2.0

-1.0

0

1.0

2.0

3.0

4.0

5.0

-3.0

Lumbar spine Total hip

Van Poznak C, et al. J Clin Oncol. 2010;28:967-975.


Ellis GK, et al. J Clin Oncol. 2008;26:4875-4882. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

Prevention of AI-Induced Bone Loss With Denosumab

Per

cen

t C

han

ge

in B

MD

Fro

m

Bas

elin

e at

Lu

mb

ar S

pin

e

8

7

6

5

4

3

2

1

0

-1

-2

-31 3 6 12 24

Mos

5.5% Difference at 12 Mos

7.4% Difference at 24 Mos

*P < .0001 vs placebo

Placebo (n = 122)Denosumab (n = 123) *

*

**

*


ABCSG-12 Trial Design

Accrual 1999-2006

1803 premenopausal patients with breast cancer

Endocrine responsive (ER+ and/or PgR+)

Stage I and II, < 10 positive nodes

No chemotherapy except neoadjuvant

Treatment duration: 3 yrs

RandomizeSurgery(+ RT)

Tamoxifen 20 mg/day

Goserelin3.6 mg q28d

Anastrozole 1 mg/day + Zoledronic Acid 4 mg q6m

Anastrozole 1 mg/day

Tamoxifen 20 mg/day + Zoledronic Acid 4 mg q6m

Gnant M, et al. N Engl J Med. 2009;360:679-691.


Gnant M, et al. Lancet Oncol. 2008;9:840-849.

Adjuvant Endocrine Therapy ± Zoledronic Acid: Changes in BMD

10

5

0

-5

-10

-15

Per

cen

t C

han

ge

in L

um

bar

Sp

ine

BM

D (

g/c

m2 )

Fro

m B

asel

ine

Mo Mo

Mo Mo

No Zoledronic Acid

Tamoxifen Anastrozole

36 60

-9.0P < .0001

-4.5NS

-13.6P < .0001

-7.8P = .003

36 60

36 60 36 60

Zoledronic Acid

Tamoxifen Anastrozole

+1.0NS

+5.2P = .04

-0.1NS

+3.1NS


Letrozole

Key endpointsPrimary: BMDSecondary: Bone markers, fractures, time to recurrence/relapse

Letrozole + Zoledronic Acid 4 mg q6mo

2193 patients withstage I-IIIa breast cancer

Postmenopausal or amenorrheic due to cancer treatment

ER+ and/or PgR+ T-score ≥ -2 SD

Delayed Zoledronic Acid

If 1 of the following occurs: BMD T-score < -2 SD Clinical fracture Asymptomatic fracture at 36 mosTreatment duration 5 yrs

R

Z-FAST/ZO-FAST/E-ZO-FAST


1.96%

*P values correspond to intergroup comparisons. †Intragroup comparisons from baseline to all time points for all treatment groups were significant (P ≤ .0003 for all).

Lumbar Spine

Mea

n (

SE

M)

Pe

rce

nt

Ch

ang

e i

n B

MD

Up-front ZOL 4 mg/6 mos Delayed ZOL 4 mg/6 mos

Brufsky A, et al. SABCS 2009. Abstract 4083. Reprint permission granted.

Z-FAST: Up-front ZOL Increases BMD in Lumbar Spine and Hip (N = 602)

P < .0001, all time points*†

8

6

4

2

0

-2

-4

-6

Mos12 24 36 48 61

3.14% 3.85%4.64%

6.19%

-2.33%-2.89% -2.99% -3.05% -2.42%

∆4.29% ∆6.03% ∆6.84% ∆7.69% ∆8.61%

1.26%

Total Hip

P < .001, all time points*†

4

3

2

1

0-1

-4

-6

Mos12 24 36 48 61

1.41% 1.68% 1.70%2.57%

-1.88%-3.15% -3.46%

-4.02% -4.12%

∆3.14% ∆4.56% ∆5.14% ∆5.72% ∆6.69%

-2-3

-5


Fractures in E/Z/ZO-FAST (3 Trials)

Over 36 mos of therapy, patients receiving up-front ZOL experienced fewer fractures than patients whose treatment was delayed

Fractures, %

Study Mos Up-front ZOL Delayed ZOL

Z-FAST[1] 36 5.7 6.3

ZO-FAST[2] 36 5.0 6.0

E-ZO-FAST[3] 12 0.8 1.9

1. Brufsky AM, et al. Clin Breast Cancer. 2009;9:77-85.2. Eidtmann H, et al. Ann Oncol. 2010;[Epub ahead of print].3. Llombart A, et al. ECCO 2007. Abstract 2044.


