New Perspective of SERM in Postmenopausal Women Health

Daniel Thiebaud MD, Medical Fellow,

Global Osteoporosis Strategy, Eli Lilly, Australia

Case Study• 63 year old woman presents with a history of acute low

back pain.

• Menopause at 44 years of age, but never received postmenopausal HRT.

• Reported a history of a Colles’ fracture at age of 60 years.

What additional questions would you ask?

• Lumbar spine films reveal a recent vert fracture (L1)

• DXA of the hip shows a BMD T-score of –1.8 SD, and of -2.7 at LS (L2-L4).

How should her case be managed?How should her case be managed?

Case Study : How should it be managed?

• What other questions should you ask?

• What other tests would you like to know?

• What general advice would you give ?

• What treatment would you consider?

The Osteoporosis Cascade

75+ Kyphotic

At risk for hip fracture & further Vertebral

fracture

55+ PostmenopausalAt greater risk for vertebral

fracture than any other type of fracture

50 Menopausal

Experiencing vasomotor symptoms

When to suspect and investigate for osteoporosis?

• Radiologists often do not mention vertebral fractures in reporting chest x-rays

• Clinicians often fail to recognize or act on x-ray reports of fractures

• Two thirds of new vertebral Two thirds of new vertebral fractures are not diagnosedfractures are not diagnosed

Gehlbach SH, et al. Osteoporos Int. 2000;11:577-582.

Delmas PD, et al. J Bone Miner Res. 2001;16(Suppl 1):S139.

Lindsay R. et. Al. JAMA 2001; 285; 320-23

VERT FRACTURES ARE OFTEN NOT RECOGNISED

Therapeutic options for osteoporosis

Stimulators of bone formation• (Fluoride)

• Parathyroid hormone

Mixed mechanism of action• Active Vitamin D metabolites• Strontium ranelate

Recommended for all women at risk for osteoporosis• Calcium and vitamin D

Inhibitors of bone resorption (Antiresorptives)

Bisphosphonates– Alendronate– Etidronate– Risedronate

• Calcitonin

• Estrogen ± progestin

• Selective estrogen receptor modulators (SERMs)– Raloxifene

SSelective

EEstrogen

RReceptor

MModulatorodulator

Concept of a SERM

• Not an estrogen, progestin or other hormoneNot an estrogen, progestin or other hormone• Binds to estrogen receptorsBinds to estrogen receptors• Has estrogen-like effects in some tissuesHas estrogen-like effects in some tissues• Blocks estrogen effects in some tissuesBlocks estrogen effects in some tissues

Chemical Structures of Estradiol andCurrently Available SERMs

SOH

OH

O

ON

Raloxifenepost-menopausal osteoporosis

prevention and treatment

ON

Tamoxifenprevention and treatment of

breast cancer

Cl

ON

Clomiphenefertility induction

ON

Cl

Toremifenetreatment of breast cancer

OH

OH

17-estradiol

New SERMs in Phase 3 trials:

- Lasofoxifene- Basedoxifene- Arzoxifene

Raloxifene

• Is not a hormone

• Binds to estrogen receptors differently than does estrogen*

• Induces conformational changes in the estrogen receptor that are distinct from those induced by estrogen*

• Leads to different biological activities depending on thetarget tissue/organ*

• Raloxifene does not accumulate in bone

Raloxifene versus Estrogen:Receptor Binding and Pharmacology

*Katzenellenbogen BS. Science 2002;295:2380-2381

Raloxifene, Kd= 54 pMEstradiol, Kd= 86 pM

Reproduced with permission from Brzozowski AM et al. Nature 389:753-58, 1997; http:www.nature.com/

Estradiol and Raloxifene Occupythe Same Ligand Binding Site

N

OH

O

O

HO S

Tissue Dependent Action

Antagonistic Effects(uterus, breast)

Agonistic Effects (bone)

Basic Side Chain

Benzothiophene

ER = Estrogen ReceptorBMD = Bone Mineral Density

ERER

• Increase BMD and reducethe risk of vertebral fractures

Estrogen Receptor Signaling

Other response elementsERE

Multiple co-regulatory

factors

Multiple ligands•estrogens•SERMs

Multiple receptor isoforms/variants

Genomic* Non- genomic**

Signal Transduction•MAP Kinase•ERK/Akt•NO synthase

Membrane ER?

