Robert Coleman,

1
Breast Cancer and Bone Health

• Robert Coleman,
• Cancer Research Centre,
• Weston Park Hospital,
• Sheffield

2
Breast Cancer and Bone Health

• Normal Bone Health
• Impact of Cancer Therapies on Bone Health
• Therapeutic Strategies
• Management Guidelines

3
Breast Cancer and Bone Health

• Normal Bone Health
• Impact of Cancer Therapies on Bone Health
• Therapeutic Strategies
• Management Guidelines

4
The Structure of Bone
Cortical Bone
Vascular Supply
Trabecular Bone
Marrow
5
Properties of the skeleton

• Skeleton composition
• 80 cortical bone (mostly in the appendicular
  skeleton)
• 20 trabecular bone (mostly in the axial
  skeleton)
• Trabecular bone
• large surface area / unit volume
• highly responsive to metabolic processes
• turnover is 8x that of cortical bone
• more sensitive for measuring changes in BMD due
  to bone loss or therapy
• annual turnover rate of 25 compared with 56
  for cortical bone.
• Fractures commonly occur in trabecular bone
• (e.g. vertebra, femoral neck, distal radius).

6
Bone Remodeling
Osteoclast
Osteoblasts
7
Bone Remodeling
8
Components of Bone Strength
Bone density
Bone quality

• Architecture
• Bone turnover
• Accumulation of lesions (microfractures)
• Secondary mineralisation

aBMD g/cm2 vBMD g/cm3
NIH Consensus Development Panel. JAMA 2001 285
(6) 785-795
9
Lifetime Changes in Bone Mass
BMD
Gain
Consolidation
Loss
Men
Women
Cancer Treatments
Age
10
Interpretation of a DEXA Scan
Z score
T score
11
Diagnosis of Osteoporosis
Adapted from Kanis, JA. Lancet 2002
359(9321)1929-36
12
BMD and Fracture Risk in the Normal Population
Average BMD _at_ 35 years
16X
8X
4X
2X
1X
-4.0
1.0
0
-1.0
-2.0
-3.0
T score
13
80 of Fractures Occur in Patients Who Have
Normal or Osteopenic BMD
Fracture rate

• Fracture rate increases 2-fold in osteopenic
  women
• Majority of fractures occur in osteopenic women
  (T-score 1.0 to 2.5)

BMD, bone mineral density. Reprinted from Siris
ES, et al. Arch Intern Med. 2004164(10)1108-1112
.
14
Sex, Age and Treatment Effects on Bioavailable
Oestradiol Concentrations
Aromatase Inhibitor Therapy
Adapted from Khosla et al. J Clin Endocrinol
Metab 2001863555-61
15
Low Oestrogen Levels Increase Relative Fracture
Risk

• Women 65 years with undetectable estrogen
  levels (lt 5 pg/mL) have a 2.5-fold increased risk
  for subsequent hip or vertebral fracturesa

1.0 1.0
1.00
Spine fracture
Hip fracture
0.75
0.5
0.5
0.50
Relative risk
0.4 0.4
0.3
0.3
0.25
0.00
lt 5
7 - 9
10
5 - 6
Endogenous serum estradiol level, pg/mL
a. Compared with women with detectable estrogen
levels. Adapted from Cummings SR, et al. N Engl
J Med. 1998339(11)733-738.
16
Normal and Cancer Treatment Related Bone Loss
Rates
10
Naturally occurring bone loss
CTIBL
7.7
8
7.0
Bone loss at I year
6
4
2.6
2.0
2
1.0
0.5
0
Postmenopausal Women gt551
Premature menopause secondary to chemotherapy4
AI therapy plus GnRH agonist in premenopausal
women3
Normal men1
AI therapy in postmenopausal women2
Menopausal Women lt551

• Kanis JA. Osteoporosis.199722-55.
• Eastell R et al. J Bone Mineral Res. 2002.
• Gnant M. San Antonio Breast Cancer Symposium,
  2002.
• Shapiro CL et al. J Clin Oncol. 2001193306-3311.