100

90

80

70

60

50

40

30

20

10

00 12 24 36 48 60 72 84

Mos Since Randomization

DF

S (

%)

HR (95% CI)Events, n vs No ZOL P Value

ZOL 54 0.64 (0.46-0.91).01

No ZOL83No ZOL ZOL

Gnant M, et al. N Engl J Med. 2009;360:679-691.Copyright © 2009 Massachusetts Medical Society. All rights reserved.

ABCSG-12: ZOL Significantly Improves DFS by 36%

Median Follow-up: 48 Mos

Eve

nts

(n

)

10

10

9

6

29*

41*

2010

Secondary malignancyContralateral BCDistantLocoregional

83

54

*Includes 23 bone metastases in No ZOL group and 16 in ZOL group.

100

90

80

70

60

50

40

30

20

10

0


Delayed ZOL(n = 532)

Up-front ZOL(n = 532)

50

45

40

35

30

25

20

15

10

5

Pat

ien

ts (

n)

3

5

20

30

10

2

Disease Recurrence (36 Mos)[2]*

1. Coleman R, et al. SABCS 2009. Abstract 4082. 2. Eidtmann H, et al. Ann Oncol. 2010;[Epub ahead of print].

ZO-FAST 48 Mos: Up-front ZOL Significantly Reduces the Risk of DFS Events by 41%

LocalDistantLymph node

0

1.0

0.8

0.6

0.4

0.2

00 6 36 42 48 54 60 66

Study Mo

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

ZOL 4 mg up-front

ZOL 4 mg delayed

12 18 24 30

Up-front DelayedPatients, n 532 533

Events/censored 32/500 53/480Median follow-up 48.0 48.1HR (95% CI) 0.59 (0.38-0.92)Up-front vs delayedlog rank P value .0175

DFS at Median Follow-up 48 Mos[1]

*Multiple sites of metastases may be reported for the same patient. Sites of distant metastases include bone, brain, liver, lung, skin, lymph node, and other.


27.4

15.5

Adjusted Mean Path CR %

6.911.7

P = .0006*

P = .146*

Coleman RE, et al. Br J Cancer. 2010;102:1099-1105.

AZURE: Neoadjuvant CT + Zoledronic Acid Reduces Residual Invasive Tumor Size

Chemotherapy aloneChemotherapy + zoledronic acid

Res

idu

al I

nva

sive

Tu

mo

r S

ize

(mm

)

60

50

40

30

20

10

0

*Multivariate analysis (N = 205).


Scope of the Problem

400,000 new patients/yr in the United States develop bone metastases


Hypercalcemia

Bone metastasis

Fracture

Spinal cord compression

Bone pain

Disease Consequences

Primary treatment

Symptomatic treatment

Optimal Management of Bone Metastases:

Treat the Disease


Incidence of Skeletal-Related Events

Lung Cancer/Others†

Prostate Cancer*

Multiple Myeloma†

Breast Cancer*

Coleman RE. Oncologist. 2004;9(suppl 4):14-27

*24 mos.†21 mos.‡Placebo arm of pamidronate or zoledronic acid randomized trials.

48

49

51

68

0 20 40 60 80

Patients With SREs (%)‡


Skeletal-Related Events and OS

Mos

As advances are made in cancer treatment, survival is increased—and with it, the risk of skeletal-related events

Median Time to a Skeletal-Related Event and Median Survival

Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. Rosen LS, et al. Cancer. 2004;100:2613-2621. Saad F, et al. J Natl Cancer Inst. 2004;96:879-892. Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

53.0

44.8

26.7

12.3

11

9

12

5.3

0 20 40 60

Prostate

Myeloma

Breast

Lung

Skeletal-related eventSurvival


Study Design: International, Randomized, Double-Blind, Active-Controlled StudyKey inclusion

Adults with advanced breast cancer and confirmed bone metastases

Key exclusion

Current or previous IV bisphosphonate administration

1° Endpoint

2° Endpoints

Time to first on-study SRE (noninferiority)

Time to first on-study SRE (superiority)

Time to first and subsequent on-study SRE (superiority)

Zoledronic acid 4 mg IV* and Placebo SC q4w (n = 1020)

Denosumab 120 mg SC and Placebo IV* q4w (n = 1026)

Supplemental Calcium and Vitamin D

*IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per zoledronic acid label).

