This document discusses bone health management in breast cancer patients receiving adjuvant therapies. Key points include: - Studies have shown that zoledronic acid and denosumab can reduce bone mineral density loss and fracture risk in premenopausal and postmenopausal breast cancer patients receiving adjuvant aromatase inhibitors or tamoxifen. - The ABCSG-12 trial found that adding zoledronic acid to adjuvant endocrine therapy improved disease-free survival and overall survival in premenopausal breast cancer patients. - The AZURE trial found no difference in disease-free survival or overall survival between breast cancer patients receiving standard adjuvant therapy with or without zoledronic acid, though pre/perimenopausal patients

1. CÁNCER DE MAMA
TERÁPIAS ÓSEAS

2. CA DE MAMA TEMPRANO: PREVENCIÓN DE FX
AUMENTO DE LA SLE CON TERAPIAS
ADYUVANTES ÓSEAS
ENFERMEDAD METASTASICA

3. Predictors of Fracture Risk
• BMD (DXA), femoral neck T-score
– Serial monitoring should be done on the same
equipment with the same reference standards at the
same site
• Age
• Drugs
• History/presence of vertebral fracture
– Best predictor of a subsequent fracture is an existing
one
• Risk of falls
• Vitamin D levels

4. Tasa de Pérdida Ósea
1. Kanis JA. Osteoporosis. 1997:22-55. 2. Eastell R, et al. J Bone Miner Res. 2006;21:1215-1223.
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.
BoneLossat1Yr(%)
Naturally Occurring Bone Loss CTIBL
0
2
4
6
8
10
Normal
Men[1]
Postmenopausal
Women[1]
Al Therapy in
Postmenopausal
Women[2]
ADT[3]
Al Therapy
+ GnRH
Agonist in
Premenopausal
Women[4]
Premature
Menopause
Secondary to
Chemotherapy[5]
0.5
1.0
2.6
4.6
7.0
7.7

5. Tamoxifen
LetrozoleAnastrozole
Fractures(%)
11.0
7.7
5.7
4.0
7.0
5.0
P < .0001
P < .001
0
2
4
6
8
10
12
14
P = .003
Exemestane
ATAC[1]
(68 mos)
IES[2]
(58 mos)
BIG 1-98[3]
(26 mos)
Riesgo de fx elevado de los IA esteroidales y
noesteroidales vs Tamoxifeno
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.

6. Oral Bisphosphonate Impact on BMD
in Patients With Breast Cancer
• Clodronate in breast cancer patients with chemotherapy-induced
premature ovarian failure
Saarto T, et al. J Clin Oncol. 1997;15:1341-1347.
• Risedronate reduces bone loss in women with chemotherapy-
induced ovarian failure
Delmas PD, et al. J Clin Oncol. 1997;15:955-962.
• Alendronate in GnRH agonist-induced premature menopause
(patients without cancer)
Ripps BA, et al. J Reprod Med. 2003;48:761-766.
• Monthly ibandronate and anastrozole-induced bone loss
Lester JE, et al. Clin Cancer Res. 2008;14:6336-6342.
• SABRE trial: study of anastrozole with risedronate
Van Poznak C, et al. J Clin Oncol. 2010;28:967-975.

7. Management of Bone Health Using
BMD
T-Score: NCCN Task Force Report
• T-score: > -1 (normal)
• T-score: -1.0 to -1.5
• T-score: -1.5 to -2.0
• T-score < -2.0 or
FRAX 10-yr fracture risk:
> 20% major fracture
> 3% for hip fracture
• Repeat DXA every 2 yrs*
• Repeat DXA every 2 yrs*
• Consider checking 25(OH) level
• Repeat DXA every 2 yrs*
• Consider checking 25(OH) level
• Consider pharmacologic
therapy
• Repeat DXA every 2 yrs*
• Consider checking 25(OH) level
• Strongly consider
pharmacologic therapy
Gralow JR, et al. J Natl Compr Canc Netw. 2009;7:S1-S32.
*In selected cases, longer or shorter intervals may be considered. If a major change in patient risk
factors or a major intervention occurs, then repeating DXA at 1 yr is reasonable.

