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

Breast Cancer and Bone

Health

Robert Coleman,

Cancer Research Centre,

Weston Park Hospital,

Sheffield

Breast Cancer and Bone Health

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

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.



QuickTime™ and aTIFF (Uncompressed) decompressor


The Structure of Bone

Cortical Bone

Trabecular Bone

Marrow

Vascular Supply

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 5–6% for cortical

bone.

Fractures commonly occur in trabecular bone (e.g. vertebra, femoral neck, distal radius).

OsteoclastOsteoclastOsteoclastOsteoclast

OsteoblastsOsteoblastsOsteoblastsOsteoblasts

Bone Remodeling

Bone Remodeling

QuickTime™ and aTIFF (LZW) decompressor




• Architecture• Bone turnover• Accumulation of lesions

(microfractures)• Secondary mineralisation

aBMD = g/cm2

vBMD = g/cm3

Components of Bone Strength

NIH Consensus Development Panel. JAMA 2001; 285 (6): 785-795

Bone density

Bonequality +

Bonestrength

Lifetime Changes in Bone Mass

BMD

Age

Gain Consolidation Loss

Men

Women

Cancer

Cancer Treatments

Interpretation of a DEXA Scan

T score Z score

Diagnosis of Osteoporosis

Adapted from Kanis, JA. Lancet 2002; 359(9321):1929-36



BMD and Fracture Risk in the Normal Population

+1.0 0 -1.0 -2.0 -3.0 -4.0

1X2X

4X

8X

16XAverage

BMD @ 35 years

T score

• Fracture rate increases ~2-fold in osteopenic womenFracture rate increases ~2-fold in osteopenic women• Majority of fractures occur in osteopenic women (T-score –1.0 to –2.5)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. 2004;164(10):1108-1112.

Fracture rateNo. of women with fractures

450

400

350

300

250

200

150

100

50

0

Nu

mb

er o

f wo

me

n w

ith fra

ctu

res

BMD distribution

BMD

50

45

40

35

30

25

20

15

10

5

0

Fra

ctu

re r

ate

pe

r 1

,00

0 p

ers

on

-ye

ars

>1.0 1.0 to 0.5 0.5 to 0.0 0.0 to –0.5 –0.5 to –1.0 –1.0 to –1.5 –1.5 to –2.0 –2.0 to –2.5 –2.5 to –3.0 –3.0 to –3.5 < –3.5

80% of Fractures Occur in Patients Who Have Normal or Osteopenic BMD

Sex, Age and Treatment Effects on Bioavailable Oestradiol Concentrations

0

40

80

120

160

200

Bio

avai

lab

le E

2, p

mo

l/l

Premenopausal women

Postmenopausal women

Normal men

Androgen Deprivation

Therapy

Adapted from: Khosla et al. J Clin Endocrinol Metab 2001;86:3555-61

AromataseInhibitorTherapy

Low Oestrogen Levels Increase Relative Fracture Risk

a. Compared with women with detectable estrogen levels. Adapted from Cummings SR, et al. N Engl J Med. 1998;339(11):733-738.

Endogenous serum estradiol level, pg/mL

Hip fracture

Spine fracture

0.00

0.25

0.50

0.75

1.00

Rel

ativ

e ri

sk

< 5 7 - 9 ≥ 10

0.3 0.3

0.5 0.5

0.4 0.4

5 - 6

1.0 1.0

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

Normal and Cancer Treatment Related Bone Loss Rates

0.51.0

2.02.6

7.07.7

0

2

4

6

8

10

Bo

ne

loss

at

I ye

ar

Normal men1

AI therapy in postmenopausal

women2

AI therapy plus GnRH agonist in

premenopausal women3

MenopausalWomen

<551

PostmenopausalWomen >551

Premature menopause

secondary to chemotherapy4

Naturally occurring bone loss

CTIBL

1. Kanis JA. Osteoporosis.1997:22-55. 2. Eastell R et al. J Bone Mineral Res. 2002.3. Gnant M. San Antonio Breast Cancer Symposium, 2002. 4. Shapiro CL et al. J Clin Oncol. 2001;19:3306-3311.