Stopeck A, et al. SABCS 2009. Abstract 22.


Baseline Characteristics

Characteristics Zoledronic Acid(N = 1020)

Denosumab(N = 1026)

Women, n (%) 1011 (99) 1018 (99)

Median age, yrs 56 57

ECOG PS 0 or 1, n (%) 932 (91) 955 (93)

Hormone receptor positive, n (%) 726 (71) 740 (72)

Median time from first bone metastasis to randomization, mos

2 2

Previous SRE, n (%) 373 (37) 378 (37)

Presence of visceral metastases, n (%) 525 (51) 552 (54)

Stopeck A, et al. SABCS 2009. Abstract 22. Reprint permission granted.


Time to First On-Study SRE

Zoledronic acid 1020 829 676 584 498 427 296 191 94 29

Denosumab 1026 839 697 602 514 437 306 189 99 26

Patients at Risk, n

*Adjusted for multiplicity.

KM Estimate ofMedian Mos

DenosumabZoledronic acid

Not reached26.5

HR: 0.82 (95% CI: 0.71-0.95;P < .0001 noninferiority;P = .01 superiority)*

Mos

1.00

Pro

po

rtio

n o

f S

ub

ject

s W

ith

ou

t S

RE

0 3 6 9 12 15 18 21 24 27 30

0.25

0.50

0.75


0


Time to First and Subsequent SRE*: Multiple Event Analysis

*Events that occurred at least 21 days apart.†Adjusted for multiplicity.

Total Number of Events


474608

Rate ratio: 0.77 (95% CI: 0.66-0.89)P = .001†

Mos

1.5

Cu

mu

lati

ve M

ean

N

um

ber

of

SR

Es

0 3 6 9 12 15 18 21 24 27 30

0.5

1.0


0


Time to Experiencing Mod or Severe Pain (Worst Pain Score > 4 Pts/Brief Pain Inv)

KM Estimate ofMedian Days


8864

HR: 0.87 (95% CI: 0.79-0.97;P = .009)

Pro

po

rtio

n o

f S

ub

ject

s

0

1.00

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75


Zoledronic acid 1020 463 318 250 209 172 126 93 56 17

Denosumab 1026 511 378 312 256 214 159 109 59 27

Patients at Risk, nMos


Pro

po

rtio

n o

f S

ub

ject

s W

ith

ou

tD

isea

se P

rog

ress

ion

0 3 6 9 12 15 18 21 24 27 30

Disease Progression

HR: 1.00 (95% CI: 0.89-1.11; P = .93)


0

1.00

0.25

0.50

0.75

Mos

Zoledronic acid 1020 842 686 563 462 370 240 148 65 17

Denosumab 1026 858 693 567 453 351 241 128 65 20

Patients at Risk, n



Overall Survival

Zoledronic acid 1020 962 897 834 757 699 515 352 184 54

Denosumab 1026 984 916 849 771 690 511 336 177 57

HR: 0.95 (95% CI: 0.81-1.11; P = .49)

Mos

1.00

Pro

po

rtio

n o

f S

ub

ject

s S

urv

ived

0 3 6 9 12 15 18 21 24 27 30

0.25

0.50

0.75

Patients at Risk, n



0


Adverse Events

Adverse Event, % Zoledronic Acid (n = 1013)

Denosumab (n = 1020)

Overall 97.0 96.0

Serious 46.0 44.0

Acute phase reactions (first 3 days) 27.3 10.4

Renal toxicity

Overall 8.5 4.9

Serious 1.5 0.2

ONJ* 1.4 2.0

*P = .39



Incremental Benefits in Breast Cancer

64% risk of skeletal complication with no bisphosphonate at 2 yrsApprox 33% risk reduction with pamidronate

64% 43% 34%

Further 20% risk reduction with zoledronic acidFurther 20% risk reduction with zoledronic acid

27%

Additional 18% risk reduction with

denosumab

Lipton A, et al. Cancer. 2000;88:3033-3037. Rosen LS, et al. Cancer. 2004;100:36-43. Stopeck A, et al. ECCO/ESMO 2009. Abstract 2LBA.