8. Key endpoints:
Primary: BMD at 12 mos
Secondary: BMD at 36 and 60 mos, disease recurrence, fractures, safety
Letrozole +
immediate Zoledronic Acid
4 mg every 6 mos
Breast cancer
stage I to IIIa
(N = 1065)
Postmenopausal or
amenorrheic due to
cancer treatment
ER+
and/or PgR+
T-score ≥ -2.0
Letrozole +
Treatment duration: 5 yrs
R
Delayed Zoledronic Acid
If 1 of the following occurs:
BMD T-score < -2
Clinical fracture
Asymptomatic fracture at
36 mos
Coleman R, et al. Ann Oncol. 2012. Oct 9.
ZO-FAST: A Phase III Study of the Use of
Zoledronic Acid With Adjuvant Letrozole

9. Coleman R, et al. Ann Oncol. 2012. Oct 9. [Epub ahead of print]
ZO-FAST (Primary Endpoint): Median
Change in LS BMD With Zoledronic Acid
Immediate zoledronic acid
Delayed zoledronic acid
P < .0001 for each
ChangeinLS(LS-L4)BMD(%)
12 Mos 24 Mos 36 Mos 48 Mos 60 Mos-6
-4
-2
0
2
4
6
+4.3
-5.4
Δ 5.9 Δ 8.2 Δ 8.8 Δ 9.2 Δ 10.0

10. Modalidades de tratamiento
Bifosfonatos orales
• Buena adherencia a sus
meds
• Rechazan meds IV
• No quieren o pueden ir a
la clínica
• Menos costosos
• Menos efectos 2os
• < riesgo de osteonecrosis
o de fx subtrocantéricas
Bifosfonatos IV
• Mayor adherencia en
pacientes con
intolerancia GI (RGE) u
otros síntomas.

11. ABCSG-12: Phase III Study of Adjuvant
Endocrine Therapy ± Zoledronic Acid
• Key endpoints
– Primary: DFS at 5 yrs
– Secondary: recurrence-free survival, OS, BMD, safety
TAM 20 mg/day
ANA 1 mg/day
Treatment 3 yrs
(median follow-up: 48 mos)
TAM + ZA 4 mg q6m
ANA + ZA 4 mg q6m
R
Long-term
monitoring
for 5 yrs for
recurrence
and survival
(DFS, OS)
3-yr
BMD
5-yr
BMD
Premenopausal patients with
stage I/II breast cancer
(goserelin 3.6 mg/28 days)
stratified by:
 ER+ and/or PgR+
 Age
 Stage
 Grade
 Lymph nodes
(N = 1803)
Gnant M, et al. N Engl J Med. 2009;360:679-691.

12. Gnant M, et al. Lancet Oncol. 2008;9:840-849.
ABCSG-12 Bone Substudy: Change in
BMD at Yrs 3 and 5
10
5
0
-5
-10
-15
PercentChangeinLS
BMD(g/cm2
)FromBaseline
Mos
Mos
No Zoledronic Acid
Tamoxifen Anastrozole
36 60
-9.0
P < .0001
-4.5
NS
-13.6
P < .0001
-7.8
P = .003
36 60
36 60 36 60
Zoledronic Acid
Tamoxifen Anastrozole
+1.0
NS
+5.2
P = .04
-0.1
NS
+3.1
NS

13. *
*
*
Ellis GK, et al. J Clin Oncol. 2008;26:4875-4882.
Denosumab in Patients With Breast
Cancer Receiving Adjuvant AIsPercentChangeinBMDFrom
BaselineatLS
8
7
6
5
4
3
2
1
0
-1
-2
-3
1 3 6 12 24
Mos
5.5% difference
at 12 mos
7.6% difference
at 24 mos
*P < .0001 vs placebo
Placebo (n = 122)
Denosumab 60 mg q6m (n = 123) *
*
Toxicity: no significant difference in AEs between denosumab and placebo arm

