1. Denosumab Treatment for 5 Years of Postmenopausal Women With Osteoporosis: Results From the First Two Years of the FREEDOM Trial Extension
Henry G Bone1, Roland Chapurlat2, Maria Luisa Brandi3, Jacques P Brown4, Edward Czerwinski5, Nadia S Daizadeh6, Andreas Grauer6, Mark-Antoine Krieg7, Cesar Libanati6, Zulema Man8, Dan Mellstrom9, Sebastiao Radominski10, Jean-Yves Reginster11, Heinrich Resch12, Jose Andres Román13, Christian Roux14, Steven R Cummings15, Socrates Papapoulos16
1Michigan Bone and Mineral Clinic, Detroit, MI, USA ; 2Hôpital Edouard Herriot, Lyon, France; 3University of Florence, Florence, Italy; 4CHUQ Research Centre, Laval University, Quebec City, QC, Canada; 5Krakow Medical Center, Krakow, Poland; 6Amgen Inc., Thousand Oaks, CA, USA; 7University Hospital of Lausanne, Lausanne, Switzerland; 8Centro TIEMPO, Buenos Aires, Argentina; 9Sahlgrenska University Hospital, Göteburg, Sweden; 10Universidade Federal do Paraná, Curitiba, Brazil; 11University of Liège, Liège, Belgium; 12St. Vincent's Hospital, Vienna, Austria; 13Hospital Universitario La Fe, Valencia, Spain; 14Paris Descartes University, Paris, France; 15San Francisco Coordinating Center, CPMC Research Institute, San Francisco, CA, USA; 16Leiden University Medical Center, Leiden, The Netherlands
AACE; San Diego, CA; April 13-17, 2011

2. Disclosures
HG Bone: Research grants and/or consulting or speaking fees from Amgen, Eli Lilly, Merck, Nordic Bioscience, Novartis, Takeda, Tarsa, and Zelos
R Chapurlat: Research grants and/or consulting fees from Amgen, Merck, Novartis, Roche, sanofi-aventis, Servier, and Warner Chilcott
ML Brandi: Research grants and/or consulting fees from Amgen, Eli Lily, GSK, MSD, NPS, Nycomed, Roche, Servier, and Stroder
JP Brown: Research grants and/or consulting or speaking fees from Abbott, Amgen, Bristol-Myers Squibb, Eli Lilly, Novartis, Merck, Pfizer, Roche, and Warner Chilcott
E Czerwinski: Research grants from Amgen, AstraZeneca, Danone Research, Eli Lilly, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, SantoSolve AS, and Servier
NS Daizadeh, A Grauer, C Libanati: Employed by Amgen and own Amgen stocks or stock options
M-A Krieg, D Mellstrom, H Resch: None
Z Man: Lecture fees and/or consulting fees from Merck, Novartis, Roche, and sanofi-aventis; Novartis steering committee member
S Radominski: Research grants from Amgen, Aventis, Bristol-Myers Squibb, Novartis, Pfizer, and Roche
J-Y Reginster: Research grants, consulting fees, and/or lecture fees from Amgen, Analis, Bristol-Myers Squibb, Ebewe Pharma, Genevrier, GSK, IBSA, Eli Lilly, Merck Sharp & Dhome, Negma, Novartis, Novo- Nordisk, Nycomed, NPS, Roche, Rottapharm, Servier, Teijin, Teva, Theramex, UCB, Wyeth, and Zodiac
JA Román: Research grants from Roche
C Roux: Research grants and/or consulting fees from Amgen, MSD, Novartis, Roche, and Servier
SR Cummings: Research grants and/or consulting fees from Amgen, Eli Lilly, Merck, and Novartis
S Papapoulos: Consulting fees from Amgen, GSK, Merck, Novartis, Procter & Gamble, and Wyeth

3. Background
FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months) assessed the efficacy and safety of 3 years of denosumab treatment compared with placebo in postmenopausal women with osteoporosis.1
FREEDOM was extended to evaluate the safety and efficacy of long-term denosumab treatment (up to 10 years of continuous exposure).
The first 2 years of the FREEDOM open-label extension are reported in this analysis (up to of 5 years of continuous denosumab exposure).
1Cummings SR et al., NEJM 2009;361:756-65

4. Study Objectives
Describe the effects of up to 5 years of continuous denosumab exposure on:
Changes in bone turnover and bone density
Safety and tolerability
Incidence of new vertebral and nonvertebral fractures