RR=1.03P =0.79

Fracture Episode Rates Throughout the ATAC Study

29842976

At risk:AT

28592824

27452699

26402572

24962419

23062208

20772000

17131645

702659

Time since randomization (years)

Annual fracture episode rates

(%)

Anastrozole (A)Tamoxifen (T)

0 1 2 3 4 5 6 7 8 90

2

3

4

1 RR=1.55P <0.0001

End ofTreatment

375 v 234fractures

146 v 143fractures

Forbes et al Lancet Oncology 2008

Fracture Rates in Adjuvant Trials of Aromatase Inhibitors

Aromatase

Inhibitor

Tamoxifen /

Placebo

% Increase Reference

ATAC(Anastrozole)

340 (11%) 237 (7.7%) 43% Howell et al Lancet 2005

BIG 1-98(Letrozole)

211 (8.6%) 141 (5.8%) 50% Coates et al JCO 2007

IES(Exemestane)

162 (7.0%) 115 (4.9%) 41% Coombes et al Lancet 2007

ABCSG (Anastrozole)

34 (2.0%) 16 (1.0%) 113% Jakesz et al Lancet 2005

MA17(Letrozole)

137 (5.3%) 119 (4.6%) 15% Perez et al

JCO 2006

• Significantly more BMD loss on anastrozole than tamoxifen – p<0.0001 for both lumbar spine and total hip BMD primary analysis

• No patient with normal baseline BMD developed osteoporosis

Lumbar spine Total hipEstimated % change (mean and 95% CI)

Time (years) Time (years)

4

2

0

-2

-4

-6

-8

-10Baseline 1 2 5

4

2

0

-2

-4

-6

-8

-10Baseline 1 2 5

Tamoxifen (n=86)

Anastrozole (n=81)

ATAC -Percentage Change in BMD Over Time

Eastell et al J Clin Oncol 26:1051, 2008.



Overall Structure of Bisphosphonates

R2 ChainR 1 Chain

PO3 H2

PO3 H2

C

Osteoclast

Key endpoints:

Primary: Bone mineral density (BMD) at 12 mo

Secondary : Fracture, disease recurrence, disease free-survival, bone markers

Letrozole + zoledronic acid 4 mg every 6 months

Letrozole

2,193 patientsBreast cancerStage I to IIIa• 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 months

Treatment duration 5 years

R

BMD = Bone mineral density; ER = Oestrogen receptor; PgR = Progesterone receptor; R = Randomisation; SD = Standard deviation.

Z-FAST / ZO-FAST / E-ZO-FAST: Trial design

Z-FAST: Immediate Zoledronic Acid Increases BMD in Lumbar Spine and 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 < .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.

Month 24†

Lumbar spine Total hip

Me

an

(S

EM

) %

ch

an

ge

BM

D

P < .0001*P < .0001*

P < .0001*P < .0001*

Month 12†

Month24†

Month12†

–4%

–3%

–2%

–1%

0%

1%

2%

3%

4%

Upfront ZOL (4 mg/6 months) Delayed ZOL (4 mg/6 months)

Month 36‡

Month 36‡

P < .0001*P < .0001*

Δ 4,4% Δ 5.9% Δ 6.7%

Δ 3.3% Δ 4.7% Δ 5.2%

(N = 602)

NORMAL T-score > -1 N=68

OSTEOPENIC T-score -1 to -2.5 N=50

OSTEOPOROTIC T-score ≤ -2.5 =13N

Anastrozole Calcichew 3 D Forte

Anastrozole Calcichew 3 D Forte

Anastrozole Calcichew D3 Forte

• Repeat 2 DXA in

Years =20N

Oral Ibandronate 150 28 mg q days =12N

RANDOMSATION 1:1

Oral Ibandronate 150 28 mg q days =25N

Placebo =25N

• Repeat 12 DXA at 24 and

months

Serum and Urine for

markers of bone

turnover

ARIBON Study Design- Monthly Oral Ibandronate

Lester et al. Clin Cancer Res, in press, 2008

ARIBON Study Results - Monthly Oral Ibandronate 150mg

SPINE HIP

Lester et al. Clin Cancer Res, in press 2008

2 yr

100

Mean percentage change in LS BMD (%)