14. Checklist for Bone Health in Patients With
Breast Cancer
Item Description
Determine
osteoporosis risk
factors
•T-score < -1.5?
•Older than 65 yrs?
•Low BMI (< 20)?
Other factors
•Family history of hip fracture?
•Personal history of fragility after 50 yrs of age?
•Oral corticosteroid use of > 6 mos?
•Smoking (current or past history)?
•10-yr probability for hip fracture (by FRAX)?
Cancer treatment–
related factors
•AIs?
•Ovarian ablation?
Assays
•DXA to assess BMD (every 2 yrs)
•25(OH)D level
•Serum calcium level
Treat the following
with bone-directed
therapy
•Hip or vertebral fracture
•T-score < -2.0
•10-yr probability for hip fracture ≥ 3%
•10-yr probability of a major osteoporotic event ≥ 20%
Hadji P, et al. Ann Oncol. 2011;22:2546-2555. National Osteoporosis Foundation.

15. T-score < -2.0Any 2 of the following risk factors
 T-score < -1.5
 Aged younger than 65 yrs
 Low BMI (< 20)
 Family history of hip fracture
 Personal history of fragility fracture after
50 yrs of age
 Oral corticosteroid use of > 6 mos
 Smoking (current or history of)
T-score > -2.0, no risk
factors
Monitor risk status and
BMD q12m*
Monitor BMD on case by case
basis for IV bisphosphonates;
q12-24m for oral
bisphosphonates
Exercise
Calcium and vitamin D
supplements
*If ≥ 10% decrease in BMD (≥ 4% to 5% if osteopenic at baseline),
investigate secondary causes and begin antiresorptive treatment. Use lowest T-score from 3 sites.
Exercise
Treatment including
bisphosphonates,
denosumab,
Calcium, and vitamin D
supplements
Guidance for Women With Breast
Cancer Initiating AI Therapy: European
Guidelines
Hadji P, et al. Ann Oncol. 2011;22:2546-2555.

16. ¿AUMENTAR LA SOBREVIDA
LIBRE DE ENFERMEDAD?
Y/O
SOBREVIDA GLOBAL?

17. DFS
ABCSG-12 (84 Mos): Efficacy
100
80
60
40
20
0
DFS(%)
0 12 24 36 48 60 72 84 96 108
Mos Since Randomization
Patients at Risk, n
No ZA
ZA
903
900
858
862
833
841
807
822
758
788
653
674
521
544
405
419
191
208
Events,
n
Univariate Multiple Cox
Regression
HR
(95% CI)
P
Value
HR
(95% CI)
P
Value
vs no
ZA
vs no
ZA
(Log-
rank)
No
ZA
132/903
0.72
(0.56-0.94)
.014 0.71
(0.55-0.92)
.01198/900ZA
OS
100
80
60
40
20
0
DFS(%)
0 12 24 36 48 60 72 84 96 108
Mos Since Randomization
Patients at Risk, n
No ZA
ZA
903
900
864
868
856
858
839
849
811
818
706
708
576
587
456
454
215
232
Events,
n
Univariate Multiple Cox
Regression
HR
(95% CI)
P
Value
HR
(95% CI)
P
Value
vs no
ZA
vs no
ZA
(Log-
rank)
No
ZA
49/903
0.63
(0.40-0.99)
.049 0.61
(0.39-0.96)
.03333/900ZA
Gnant M, et al. SABCS 2011. Abstract S1-2.