Multiple genomic sequences**Simoncini T et al. Steroids

67:935-939, 2002* McDonnell and Norris, Osteoporosis Int 1997;S29-4Bryant HU, Reviews in Endocrine and Metabolic Disorders 2:129-38, 2001

Women with and withoutPrevalent Vertebral Fractures

Women withPrevalent Vertebral Fractures

Placebo RLX 60

% o

f Wom

en w

ith

New

Cli

nic

al V

erte

bra

l F

ract

ure

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

RR 0.32 (95% CI, 0.13 - 0.79)

Placebo RLX 600.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

RR 0.34 (95% CI, 0.11 - 0.77)

66%

68%

Risk of New Clinical Vertebral Fractures at 1 Year

Marici et al, Arch. Int med, 2002

0

1

2

% o

f Pat

ient

s

Placebo

Risk Reduction inClinical Vertebral Fractures at 1 Year

59%59%p<.03

69%69%p=.009

p=.0168%68%

MORE1

RaloxifeneFIT-I/FIT-II2

AlendronateVERT-MN/VERT-NA3

Risedronate*

*Clinical vertebral fractures derived from pooled post-hoc analysis of VERT-NA/VERT-MN.1. Ettinger B, et al. JAMA. 1999;282(7):637-645. 2. Black DM, et al. J Clin Endocrinol Metab. 2000;85(11):4118-4124. 3. Data on file, Procter & Gamble.

• Multicenter, double-blind, placebo-controlled trial

• 25 countries, 180 centers, 3 years with 1 year extension

• 7705 postmenopausal women with osteoporosis

• Mean age 66.5 years

• Raloxifene 60 mg =Evista, 120 mg, or placebo

• All patients given daily calcium (500 mg) and vitamin D (600 IU)

• Primary endpoints: radiographic vertebral fracture, BMD, safety

• Secondary endpoints: all osteoporotic fractures, cardiovascular health, breast cancer, cognitive function

Ettinger B et al. JAMA 282:637-45, 1999Cummings SR et al. JAMA 281:2189-97, 1999

MOREMOREMMultiple ultiple OOutcomes of utcomes of RRaloxifene aloxifene EEvaluationvaluation

Cumulative Incidence of New Clinical Vertebral Fractures in the First Year of MORE

7705 postmenopausal women with osteoporosis

*P=0.007 in the first 6 months foreach raloxifene group compared with placebo

Qu Y, et al. CMRO, 2005, 21 (12): 1955-59.Months

2 4 6 8 10 12 14 16

0.0

0.2

0.4

0.6

0.8

1.0

PlaceboRaloxifene 60 mg/dRaloxifene 120 mg/d

Clin

ica

l Ve

rte

bra

l Fra

ctu

re (

%)

Wom

en w

ith N

ew

Clin

ical V

ert

ebra

l F

ractu

re (

%)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.04%(n=1)

0.04%(n=1)

0.04%(n=2)

RR 0.10 (95% CI 0.02-0.41)**

RR 0.10 (95% CI 0.01-0.62)**

RR 0.10 (95% CI 0.01-0.63)**

0.44%(n=10)

Placebo Raloxifene60 mg/d

Raloxifene120 mg/d

RaloxifenePooled

0.44%(n=10)

Effect of Raloxifene on New Clinical Vertebral Fractures at 6 Months

Qu Y, et al. CMRO, 2005, 21 (12): 1955-59.

Effect of raloxifene on clinical fractures in Asian (China, Japan) women with osteoporosis

Baseline Characteristics a Japan (N=284)b China (N=204)c

Age (years) 64.8±6.3 65.3±6.0

Years Postmenopausal 15.2±6.5 16.9±7.3

Body Mass Index (kg/m2) 21.8±2.8 23.0±2.9

Prevalent Vertebral Fracture (%) 26.4 13.7

Lumbar Spine BMD (g/cm2)

T-score0.63±0.05

-3.77±0.460.69±0.07

-3.52±0.51

a : Mean ± standard deviation for continuous variables presentedb : N=97 for placebo ; N=92 for raloxifene 60 mg/d ; N=95 for raloxifene 120 mg/dc : N=102 for placebo ; N=102 for raloxifene 60 mg/d