Strategies for Bone-Directed Therapy in Prostate Cancer


Spectrum of Bone Disease in Prostate Cancer

Treatment-Related Fractures

Disease-Related Skeletal Complications

Castrate sensitive, nonmetastatic

Castrate resistant, nonmetastatic

Castrate resistant, metastatic

New Bone Metastases


Clinical Complications of Osteoblastic Metastases Pain

Fractures

Spinal cord compression

Myelophthisis


Reprinted with permission from the American Association of Cancer Research. Cook RJ, et al. Clin Cancer Res. 2006;12:3361-3367. Figure 1B.

Markers of Osteoblast (BAP) and Osteoclast (NTx) Activity in Men With PC

NTx (nmol/mmol Creatinine)

BA

P (

U/L

)

Correlation coefficient = 0.67

Normal


Brown JE, et al. J Natl Cancer Inst. 2005;97:59-69. http://jnci.oxfordjournals.org Copyright © 2005 Oxford University Press.

Mos

High NTx Low NTx

Elevated NTx Is Associated With Greater Risk for SRE and Death

Pro

po

rtio

n W

ith

at

Lea

st 1

SR

E (

%)

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24

Mos

Pro

po

rtio

n D

ied

(%

)

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24


Zoledronic Acid Study 039

Primary endpoint: incidence of skeletal-related events

Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.

Placebo q3w

Zoledronic Acid q3w

Randomize

Castrate-resistant prostate cancer

patients with bone metastases

(N = 643)


Mos

0 1 3 6 9 12 15-80

-60

-40

-20

0

20

Ch

ang

e F

rom

Bas

elin

e (%

)

Zoledronic Acid Inhibits Urinary NTx

Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. http://jnci.oxfordjournals.org Copyright © 2002 Oxford University Press.

Zoledronic acid Placebo


ZOL Reduced the Cumulative Incidence of Skeletal-Related Events Skeletal-related events

– Radiation to bone

– Pathologic fracture

– Spinal cord compression

– Surgery to bone

– Change in antineoplastic therapy

Saad F, et al. J Natl Cancer Inst 2004;96:879–882. Saylor PJ, et al. Prostate Cancer Prostatic Dis. 2010;13:20-27.

Patients in ZOL (4 mg) arm had significantly fewer SREs vs placebo (33.2 vs 44.2%; P = .02)

Median time to first SRE extended from 321 to 488 days (P = .009).


Denosumab to Prevent Skeletal-Related Events

Primary endpoint skeletal-related events: fracture, radiation or surgery to bone, spinal cord compression

ClinicalTrials.gov. NCT00321620.

Denosumab 120 mg SC +Placebo IV q4w

(n = 950)

Zoledronic Acid 4 mg IV + Placebo SC q4w

(n = 951)

Patients with CRPC and bone metastases,no current or previous

IV treatment with bisphosphonate

(N = 1901)


Baseline Characteristics

Characteristic Zoledronic Acid(N = 951)

Denosumab(N = 950)

Age, median yrs 71.0 71.0

ECOG performance score of 0 or 1, n (%) 886 (93) 882 (93)

Stratification factors Proportion of subjects with PSA

≥ 10 ng/mL, n (%) 806 (85) 805 (85)

Chemotherapy (≤ 6 wks before randomization), n (%) 132 (14) 132 (14)

Previous SRE, n (%) 231 (24) 232 (24)

Time from first bone metastasis to randomization, median mos (Q1, Q3) 5.2 (1.3, 16.1) 3.9 (1.2, 15.7)

Fizazi K, et al. ASCO 2010. Abstract LBA4507. Reprinted with permission.


Drug Exposure and Adjustments for Renal Function


Overall Exposure Zoledronic Acid(n = 946)

Denosumab (n = 942)

Median number of doses (Q1, Q3) 10.5 (5.0, 17.0) 13.0 (6.0, 19.0)

Cumulative exposure, patient-yrs 913.6 991.3

Adjustments for Renal Function

Subjects with dose adjustments for creatinine clearance at baseline, n (%)

213 (22.5) Not applicable*

Subjects with doses withheld for serum creatinine increases on study, n (%)

143 (15.1) Not applicable*

Total number of does withheld due to serum creatinine increases on study

592 Not applicable*

*Per protocol.