18. ZA treatment duration: 5 yrs
AZURE: Study Design
Accrual September 2003 - February 2006
Country Centers,
n
Patients, n
United
Kingdom
123 2710
Ireland 10 247
Australia 28 226
Spain 8 107
Portugal 1 32
Coleman RE, et al. N Engl J Med. 2011;365:1396-1405.
Standard therapy
Standard therapy +
ZA 4 mg
Mos 6 30 60
3360 patients
with stage II/III
breast cancer
R
6 doses
q3-4w
8 doses
q3m
5 doses
q6m
 Primary endpoint: DFS, with recurrence
defined as date first suspected

19. AZURE: DFS and IDFS
Patients at Risk, n
1681 1591 1465 1354 1241 580 83
1678 1583 1445 1344 1252 561 71
DFS
0
ZA
Control
0
Patients at Risk, n
1681 1578 1443 1337 1222 570 82
1678 1574 1426 1316 1221 544 68
IDFS
0
ZA
Control
DFS IDFS
1 2 3 4 5 6 7
20
40
60
80
Yrs
Control (n = 1678)
Adjusted HR: 0.98 (95% CI: 0.85-1.13;
P = .79)
Surviving(%)
0
0
ZA (n = 1681)
0
100100
0
0 1 2 3 4 5 6 7
20
40
60
80
Yrs
Surviving(%)
0
0
100
0
0
Control (n = 1678)
Adjusted HR: 0.98 (95% CI: 0.85-1.12;
P = .73)
ZA (n = 1681)
Coleman RE, et al. N Engl J Med. 2011;365:1396-1405.

20. AZURE: IDFS and OS by
Menopausal Status
0
Mos Since Randomization
1.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
0.8
0.6
0.4
0.2
0
ProportionAliveand
invasiveDiseaseFree
IDFS: Pre, Peri, and Unknown Menopausal Status
Adjusted HR: 1.15
(95% CI: 0.97-1.36; P = .11)
288 vs 256 events
Patients at Risk, n
ZA:
No ZA:
1162 1088 996 919 829 393 57 0
1156 1092 995 920 853 388 47 0
0
Mos Since Randomization
1.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
0.8
0.6
0.4
0.2
0
ProportionAlive
OS: Pre, Peri, and Unknown Menopausal Status
Adjusted HR: 0.97
(95% CI: 0.78-1.21; P = .81)
161 vs 165 events
Patients at Risk, n
ZA:
No ZA:
1162 1131 1078 1020 955 466 71 0
1156 1123 1076 1032 963 446 60 0
0
Mos Since Randomization
1.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
0.8
0.6
0.4
0.2
0
ProportionAliveand
invasiveDiseaseFree
IDFS: > 5 Yrs Postmenopausal
Adjusted HR: 0.75
(95% CI: 0.59-0.96; P = .02)
116 vs 147 events
Patients at Risk, n
ZA:
No ZA:
519 490 447 418 393 177 25 0
522 482 431 396 368 156 21 0
0
Mos Since Randomization
1.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
0.8
0.6
0.4
0.2
0
ProportionAlive
OS: > 5 Yrs Postmenopausal
Adjusted HR: 0.74
(95% CI: 0.55-0.98; P = .04)
82 vs 111 events
Patients at Risk, n
ZA:
No ZA:
519 502 482 448 422 190 29 0
522 509 475 441 401 177 26 0
Coleman RE, et al. N Engl J Med. 2011;365:1396-1405.

21. Typical OR
Menopausal Group
Description
Total: -1% ± 7%
Z = .13; P = .9
χ2
1 (heterogeneity) = 7.91; P = .005
Odds Reduction (± SD)
n = 1041
263 events
n = 2318
544 events
HR: 0.75
(95% CI: 0.59-0.96)
HR: 1.15
(95% CI: 0.97-1.36)
Pre + < 5 yrs post
+ unknown status
> 5 yrs postmenopausal
High estrogen
environment
Low estrogen
environment
1.0 1.2 1.4 1.6 1.8 2.00.2 0.4 0.6 0.8
AZURE: Treatment Effect on IDFS
by Menopausal Status
Coleman RE, et al. N Engl J Med. 2011;365:1396-1405.