T.Nakamura et al.JBMM, 24:414-418, 2006

New Clinical Vertebral Fractures Combining the Japan and China Studies

RaloxifenePooled

3

2

1

0

（%）

3.5%3.5%（（ n=7n=7））

0%0%（（ n=0n=0））

Placebo Raloxifene60mg/day

4

5

6

0%0%（（ n=0n=0））

******

＊＊＊＊ :p<0.002 vs. placebo:p<0.002 vs. placebo

＊＊ :p<0.01 vs. placebo:p<0.01 vs. placebo

N=199 N=194 N=289

T.Nakamura et. Al, JBMM; 24:414-418; 2006

RaloxifenePooled

7

6

5

4

3

2

1

0

（%）

6.0%6.0%（（ n=12n=12）） 1.0%1.0%

（（ n=2n=2）） 0.7%0.7%（（ n=2n=2））

RRRR：： 0.110.11（（ 0.03 - 0.510.03 - 0.51））

RRRR：： 0.170.17（（ 0.04 - 0.750.04 - 0.75））

Placebo Raloxifene60mg/day

8

9

******

＊＊＊＊ :p<0.001 vs. placebo:p<0.001 vs. placebo＊＊ :p<0.01 vs. placebo:p<0.01 vs. placebo

Any New Clinical Fractures Combining the Japan and China Studies

T.Nakamura et. al.JBMM; 24:414-418, 2006

Raloxifene Reduces Risk of at least 1 New Nonvertebral* Fracture in Women with Severe Fracture

*Clavicle, humerus, wrist, pelvis, hip, leg

Delmas PD et al. Bone 2003;33;4:522-532

0

5

10

15

20

% o

f W

om

en

wit

h a

t le

ast

1

Ne

w N

on

vert

eb

ral F

rac

ture

RH=0.53 (95% CI 0.29, 0.99)

Placebo Raloxifene 60 mg/d

47%

MORE Trial - 3 Years

P=0.046

Raloxifene prevents Non Vertebral Fracture in Women with 2 Prevalent Vertebral Fractures

(n= 1369, mean age 69y MORE Trial - 3 Years – pooled raloxifene

Nonvertebral Fracture *

Farrerons et al., CTI, 2003;72(4):391(P230)

0

10

20

30

40%

of W

om

en

With

at L

ea

st

1 N

ew n

on-V

ert

ebra

l Fra

ctur

e RR=0.69 (95% CI 0.48, 0.99) P<0.05

Placebo Raloxifene

31%

* Clavicle, humerus, wrist, pelvis, hip, leg

EVA Trial (Evista Versus Alendronate)

• First ever head-to-head fracture outcome trial• Compare the osteoporotic fracture risk reduction

efficacy of raloxifene and alendronate• Approximately 2000 postmenopausal women with

osteoporosis • Double-blind, randomized, controlled, 1-3 year trial with

raloxifene 60 mg/d vs alendronate 10 mg/d– Calcium 500 mg/d + vitamin D 400 IU/d to all patients– Sites in US, Canada, and Puerto Rico

Recker RR, et al. J Bone Miner Res. 2005;20(suppl 1):S97, Bone in press 2007.

Baseline CharacteristicsCharacteristic Raloxifene

(N=707)

Alendronate

(N=716)

P-value

Age (years) 65.5 65.7 0.56

Caucasian (%) 86.7 86.9 0.83

BMI (kg/m2) 24.8 24.6 0.42

LS BMD (g/cm2)

0.82 0.82 0.79

T-score -2.32 -2.34 0.65

FN BMD (g/cm2) 0.61 0.61 0.98

T-score -2.39 -2.39 0.77

Hip BMD (g/cm2) 0.71 0.71 0.71

T-Score -1.99 -2.01 0.64

EVA trial : Ralo vs AlendronateBMD changes after 2 years

01234567

ALN RLX01234567

ALN RLX01234567

ALN RLX

Recker R et al, ASBMR 2005, J Bone Miner Res. 2005;20(suppl 1):S97, Bopne in press 2007

Lumbar Spine Femoral Neck Total Hip

*

*

*

*

*

*

P<0.0001

P= 0.002 P=0.041

Age 65 yrs, BMD LS Tscore = -2.3, Hip FN Tscore = -2.4

* Significant change compared with baseline (P<0.05)

EVA Trial: Incidence of VFx and Non-V Fx

Women with ≥1 new Fx, n(%)Type of Fracture ALN, 10mg/d RLX 60mg/d P value

N=713 N=699

Age, yrs 65.7± 7.8 65.5± 7.7 0.56

Vert or Non Vert 22 (3.1) 20 (2.9) 0.84

Vertebral 8 (3.1) 5 (1.9) 0.53 Moderate/Severe 4 (1.6) 0 0.04 Clinical Vertebral 3 (0.4) 0 0.1

NonVertebral 14 (2.0) 15 (2.2) 0.86 Nonvertebral-Sixb 11 (1.5) 10 (1.4) 0.89

b Includes the clavicule, humerus, wrist, pelvis, hip and leg.