5. FREEDOM Extension Study Design
International, multicenter, open-label, single-arm study
FREEDOM
EXTENSION
Year 1 2 3 4 5 6 7 8 9 10 R A N D O M I Z T
Denosumab 60 mg
SC Q6M
(N = 3902)
Denosumab 60 mg
SC Q6M
(N = 2343)
Long-term
Denosumab
Calcium and Vitamin D
Placebo
SC Q6M
(N = 3906)
Denosumab 60 mg
SC Q6M
(N = 2207)
Cross-over
Denosumab
Year 1 2 3 4 5 6 7
Key Inclusion Criteria:
Must have completed the FREEDOM study (received denosumab or placebo)
Not receiving any other osteoporosis medications

6. Baseline Characteristics
Long-term DMAb Treatment EXTENSION Subjects
N = 2343
Cross-over DMAb Treatment EXTENSION Subjects
N = 2207
FREEDOM Baseline
EXTENSION Baseline
Age (years)
71.9
74.9
71.8
74.8
Age groups (%)
≥ 65 years
94.3%
97.9%
93.7%
97.4%
≥ 75 years
28.3%
53.7%
52.2%
Prevalent vertebral fractures (%)
23.9%
24.5%
22.0%
25.0%
LS BMD T-score
–2.83
–2.14
–2.84
–2.81
TH BMD T-score
–1.85
–1.50
–1.93
CTX* (ng/mL)
0.524
0.183
0.554
0.568
P1NP* (µg/L)
46.72
17.49
54.24
48.80
N = number of subjects enrolled in the EXTENSION. Data are mean unless otherwise noted.
*Includes data from 65 subjects (long-term) and 36 subjects (cross-over); values are medians.
Demographics and baseline characteristics of the EXTENSION study subjects were similar to the parameters of ALL subjects enrolled in FREEDOM study (N = 7808)
CTX (mean [SD]) was (0.251) ng/mL and (0.335) ng/mL for the De Novo and Long-Term groups at Extension Study Baseline

7. Percent Change in Serum CTX and P1NP
Placebo
Denosumab
sCTX
P1NP 80 80
FREEDOM
EXTENSION
FREEDOM
EXTENSION 60 60 40 40 20 20
Percent Change From Baseline
Percent Change From Baseline
-20
-20
-40
-40
-60
-60
-80
-80
-100
-100 1 2 3 4 5 1 2 3 4 5
Year
Year
Median (IQR) 7

8. Percent Change in Lumbar Spine and Total Hip BMD
Placebo
Denosumab
Lumbar Spine
Total Hip 16 10
FREEDOM
EXTENSION
FREEDOM
EXTENSION 14 ^ † 8 12 ^ ^ † ^ 10 6 ^ † 8 4
Percent Change From Baseline
Percent Change From Baseline 6 ^ ^ † 4 2 ^ 2 * * * * * -2 -2
0.5 1 2 3 4 5
0.5 1 2 3 4 5
Year
Year
LS Mean (95% CI)
*p < 0.05 vs FREEDOM baseline; ^p < 0.05 vs FREEDOM and EXTENSION baseline; †p < 0.05 vs year 4.

9. 289 study 5-year data, Long-term treated subjects
Exposure-adjusted Subject Incidence of Adverse Events (Rates per 100 Patient-years)
Placebo
Denosumab
FREEDOM
Years 1-3
N = 3883
Rate (n)
N = 3879
EXTENSION
Long-term
Years 4-5
N = 2343
Cross-over
Years 1-2
N = 2206
All AEs
156.1
154.3
113.2
111.4
Infections
30.7
29.3
25.1
27.4
Malignancies
1.6
1.8
2.0
Eczema
0.6
1.1
0.9
Hypocalcemia
< 0.1 (3)
< 0.1 (1)
0.1 (5)
Pancreatitis
< 0.1 (7)
Serious AEs
10.4
10.6
10.8
11.1
1.3
1.5
1.2
Cellulitis or
Erysipelas
0.1 (12)
ONJ
< 0.1 (2)
Atypical fracture 9

10. Yearly Incidence of New Vertebral Fractures: Long-term Denosumab Group
Placebo
Denosumab
FREEDOM
EXTENSION
3.5%
3.1%
3.1%
3.0%
New Vertebral Fractures
Yearly Incidence of
2.5%
2.2%
2.0%
1.5%
1.4%
1.1%
1.0%
0.9%
N = number of subjects in the primary efficacy analysis set who were still on study at the beginning of each period
0.7%
0.5%
0.0% n 82 32
107 24 98 35
59 (2-year total) N
3691
3702
3400
3453
3186
3247
2100 1 2 3
4 and 5*
Years of Treatment Exposure
n = number of subjects with ≥ 1 fracture
N = number of randomized subjects who remained on study at the beginning of each period
*Annualized rate