22. Niveles de Vit D 25 OHD > 30 ng/ml (suficientes)
predicen beneficio del Ac Zoledrónico en las
tasas de recidiva a distancia en pacientes
posmenopausicas

23. Marshall H, et al. ASCO 2012. Abstract 502.
Adjuvant Zoledronic Acid in Early Breast
Cancer: Expert Perspectives
• No benefit in overall unselected population
• Significant benefit in postmenopausal women seen in
multiple studies
– Effect of menopause on DFS driven by influences on
nonbone recurrence
• Potential for harm in pre- and perimenopausal women
• These subset analyses do not justify the routine use of
adjuvant zoledronic acid in postmenopausal women

24. Letrozole +
ZA 4 mg q6m
Letrozole + Delayed*
ZA 4 mg q6m
*If 1 of the following occurs:
BMD T-score < -2 SD
Clinical fracture
Asymptomatic fracture at 36 mos
Stage I-IIIa breast cancer
 Postmenopausal or
amenorrheic due to
cancer treatment
 ER+ and/or PgR+
 T-score ≥ -2 SD
N = 1060
Treatment duration: 5 yrs
De Boer R, et al. SABCS 2011. Abstract S1-3.
ZO-FAST: 5-yr Final Analysis

25. *Censored patients at initiation of D-ZA (n = 144).
Time on Study (mos)
532
533
518
511
500
491
488
475
475
463
376
368
IM-ZA
D-ZA
Patients at Risk, n
Time on Study (mos)
532
533
518
459
500
402
488
376
475
350
376
267
IM-ZA
D-ZA
Patients at Risk, n
ITT Population
100
90
80
70
60
50
40
30
20
10
0
DFS(%)
0 6 12 18 24 30 36 42 48 54 60 66
HR: 0.66; log-rank P value = .0375
IM-ZA 4 mg (42 events)
D-ZA 4 mg (62 events)
Censored Analysis*
100
90
80
70
60
50
40
30
20
10
0DFS(%)
0 6 12 18 24 30 36 42 48 54 60 66
HR: 0.62; log-rank P value = .024
IM-ZA 4 mg (42 events)
D-ZA 4 mg (53 events)
De Boer R, et al. SABCS 2011. Abstract S1-3.
27% of patients (n = 144) in the delayed arm initiated ZA on-study
DFS HR: 0.46; P = .033
ZO-FAST: Final 5-yr DFS

26. HR
ZO-FAST[1]
 104 events
ABCSG-12[3]
 230 events
0.2 0.4 0.6 0.8 1 1.2 1.4
N = 1803
1. De Boer R, et al. SABCS 2011. Abstract S1-3. 2. Coleman RE, et al. N Engl J Med. 2011;365:1396-
1405. 3. Gnant M, et al. SABCS 2011. Abstract S1-2.
N = 1065
n = 1041
AZURE - > 5 yrs postmenopausal[2]
 263 events
P Value
.02
.0375
.011
0.75
0.66
0.71
ZA Studies: DFS Comparison

27. NSABP B-34: Phase III Study of
Adjuvant Clodronate in Breast Cancer
• Primary endpoint: DFS
• Secondary endpoints: incidence of metastases, OS,
SREs, adverse events, and prognostic serum markers
Clodronate
1600 mg qd
Placebo
3323 patients with
stage I-II breast cancer
receiving adjuvant
standard therapy
Treatment duration: 3 yrs
R
Median follow-up: 8.4 yrs
Two thirds aged > 50 yrs; 25% N positive

28. NSABP B-34: DFS
Paterson A, et al. SABCS 2011. Abstract S2-3.
DiseaseFree(%)
100
80
60
40
20
0
0 2 4 6 8
Yrs After Randomization
Treatment
Placebo
Clodronate
N
1656
1655
Events, n
312
286
HR: 0.91; P = .27

29. NSABP B-34: Analysis of
Specified Endpoints and Safety
• Adverse events comparable in clodronate and placebo arms
– 1 case of ONJ observed in clodronate arm vs no cases in placebo
arm
Endpoint Events, n HR (95% CI) P Value
Clodronate
(n = 1662)
Placebo
(n = 1661)
DFS 286 312 0.913 (0.778-1.072) .266
OS 140 167 0.842 (0.672-1.054) .131
RFI 148 177 0.834 (0.671-1.038) .101
BMFI 61 80 0.765 (0.548-1.068) .114
NBMFI 78 105 0.743 (0.554-0.996) .046
Paterson A, et al. SABCS 2011. Abstract S2-3.