+2.8

-2.6

Baseline

102

101

103

99

98

97

Time

P<0.001

Ibandronate Placebo

1 yr

96

104

P<0.001

+3.2

-3.7 N=25

N=18

N=17

N=23

2 yr

100

Mean percentage change in Hip BMD (%)

Baseline

102

101

103

99

98

97

Time

P=0.002

Ibandronate Placebo

1 yr

96

104

P<0.001

+0.8

-4.1

+1.4

-2.3

N=25

N=17

N=18

N=23

Randomize1 : 1 : 1: 1

ABCSG-12 - Bone Protection Study with Zoledronic Acid

Surgery(+RT)

Tamoxifen 20 mg/d

Goserelin3.6mg q28d

Anastrozole 1 mg/d+ Zoledronic Acid 4mg q6m

Anastrozole 1 mg/d

Tamoxifen 20 mg/d+ Zoledronic Acid 4mg q6m

• Premenopausal women with early breast cancer• No chemotherapy

Gnant MF, et al. J Clin Oncol. 2007;25:820-828.

ABCSG XII: 6 Monthly Zoledronic Acid Reduces Bone Loss

ABCSG-12 = Austrian Breast and Colorectal Cancer Study Group Trial 12.

Anastrozole alone: p<0.0001

Tamoxifen alone: p<0.0001

Ana + ZA: p<0.0001Tam + ZA: p=0.049END OF TREATMENT

Gnant MF, et al. Lancet Oncology 2008

0

20

40

60

80

100

0 6 12 36

Time, mo

Pat

ien

ts,

%

Zoledronic Acid Preserves BMD During

3 Years of Adjuvant Therapy

OsteoporosisOsteopeniaNormal

Goserelin/Anastrozole Goserelin/Anastrozole + ZOL

BMD = Bone mineral density; ZOL = Zoledronic acid. Adapted from Gnant MF, et al. J Clin Oncol. 2007;25(7):820-828.

0

20

40

60

80

100

0 6 12 36

Time, mo

Pat

ien

ts,

%

First DFS Events (ITT Population)

10

41

29

10

6

10

9

20

0

2

0

10

20

30

40

50

60

70

80

90

No ZOL ZOL

Death without prior recurrence

Secondary malignancy

Contralateral breast cancer

Distant recurrence

Locoregional recurrence

Fir

st e

vent

pe

r p

atie

nt,

n

(n = 904) (n = 899)

No ZOL vs ZOL

DFS = Disease-free survival; ITT = Intent-to-treat; ZOL = Zoledronic acid.

H.R. 0.65; p=.017

Gnant M, et al. NEJM 2009

Denosumab For Treatment of Bone Loss on Aromatase Inhibitors

• RANKL stimulates osteoclasts and bone resorption

• Denosumab

– Novel fully human monoclonal antibody to RANKL

RANKL RANK

Bone

Cancer Cells in Bone

Cytokines and Growth

Factors (IL-6, IL-8, IL-1,PGE-2, TNF-, CSF-1, PTHrP) Osteoclast

Growth Factors (TGF-, IGFs, FGFs,

PDGFs, BMPs)

OsteoblastLineage

Direct effects on tumor?

BoneResorption

RA

NK

L RANKL

Denosumab: Effect on Lumbar Spine Bone Mineral Density

Ellis G, et al. J Clin Oncol 2008



Copyright © American Society of Clinical Oncology ASCO Guidelines 2003 Hillner, B. E. et al. J Clin Oncol; 21:4042-4057 2003

ASCO Guidelines on Bone Health

UK Management for Bone Loss in Breast Cancer - NOS/NCRI

Post-menopausal women >age 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 > -1 and no risk factors– No monitoring required

• Monitor BMD of osteopaenic patients every 2 years– Baseline T score <-1

• Intervention with bisphosphonates– > age 75 and > 1 risk factor for osteoporotic fracture– T score < -2 either at baseline or on follow-up– T score < -1 at baseline and annual bone loss >4%

Reid et al. Cancer Treatment Reviews 2008.