11. Yearly Incidence of Nonvertebral Fractures: Long-term Denosumab Group
Placebo
Denosumab
FREEDOM
EXTENSION
3.5%
3.1%
2.9%
3.0%
Nonvertebral Fractures
Yearly Incidence of
2.6%
2.5%
2.5%
2.2%
2.1%
2.0%
1.5%
1.4%
1.1%
1.0%
0.5%
0.0% n
116 98
103 75 83 73 32 25 N
3906
3902
3688
3682
3454
3487
2343
2242 1 2 3 4 5
Years of Treatment Exposure
n = number of subjects with ≥ 1 fracture
N = number of randomized subjects who remained on study at the beginning of each period

12. New Vertebral Fractures Years of Treatment Exposure
Yearly Incidence of New Vertebral Fractures: Cross-over Denosumab Group
Placebo
Denosumab
Denosumab Cross-over
FREEDOM
EXTENSION
3.5%
3.0%
New Vertebral Fractures
Yearly Incidence of
2.5%
2.5%
2.0%
1.5%
0.9%
N = number of subjects in the primary efficacy analysis set who were still on study at the beginning of each period
1.0%
0.7%
0.5%
0.0% n
183 53 34 N
3691
3702
1978
1 and 2*
1 and 2*
Years of Treatment Exposure
n = number of subjects with ≥ 1 fracture
N = number of randomized subjects who remained on study at the beginning of each period
*Annualized rate

13. Yearly Incidence of Nonvertebral Fractures: Cross-over Denosumab Group
Placebo
Denosumab
Denosumab Cross-over
FREEDOM
EXTENSION
FREEDOM
EXTENSION
3.5%
3.1%
2.9%
3.0%
Nonvertebral Fractures
Yearly Incidence of
2.6%
2.4%
2.5%
2.1%
2.0%
1.7%
1.5%
1.0%
N = number of subjects in the primary efficacy analysis set who were still on study at the beginning of each period
0.5%
0.0% n
116 98 52
103 75 35 N
3906
3902
2207
3688
3682
2104 1 1 2 2
Years of Treatment Exposure
n = number of subjects with ≥ 1 fracture
N = number of randomized subjects who remained on study at the beginning of each period

14. Summary Denosumab treatment for 5 years (long-term group):
Maintained the reduction in bone turnover
Significantly increased BMD year over year
Remained well tolerated with an AE profile similar in years 4 and 5 to that observed in the 3 years of the placebo-controlled FREEDOM study
Maintained a low incidence of new vertebral and nonvertebral fractures
Denosumab treatment for 2 years (cross-over group) largely reproduced the original findings from FREEDOM 14

15. Denosumab Treatment for 5 Years of Postmenopausal Women With Osteoporosis: Results From the First Two Years of the FREEDOM Trial Extension
Henry G Bone1, Roland Chapurlat2, Maria Luisa Brandi3, Jacques P Brown4, Edward Czerwinski5, Nadia S Daizadeh6, Andreas Grauer6, Mark-Antoine Krieg7, Cesar Libanati6, Zulema Man8, Dan Mellstrom9, Sebastiao Radominski10, Jean-Yves Reginster11, Heinrich Resch12, Jose Andres Román13, Christian Roux14, Steven R Cummings15, Socrates Papapoulos16
1Michigan Bone and Mineral Clinic, Detroit, MI, USA ; 2Hôpital Edouard Herriot, Lyon, France; 3University of Florence, Florence, Italy; 4CHUQ Research Centre, Laval University, Quebec City, QC, Canada; 5Krakow Medical Center, Krakow, Poland; 6Amgen Inc., Thousand Oaks, CA, USA; 7University Hospital of Lausanne, Lausanne, Switzerland; 8Centro TIEMPO, Buenos Aires, Argentina; 9Sahlgrenska University Hospital, Göteburg, Sweden; 10Universidade Federal do Paraná, Curitiba, Brazil; 11University of Liège, Liège, Belgium; 12St. Vincent's Hospital, Vienna, Austria; 13Hospital Universitario La Fe, Valencia, Spain; 14Paris Descartes University, Paris, France; 15San Francisco Coordinating Center, CPMC Research Institute, San Francisco, CA, USA; 16Leiden University Medical Center, Leiden, The Netherlands
AACE; San Diego, CA; April 13-17, 2011