30. NSABP B-34 Subset Analysis: DMFI,
RFI, BMFI, and NBMFI in Patients ≥ 50
Yrs
Endpoint for Patients 50
Yrs of Age or Older
HR P Value
DMFI 0.62 .003
RFI 0.76 .05
BMFI 0.61 .024
NBMFI 0.63 .015
Paterson A, et al. SABCS 2011. Abstract S2-3.
DMFI: distant metastasis-free interval
RFI: relapse-free interval
BMFI: bone-metastasis-free interval
NBMFI: non-bone metastasis-free interval

31. GAIN Trial: Study Design
Möbus V, et al. SABCS 2011. Abstract S2-
4.
Arm A1: Arm B1:
Epirubicin
150 mg/m2
q2w
Ibandronate
50 mg PO QD 2 yrs
Paclitaxel
225 mg/m2
q2w
Cyclophosphamide
2000 mg/m2
q2w
Arm B2:
Observation
Arm A2:
Paclitaxel
67.5 mg/m2
qw
Capecitabine
2000 mg/m2
Days 1-14 q3w
Epirubicin
112.5 mg/m2
Cyclophosphamide
600 mg/m2
q2w
Pegfilgrastim
Ciprofloxacin
Darbepoetin alfa or Epoetin beta
Ciprofloxacin
Pegfilgrastim
Darbepoetin alfa or Epoetin beta

32. GAIN: DFS and OS (ITT)
1.0
0.8
0.6
0.4
0.2
0
SurvivalProbability(%)
DFS (Mos)
0 12 24 36 48 60
1
2
1996
998
1814
871
1590
727
1057
483
555
264
210
105
3-Yr DFS
Ibandronate: 87.6%
Observation: 87.2%
Cox Regression
HR: 0.945 (95% CI: 0.768-1.16; P = .
59)
Ibandronate Observation
Product-Limit Survival Estimates
With Number of Patients at Risk
+ Censored
1.0
0.8
0.6
0.4
0.2
0.0
OS (Mos)
0 12 24 36 48 60
1
2
1996
998
1836
886
1653
756
1121
506
586
277
219
112
3-Yr OS
Ibandronate: 94.7%
Observation: 94.1%
Cox Regression
HR: 1.04 (95% CI: 0.763-1.42; P = .80)
Product-Limit Survival Estimates
With Number of Patients at Risk
+ Censored
Möbus V, et al. SABCS 2011. Abstract S2-
4.

33. GAIN: Subgroup Analyses
DFS for Ibandronate in Subgroups
HR
0.5 1.0 1.5
Better With Ibandronate Worse With Ibandronate
pN1
pN2
pN3
ER and/or PgR positive
ER and PgR negative
Pre- and perimenopausal
Postmenopausal
< 60 yrs
≥ 60 yrs
HR: 1.04 (95% CI: 0.652-1.65; P = .877)
HR: 0.875 (95% CI: 0.599-1.28; P = .490)
HR: 0.951 (95% CI: 0.710-1.27; P = .734)
HR: 0.952 (95% CI: 0.736-1.23; P = .706)
HR: 0.856 (95% CI: 0.604-1.21; P = .383)
HR: 1.02 (95% CI: 0.756-1.37; P = .912)
HR: 0.897 (95% CI: 0.671-1.20; P = .462)
HR: 1.02 (95% CI: 0.807-1.30; P = .842)
HR: 0.746 (95% CI: 0.490-1.14; P = .172)
Möbus V, et al. SABCS 2011. Abstract S2-
4.