Recker R et al, ASBMR 2005, Abstract in JBMR 2005, 20,Suppl 1,S97, Bone in press 2007

Adverse Events: All no significant difference

Incidence Significantly Different Between Raloxifene and Alendronate

No. of Patients (%)

Event RLX

(N=707)

ALN

(N=716)

P-Value

Colonoscopy 1 (0.14) 8 (1.12) 0.04

Diarrhea 11 (1.56) 27 (3.77) 0.01

Nausea 22 (3.11) 38 (5.31) 0.047

R.Recker et al : ASBMR 2005

Evista Safety

Daniel Thiebaud MD, Medical Fellow,

Global Osteoporosis Strategy, Eli Lilly, Australia

MORE, Multiple Outcomes of Raloxifene Evaluation; CORE, Continuing Outcomes Relevant to EVISTA; RUTH, Raloxifene Use for The Heart; STAR, Study of Tamoxifen and Raloxifene; EVA, EVISTA-Alendronate Comparison

0

5000

10000

15000

20000

1,764

7,705

4,011

10,101

19,747

Nu

mb

er

of E

nro

lled

Wo

men

OsteoporosisPrevention

MORE CORE RUTH STAR EVA

1,400

Large-Scale Raloxifene Clinical Trials

Rationale for the RUTH TrialRationale for the RUTH Trial

• Coronary outcomes, based on:– favorable impact of raloxifene on cardiovascular risk markers1 – evidence from observational studies that treatment with estrogen

was associated with a reduced risk of CHD in postmenopausal women2,3

• Invasive breast cancer, based on:– anti-estrogenic effects of raloxifene in the breast4

– 72% reduction in invasive breast cancer in a secondary analysis of data from the MORE trial5

RUTH was designed to determine the effect of raloxifene on:

1Blumenthal R et al. Am Heart J 20042Stampfer MJ et al. Prev Med 19913Grady D et al. Ann Intern Med 19924Brzozowski AM et al. Nature 19975Cauley J et al. Breast Cancer Res Treat 2001

Relevant Clinical Trial FindingsRelevant Clinical Trial FindingsAfter RUTH CommencedAfter RUTH Commenced

• Estrogen and Estrogen Plus ProgestinTherapy– HERS trial: Estrogen plus progestin did not reduce the overall rate of CHD

events in postmenopausal women with established coronary disease1

– WHI trial: Early increase in risk of coronary events with estrogen plus progestin therapy and estrogen alone in healthy postmenopausal women2,3

• Raloxifene– MORE trial results suggested no overall effect of raloxifene on

cardiovascular (CV) events, and a reduced risk for CV events in the subset of postmenopausal women retrospectively defined as at increased CV risk (post hoc analysis)4

1Hulley et al, JAMA 19982Writing Group for the Women's Health Initiative Investigators, JAMA 20023Anderson GL et al. JAMA 20044Barrett Connor et al, JAMA 2002

STAR Results: Invasive Breast Cancer

• The number of invasive breast cancers in the tamoxifen group (163 cases of 9,726) versus the raloxifene group (168 cases of 9,745) were statistically equivalent.

• Tamoxifen is known to reduce breast cancer risk by 50%, and STAR shows that raloxifene produces similar results.

Vogel et al, JAMA , 2006; 295, June 2006 2. Fisher B, et al. J Natl Cancer Inst 1998; 90:1371-1388.

MORE plus CORE Study Design

0 1 2 3 4 5 6 7 8

Placebo

Raloxifene HCl 60 mg/day

Raloxifene HCl 120 mg/day

Placebo

Raloxifene HCl 60 mg/day

Year

8 Years Total Follow-up

MORE (N=7705)Three Treatment

Groups

CORE (n=4011)Two Treatment

Groups

GapMORE ConclusionCORE Screening

Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761

Incidence of Invasive Breast Cancer8 Years of MORE plus CORE (N=7705)

Years in Study

0 1 2 3 4 5 6 7 80.0

1.0

2.0

3.0

4.0

HR 0.34 (95% CI = 0.22-0.50)

Placebo4.2 per 1000 Women-Yrs

Raloxifene1.4 per 1000 Women-Yrs

p <0.001

Cu

mu

lati

ve In

cid

enc

e (%

)