Denosumab vs Zoledronic Acid: Time to First On-Study SRE


1.00

0.75

0.50

0.25

00 3 6 9 12 15 18 21 24 27

Pro

po

rtio

n o

f S

ub

ject

s W

ith

ou

t S

RE

Study Mo


HR: 0.82 (95% CI: 0.71-0.95;P = .0002 noninferiority;P = .008 superiority)

KM Estimate ofMedian, Mos

20.717.1

Patients at Risk, nZoledronic acidDenosumab

951950

733758

544582

407472

299361

207259

140168

93115

6470

4739


Time to First and Subsequent On-Study SRE* (Multiple Event Analysis)

*Events occurring at least 21 days apart.

Rate ratio: 0.82 (95% CI: 0.71-0.94; P = .008)

Study Mo

0.0

2.0

0 3 6 9 12 15 18 21 24 27

Cu

mu

lati

ve M

ean

Nu

mb

er o

f S

RE

s p

er P

atie

nt

30 33 36

0.2

0.6

1.0

1.4

1.8

0.4

0.8

1.2

1.6

Denosumab Zoledronic acid 584584

494494

Events



Overall Disease Progression

0

Pro

po

rtio

n o

f S

ub

ject

sW

ith

ou

t D

isea

se P

rog

ress

ion

0 3 6 9 12 15 18 21 24 27

Study Mo

1.00

0.25

0.50

0.75


HR: 1.06 (95% CI: 0.95-1.18)

Zoledronic acid 951 708 507 356 246 168 108 74 50 33Denosumab 950 715 518 370 273 180 111 71 51 32

Patients at Risk, n



Overall Survival

Zoledronic acid 951 864 745 635 519 401 297 207 143 98 55Denosumab 950 872 746 645 552 427 310 233 156 99 54

Pro

po

rtio

n o

f S

ub

ject

s S

urv

ived

0 3 6 9 12 15 18 21 24 27 30

Patients at Risk, n

HR: 1.03 (95% CI: 0.91-1.17)

0

1.00

0.25

0.50

0.75

Study Month




Denosumab vs Zoledronic Acid: Safety


Adverse Event, % Zoledronic Acid (n = 945)

Denosumab (n = 943)

Serious adverse events 60 63

Adverse events causing treatment discontinuation 15 17

Anemia 36 36

Back pain 30 32

Decreased appetite 29 28

Nausea 26 29

Fatigue 24 27

Acute-phase reactions (first 3 days) 17.8 8.4

Renal adverse events 16.2 14.7

ONJ 1.3 2.3

Hypocalcemia 5.8 12.8

New primary malignancy 1.1 1.9


Conclusions

Disease-related skeletal complications are common in men with metastatic prostate cancer

Zoledronic acid decreases risk of skeletal-related events in men with castrate-resistant disease and bone metastases

Denosumab is superior to zoledronic acid for delay in first skeletal-related events and rate of skeletal-related events in this setting


Spectrum of Bone Disease in Prostate Cancer

MetastasisPrevention





Natural History of Castrate-Resistant Nonmetastatic Prostate Cancer

Smith MR, et al. J Clin Oncol. 2005;23:2918-2925.

Patients (n = 201) in the analysis from the placebo control group of aborted clinical trial that investigated the effects of zoledronic acid on time to first bone metastasis in castrate-resistant nonmetastatic prostate cancer

Patients with bone metastases at 2 yrs: 33%

Median bone metastasis-free survival: 30 mos

Baseline PSA (> 10 ng/mL) and PSA doubling time independently predicted shorter time to first bone metastasis, metastasis-free survival, and OS


Denosumab to Prevent Metastases

Primary endpoint: bone metastasis–free survival


RANDOMI ZE

Denosumab 60 mg monthlyPatients with castrate-

resistant prostate cancer and no bone metastases;

PSA > 8 or PSADT < 10 mos

(Planned N = 1435)Placebo monthly

Accrual complete: Q2 2008 Final analyses: 2010


ZEUS: Zoledronic Acid to Prevent Metastases

Primary endpoint:first bone metastasis

Wirth M, et al. ASCO GU 2008. Abstract 184.