34. Variable Efficacy in
an Unselected Population
*Analysis relates to bone metastasis-free survival.
1. Coleman RE, et al. N Engl J Med. 2011;365:1396-1405. 2. Gnant M, et al. SABCS 2011. Abstract S1-2.
3. De Boer R, et al. SABCS 2011. Abstract S1-3. 4. Paterson A, et al. SABCS 2011. Abstract S2-3.
5. Powles T, et al. Breast Cancer Res. 2006;8:R13. 6. Mobus V, et al. SABCS 2011. Abstract S2-4.

35. Consistent Efficacy in
“Postmenopausal” Women
*Includes patients > 40 yrs on goserelin; no significant effect for patients < 40 yrs.
†
Analysis relates to OS.
‡
≥ 60 yrs at study entry.
1. Coleman RE, et al. N Engl J Med. 2011;365:1396-1405. 2. Gnant M, et al. SABCS 2011. Abstract S1-2.
3. De Boer R, et al. SABCS 2011. Abstract S1-3. 4. Paterson A, et al. SABCS 2011. Abstract S2-3.
5. Powles T, et al. Breast Cancer Res. 2006;8:R13. 6. Mobus V, et al. SABCS 2011. Abstract S2-4.

36. Conclusions
• Targeting the host environment may complement activity
of direct anticancer treatments
• Adjuvant benefit from bone-targeted treatment appears to
be dependent on a low reproductive hormone environment
– Biologic mechanisms need further evaluation
• Inhibiting the vicious cycle may not always be beneficial
• Adjuvant ZA should be considered in women with a low
estrogen environment
– Prevent bone loss and fragility fracture
– Potentially improve disease outcomes

37. Shepherd LE, et al. ASCO 2012. Abstract 501. Used with permission.
Exemestane vs Anastrozole in Early Breast
Cancer (MA.27): EFS Analysis
• EFS significantly improved with vs without osteoporosis therapy
(HR: 0.70; P < .00001)
Patient-
Reported
Outcome,
n (%)
Osteoporosis
Yes
(n =
1294)
No
(n =
6282)
Osteoporosis
therapy
(n = 2711)
1101
(85)
1610
(25.6)
No
osteoporosis
therapy
(n = 4865)
193
(15)
4672
(74.4)
100
80
0
PatientsWithoutEvent(%)
0 1 2 3 4 5 0
Yrs
P = .0003
Osteoporosis/no osteoporosis therapy
Osteoporosis/osteoporosis therapy
No osteoporosis/no osteoporosis therapy
No osteoporosis/osteoporosis therapy

38. FDA-Approved Antiosteoclast Agents for
Reduction of SREs in MBC
• Both ASCO and NCCN recommend all 3 agents
• No agent recommended over another
Agent Drug Class
Recommended Dose and
Schedule
Zoledronic
acid
Bisphosphonate 4 mg IV q3-4w
Pamidronate Bisphosphonate 90 mg IV q3-4w
Denosumab RANKL-targeted MAb 120 mg SQ q4w
1. Van Poznak CH, et al. J Clin Oncol. 2011;29:1221-1227. 2. National Comprehensive Cancer Network.
Clinical practice guidelines in oncology: breast cancer. v.1.2012.

39. Denosumab vs Zoledronic Acid: 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
KM Estimate of
Median Mos
Denosumab
Zoledronic acid
Not reached
26.4
HR: 0.82 (95% CI: 0.71-0.95; P < .001
noninferiority; P = .01 superiority*)
Mos
0
1.00
ProportionofSubjects
WithoutSRE
0 3 6 9 12 15 18 21 24 27 30
0.25
0.50
0.75
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

40. 40
20
0
Mo 12 Mo 18 At Time of Analysis
Denosumab (n = 1026)Zoledronic acid (n = 1020)
PercentofSubjects
WithSREs(95%CI)
4.5%
relative reduction
11.4%
relative reduction
15.4%
relative reduction
10
30
28.8%32.5% 32.9%38.9%25.4%26.6%
Stopeck A, et al. SABCS 2010. Abstract P6-14-01.
Denosumab vs Zoledronic Acid: Proportion
Experiencing ≥ 1 SRE

41. GRACIAS