17
Breast Cancer and Bone Health

• Normal Bone Health
• Impact of Cancer Therapies on Bone Health
• Therapeutic Strategies
• Management Guidelines

18
Fracture Episode Rates Throughout the ATAC Study
4
End of Treatment
Anastrozole (A)Tamoxifen (T)
146 v 143 fractures
3
Annual fracture episode rates ()
2
375 v 234 fractures
1
RR1.03 P 0.79
RR1.55 P lt0.0001
0
0
1
2
3
4
5
6
7
8
9
Time since randomization (years)
At risk
2984 2976
A T
2859 2824
2745 2699
2640 2572
2496 2419
2306 2208
2077 2000
1713 1645
702 659
Forbes et al Lancet Oncology 2008
19
Fracture Rates in Adjuvant Trials of Aromatase
Inhibitors
20
ATAC -Percentage Change in BMD Over Time
Anastrozole (n81)
Tamoxifen (n86)
Lumbar spine
Total hip
Estimated change (mean and 95 CI)
4
4
2
2
0
0
-2
-2
-4
-4
-6
-6
-8
-8
-10
-10
Baseline
1
2
5
Baseline
1
2
5
Time (years)
Time (years)

• Significantly more BMD loss on anastrozole than
  tamoxifen
• plt0.0001 for both lumbar spine and total hip BMD
  primary analysis
• No patient with normal baseline BMD developed
  osteoporosis

Eastell et al J Clin Oncol 261051, 2008.
21
Breast Cancer and Bone Health

• Normal Bone Health
• Impact of Cancer Therapies on Bone Health
• Therapeutic Strategies
• Management Guidelines

22
Overall Structure of Bisphosphonates
PO
H
3
2
R
Chain
2
Chain
R
1
C
PO
H
3
2
23
Z-FAST / ZO-FAST / E-ZO-FAST Trial design
Key endpoints Primary Bone mineral density
(BMD) at 12 mo Secondary Fracture, disease
recurrence, disease free-survival, bone markers

• 2,193 patients
• Breast cancer
• Stage I to IIIa
• Postmenopausal or amenorrheic due to cancer
  treatment
• ER and/or PgR
• T-score 2 SD

R
Letrozole zoledronic acid 4 mg every 6 months

• Delayed zoledronic acid
• If 1 of the following occurs
• BMD T-score lt 2 SD
• Clinical fracture
• Asymptomatic fracture at 36 months

Letrozole
Treatment duration 5 years
BMD Bone mineral density ER Oestrogen
receptor PgR Progesterone receptor R
Randomisation SD Standard deviation.
24
Z-FAST Immediate Zoledronic Acid Increases BMD
in Lumbar Spine and Hip
Upfront ZOL (4 mg/6 months)
Delayed ZOL (4 mg/6 months)
(N 602)
P lt .0001
P lt .0001
P lt .0001
4
P lt .0001
P lt .0001
P lt .0001
3
2
? 4,4
? 6.7
1
? 5.9
? 3.3
? 4.7
? 5.2
Mean (SEM) change BMD
0
1
2
3
4
Month 24
Month 12
Month24
Month12
Month 36
Month 36
Lumbar spine
Total hip
SEM Standard error of the mean BMD Bone
mineral density ZOL Zoledronic acid.P values
correspond to intergroup comparisons.Intragroup
comparisons from baseline to month 12 or 24 for
all treatment groups were significant (P lt .0001
for all). Adapted from Brufsky A, et al.
Presented at 29th SABCS 2006, Abstract
5060.Brufsky A, et al. Presented at 30th
SABCS 2007, Abstract 27.
25
ARIBON Study Design- Monthly Oral Ibandronate
Lester et al. Clin Cancer Res, in press, 2008
26
ARIBON Study Results - Monthly Oral Ibandronate
150mg
SPINE
HIP
Lester et al. Clin Cancer Res, in press 2008
27
ABCSG-12 - Bone Protection Study with Zoledronic
Acid