POST-MENOPAUSAL WOMEN

UK Guidance Algorithm on Management of Bone Loss in Early Breast Cancer

Reid et al. Cancer Treatment Reviews 2008

UK Management for Bone Loss in Breast Cancer - NOS/NCRI

Premature menopause at age <45

• 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 > -1 and not on concomitant AI

– No monitoring required

• Monitoring of BMD – Perform every 2 years if:

• T score < -1 without an AI• All patients if concomitant AI

• Intervention with bisphosphonates– Concomitant AI and T score < -1– T score < -2 either at baseline or on follow-up– Annual bone loss >4% on serial BMD monitoring


PREMATURE MENOPAUSE BEFORE AGE 45


UK Guidance Algorithm on Management of Bone Loss in Early Breast Cancer

T-score < –2.0T-score ≥ –2.0, no risk factors

Monitor risk status and BMD every

1 to 2 yearsa

Zoledronic acid (4 mg / 6 months)

calcium and vitamin D supplements

Monitor BMD every 2 years

Calcium and vitamin D supplements

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. 2008;19(8):1407-1416.

European Recommendations for Women Initiating Aromatase Inhibitor Therapy

• Data for oral bisphosphonates are emerging• Evidence from 4 clinical trials indicates that

zoledronic acid prevents AI-associated bone loss

Any 2 of the following risk factors:• T-score < –1.5

• Age > 65 years

• Low BMI (< 20 kg/m2)

• Family history of hip fracture

• Personal history of fragility fracture after age 50

• Oral corticosteroid use of > 6 months

• Smoking (current or history of)

WHO FRAX Index (www.shef.ac.uk/FRAX)

Bone Metastases in Cancer

Economic Burden

Poor functionalcapacity

Impaired mobility

Long and painfulrecovery from

fractures

Severe bone pain

HypercalcaemiaInconvenienthospital/clinic

visits

Pain and paralysis

from spinal cordcompression

Metastatic Bone Disease

Consequences of Bone Metastases

Bone Metastases Can Lead to SREs

Data are from placebo-controlled arms of bisphosphonate trials.

Lipton A et al. Cancer. 2003;98:962-969. Berenson JR et al. J Clin Oncol. 1998;16:593-602. Kohno N et al. J Clin Oncol. 2005;23:3314-3321. Saad F et al. J Natl Cancer Inst. 2004;96:879-882. Rosen LS et al. Cancer. 2004;100:2613-2621.

74%

51% 50% 49% 46%

0

30

60

90

% o

f pat

ient

s

Patients who will likely develop an SRE without treatment

Renal cellcarcinom

a(n=74)

Multiplemyelom

a(n=179)

Breast

(n=114)

Prostate

(n=208)

NSCLC

(n=250)

The Vicious Cycle of Bone Destruction

• Growth factors and cytokines released by tumor cells

Tumor Cells

PTHrP

IL-6

IL-8,

PGE2

TNF-

CSF-1

BMP

PDGF

FGFs

IGFs

TGF-β

Osteoclast

• Osteoclastic resorption stimulated

Peptides (eg, TGF-β) released by bone resorption

Tumor cell production of factors increased

More bone resorption

Tumor cell proliferation

Bone Adapted from Mundy GR, Yoneda T.

N Engl J Med. 1998;339:398-400.

Courtesy John Mackey

PTHrP

BMP

PDGF

FGFs

IGFs

TGF-β

Effect of Bisphosphonates on Vicious Cycle of Bone Destruction

Adapted from Mundy GR, Yoneda T.

N Engl J Med. 1998;339:398-400.

Courtesy John Mackey

Tumor Cells

IL-6

IL-8,

PGE2

TNF-

CSF-1

BMP

PDGF

FGFs

IGFs

TGF-β

– Decrease activity of osteoclasts

– Reduction in release of peptides

– Slowed tumor-cell growth

– Reduced production of PTHrP and other factors

– Decrease in bone resorptionOsteoclast

Bone

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

Further 20% risk reduction with zoledronic acid

Added Benefit of Zoledronic Acid Over Pamidronate in Breast Cancer

64% 43% 34%Lipton A, et al Cancer 2000; 88:3033-3037; Rosen LS, et al Cancer 2003;100:36-43.

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

Documents

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