RANDOMI ZE

Zoledronic acid q3m for 48 mos

Patients with high-risk prostate cancer:

Gleason sum 8-10, pN+, or PSA >20 ng/mL at diagnosis; no bone

metastases

(N = 1433)

Placebo q3m for 48 mos

Study does not control for ADT

1. Some men will develop bone metastases prior to ADT

2. Dramatic variation in duration of response to ADT


Conclusions: Metastasis Prevention

Prevention of bone metastases is an important unmet clinical need

Failure of previous studies is related, at least in part, to previously poorly defined natural history of castrate-resistant nonmetastatic disease

An ongoing randomized clinical trial in high-risk subjects will evaluate whether denosumab prevents metastases


Spectrum of Bone Disease in Prostate CancerTreatment-Related

FracturesDisease-Related

Skeletal Complications




New Bone Metastases


Inci

den

ce/1

,000

,000

Per

son

-Yrs

Age (Yrs)

4000

3000

2000

1000

35-39 ≥ 85 ≥ 85

HipSpine

Men Women

Melton LJ 3rd, et al. J Bone Miner Res. 1992;7:1005-1010.

Fracture Risk by Sex and Age

35-39


Proportion of Patients With Fractures1-5 Yrs After Cancer Diagnosis

Shahinian VB, et al. N Engl J Med. 2005;352:154-164

0

3

6

9

12

15

18

Any Fracture Fracture Resulting in Hospitalization

Fre

qu

ency

(%

)

+2.8%; P < .001

+6.8%; P < .001

ADT (n = 6650)No ADT (n = 20,035)

12.6

21

5.2

19.4

2.4


LumbarSpine

TotalHip

P < .001 for each comparison

12-mo data

Per

cen

t C

han

ge

Mittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661.

GnRH Agonists Decrease BMD in Men With Prostate Cancer

-5

-4

-3

-2

-1

0

1

2

GnRH agonistControl


Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy

LumbarSpine

TotalHip

Final 12-mo dataBM

D P

erce

nt

Ch

ang

e

-6

-4

-2

0

2

4

6Placebo

Zoledronic acid

Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042.


LumbarSpine

TotalHip

12-mo data

Greenspan SL, et al. Ann Intern Med. 2007;146:416-424.

Alendronate Increases BMD During GnRH Agonist Therapy

BM

D P

erce

nt

Ch

ang

e

-3

-2

-1

0

1

2

3

4

5Placebo

Alendronate

P < .005 for each comparison


Endpoint Subjects Sample Size

BMD All 50-100

Vertebral fractures High risk >1000

Hip fractures High risk > 5000

Clinical Trial Design for Osteoporosis


Denosumab Fracture Prevention Study

Primary endpoints: bone mineral density, new vertebral fractures


Current androgen deprivation therapy for prostate cancer patients older than 70 yrs of age or with T score < -1.0

(N = 1468)

Denosumab q6mfor 3 yrs

Placebo q6mfor 3 yrs


Denosumab to Increase BMD in Prostate Cancer Patients Receiving ADT

Smith MR. N Engl J Med. 2009;361:745-755. Copyright © 2009 Massachusetts Medical Society.All rights reserved.

Denosumab

Difference at 24 mos: 6.7 percentage points

Lumbar Spine

Mos

Per

cen

t C

han

ge

in B

MD

F

rom

Bas

elin

e

10

8

6

4

2

0

-2

-4

-601 3 6 12 24 36

Placebo

Difference at 24 mos: 4.8 percentage points

Total Hip

Mos

Per

cen

t C

han

ge

in B

MD

F

rom

Bas

elin

e

10

8

6

4

2

0

-2

-4

-601 3 6 12 24 36


Denosumab to Prevent Fractures

12Mos

24 36

P = .004 P = .004 P = .006

1.9

0.3

3.3

1.0

3.9

1.5

0

2

4

6

8

10

New

Ver

teb

ral

Fra

ctu

re (

%) Placebo

Denosumab

13 2 22 7 26 10Patients, nSmith MR. N Engl J Med. 2009;361:745-755. Copyright © 2009 Massachusetts Medical Society.All rights reserved.


Summary: Prevention of Treatment-Related Fractures Androgen deprivation therapy increases fracture risk

Bisphosphonates increase bone mineral density during androgen deprivation therapy

– Not shown to prevent treatment-related fractures in men with prostate cancer

Denosumab increases bone mineral density and decreases fractures during androgen deprivation therapy

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