• Premenopausal women with early breast cancer
• No chemotherapy

Tamoxifen 20 mg/d
Tamoxifen 20 mg/d Zoledronic Acid 4mg q6m
Surgery (RT)
Goserelin 3.6mg q28d
Randomize 1 1 1 1
Anastrozole 1 mg/d
Anastrozole 1 mg/d Zoledronic Acid 4mg q6m
Gnant MF, et al. J Clin Oncol. 200725820-828.
28
ABCSG XII 6 Monthly Zoledronic Acid Reduces Bone
Loss
Ana ZA plt0.0001
END OF TREATMENT
Tam ZA p0.049
Tamoxifen alone plt0.0001
Anastrozole alone plt0.0001
Gnant MF, et al. Lancet Oncology 2008
ABCSG-12 Austrian Breast and Colorectal Cancer
Study Group Trial 12.
29
Zoledronic Acid Preserves BMD During 3 Years of
Adjuvant Therapy
Goserelin/Anastrozole ZOL
Goserelin/Anastrozole
BMD Bone mineral density ZOL Zoledronic
acid. Adapted from Gnant MF, et al. J Clin
Oncol. 200725(7)820-828.
30
First DFS Events (ITT Population)
No ZOL vs ZOL
First event per patient, n
H.R. 0.65 p.017
(n 904)
(n 899)
DFS Disease-free survival ITT
Intent-to-treat ZOL Zoledronic acid.
Gnant M, et al. NEJM 2009
31
Denosumab For Treatment of Bone Loss on Aromatase
Inhibitors

• RANKL stimulates osteoclasts and bone resorption
• Denosumab
• Novel fully human monoclonal antibody to RANKL

Cancer Cells in Bone
Direct effects on tumor?
Cytokines and GrowthFactors (IL-6, IL-8,
IL-1b,PGE-2, TNF-a, CSF-1, PTHrP)
Growth Factors (TGF-b, IGFs, FGFs,PDGFs, BMPs)
Osteoclast
RANKL
RANKL
BoneResorption
OsteoblastLineage
Bone
32
Denosumab Effect on Lumbar Spine Bone Mineral
Density
Ellis G, et al. J Clin Oncol 2008
33
Breast Cancer and Bone Health

• Normal Bone Health
• Impact of Cancer Therapies on Bone Health
• Therapeutic Strategies
• Management Guidelines

34
ASCO Guidelines on Bone Health
ASCO Guidelines 2003 Hillner, B. E. et al. J
Clin Oncol 214042-4057 2003
35
UK Management for Bone Loss in Breast Cancer -
NOS/NCRIPost-menopausal women gtage 45

• Baseline DEXA scan and risk assessment if for AI
  therapy
• Risk adapted strategy
• Lifestyle advice and adequate calcium and vitamin
  D
• 1 g calcium and 800iu vitamin D
• Reassure if T score gt -1 and no risk factors
• No monitoring required
• Monitor BMD of osteopaenic patients every 2 years
• Baseline T score lt-1
• Intervention with bisphosphonates
• gt age 75 and gt 1 risk factor for osteoporotic
  fracture
• T score lt -2 either at baseline or on follow-up
• T score lt -1 at baseline and annual bone loss gt4

Reid et al. Cancer Treatment Reviews 2008.
36
UK Guidance Algorithm on Management of Bone Loss
in Early Breast Cancer
POST-MENOPAUSAL WOMEN
Reid et al. Cancer Treatment Reviews 2008
37
UK Management for Bone Loss in Breast Cancer -
NOS/NCRIPremature menopause at age lt45

• Baseline DEXA scan and risk assessment
• Lifestyle advice and adequate calcium and vitamin
  D
• 1g calcium and 800iu vitamin D
• Risk adapted strategy
• Reassure if T score gt -1 and not on concomitant
  AI
• No monitoring required
• Monitoring of BMD
• Perform every 2 years if
• T score lt -1 without an AI
• All patients if concomitant AI
• Intervention with bisphosphonates
• Concomitant AI and T score lt -1
• T score lt -2 either at baseline or on follow-up
• Annual bone loss gt4 on serial BMD monitoring

Reid et al. Cancer Treatment Reviews 2008
38
UK Guidance Algorithm on Management of Bone Loss
in Early Breast Cancer
PREMATURE MENOPAUSE BEFORE AGE 45
Reid et al. Cancer Treatment Reviews 2008
39
European Recommendations for Women Initiating
Aromatase Inhibitor Therapy

• Any 2 of the following risk factors
• T-score lt 1.5
• Age gt 65 years
• Low BMI (lt 20 kg/m2)
• Family history of hip fracture
• Personal history of fragility fracture after age
  50
• Oral corticosteroid use of gt 6 months
• Smoking (current or history of)

T-score lt 2.0
T-score 2.0, no risk factors
Calcium and vitamin D supplements
Zoledronic acid (4 mg / 6 months)calcium and
vitamin D supplements
Monitor BMD every 2 years
Monitor risk status and BMD every 1 to 2 yearsa

• Data for oral bisphosphonates are emerging
• Evidence from 4 clinical trials indicates that
  zoledronic acid prevents AI-associated bone loss

a. 5 drop in BMD should trigger zoledronic
acid treatment (4 mg / 6 mo). Use lowest T-score
from 3 sites.BMI Body mass index BMD Bone
mineral density AI Aromatase
inhibitor.Adapted from Hadji P, et al. Ann
Oncol. 200819(8)1407-1416.
40
WHO FRAX Index (www.shef.ac.uk/FRAX)
41
Bone Metastases in Cancer
42
Consequences of Bone Metastases
Economic Burden
Poor functional capacity
Impaired mobility
Long and painful recovery from fractures
Severe bone pain
Metastatic Bone Disease
Hypercalcaemia
Inconvenient hospital/clinic visits
Pain and paralysis from spinal cord compression
43
Bone Metastases Can Lead to SREs
Patients who will likely develop an SRE without
treatment
of patients
Renal cell carcinoma (n74)
Multiple myeloma (n179)
Breast (n114)
Prostate (n208)
NSCLC (n250)
Data are from placebo-controlled arms of
bisphosphonate trials. Lipton A et al. Cancer.
200398962-969. Berenson JR et al. J Clin Oncol.
199816593-602. Kohno N et al. J Clin Oncol.
2005233314-3321. Saad F et al. J Natl Cancer
Inst. 200496879-882. Rosen LS et al. Cancer.
20041002613-2621.
44
The Vicious Cycle of Bone Destruction

• Growth factors and cytokines released by tumor
  cells

Tumor Cells

• Osteoclastic resorption stimulated

PTHrP IL-6 IL-8, PGE2 TNF-? CSF-1

• Peptides (eg, TGF-ß) released by bone resorption

BMP PDGF FGFs IGFs TGF-ß

• Tumor cell production of factors increased

• More bone resorption

• Tumor cell proliferation

Osteoclast
Adapted from Mundy GR, Yoneda T. N Engl J Med.
1998339398-400. Courtesy John Mackey
Bone
45
Effect of Bisphosphonates on Vicious Cycle of
Bone Destruction

• Decrease activity of osteoclasts

Tumor Cells

• Reduction in release of peptides

• Slowed tumor-cell growth

• Reduced production of PTHrP and other factors

• Decrease in bone resorption

Bone
Adapted from Mundy GR, Yoneda T. N Engl J Med.
1998339398-400. Courtesy John Mackey
46
Added Benefit of Zoledronic Acid Over
Pamidronate in Breast Cancer
64 risk of skeletal complication with no
bisphosphonate at 2 years
Approx 33 risk reduction with pamidronate
Further 20 risk reduction with zoledronic acid
34
64
43
Lipton A, et al Cancer 2000 883033-3037 Rosen
LS, et al Cancer 200310036-43.
47
Conclusions

• Important effects of cancer treatments on bone
  health
• Ovarian suppression
• Aromatase inhibitors
• Effective management and treatment strategies
  emerging
• DEXA baseline assessment required
• Risk adapted monitoring and intervention
• Bisphosphonates effective in preventing bone loss
  
• Bone metastases cause considerable morbidity
• Bisphosphonates markedly reduce number and
  severity of skeletal complications