66%

Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761

Summary of Adverse Outcomes over the 8 Years of MORE-CORE (N=4011)

%Percentage of participants who experienced event (n)

P-valuePlacebo(N=1286)

Raloxifene(N=2725)

Mortality 2.3 (29) 1.7 (47) 0.27

All cancers† 8.6 (110) 5.7 (156) 0.001

All cancers† excluding breast cancer 6.3 (81) 4.6 (126) 0.027

Hospitalization 40.9 (526) 38.8 (1057) 0.21

Treatment-emergent AEs 99.0 (1273) 98.6 (2688) 0.45

Treatment-emergent serious AEs 45.5 (585) 42.3 (1154) 0.07

Study discontinuation CORE due to AE 2.4 (31) 1.9 (53) 0.35

†Excluding non-melanoma skin cancersMartino S et al. Curr Med Res Opin 2005

Summary of Gynecological AE Data over 8 Years of MORE-CORE (N=4011)

%Percentage of participants who experienced event (n)

P-valuePlacebo(N=1286)

Raloxifene(N=2725)

Uterine cancer†‡ 0.39 (4) 0.32 (7) 0.75

Endometrial hyperplasia‡ 0.29 (3) 0.37 (8) >0.99

Ovarian cancer 0.16 (2) 0.11 (3) 0.66

Postmenopausal bleedingठ5.4 (55) 5.5 (120) 0.87

Uterine polyps‡ 1.9 (19) 3.2 (70) 0.028

Vulvovaginal signs and symptoms 5.8 (75) 5.0 (135) 0.26

Martino S et al. Curr Med Res Opin 21;1441-52, 2005

Flushing (hot flushes) 89 (6.9) 342 (12.6) <0.001

Leg cramps 152 (11.8) 407 (14.9) 0.008

Peripheral edema 120 (9.3) 288 (10.6) 0.240

Adverse Events Reported During MORE Plus CORE – 8 Years

Number (%)

Placebo Raloxifene p-value(n=1286) (n=2725)

Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761

Therapeutic options for osteoporosis

Stimulators of bone formation• (Fluoride)• Parathyroid hormone

Mixed mechanism of action• Vitamin D and metabolites• Strontium ranelate

Recommended for all women at risk for osteoporosis• Calcium and vitamin D

Inhibitors of bone resorption

Bisphosphonates– Alendronate– Etidronate– Risedronate

• Calcitonin

• Estrogen ± progestin

• Selective estrogen receptor modulators (SERMs)– Raloxifene

Bone StrengthNIH Consensus Statement 2000

BoneQuality

BoneStrength and

Architecture and geometry

Turnover/ remodeling rateDegree of MineralizationDamage AccumulationProperties of collagen/mineral matrix

Shifting the Osteoporosis Paradigm

BoneDensity

NIH Consensus Development Panel on Osteoporosis. JAMA 285 (2001): 785-95

Antiresorptive Agents Increase BMD by Decreasing Remodeling Space and

Prolonging Mineral Acquisition

Remodeling space

Antiresorptive Agent

High Turnover

Low Turnover

New relatively under-mineralized bone

Adapted from David Dempster, Ph.D.

Older, relatively highlyMineralized bone

Markers of collagen degradation and synthesis in women treated with raloxifene or alendronate

Stepan J, Vokrouhlicka J, CCA 288, 1999, 121-135

Resorption Formation

Stepan et al, ASBMR 2002

What Is the Optimal Reduction in Bone Turnover for an Antiresorptive Drug?

Adapted from Weinstein RS, J Bone Miner Res 2000; 15 621.

Physiological Physiological RRangeange

Bo

ne

Str

en

gth

Bone Turnover

Excessive turnover• Increase in stress risers (weak zones)• Increase in perforations• Loss of connectivity

Insufficient turnover• Accumulation of microdamage• Increased brittleness due to excessive

mineralization

Time

100 -

50 -

0 -

Min

eral

iza

tion

(%

)

Primary mineralization(3 months: during bone formation)

Cortical bone

Secondary mineralization (Years after bone formation)　　 Maturation

Labels under epi-fluorescent microscope)

Mineralization of boneMineralization of boneNormal = 63-68% and heterogenousNormal = 63-68% and heterogenousNormal = 63-68% and heterogenousNormal = 63-68% and heterogenous

(Adopted from Wainwright, Biggs, Currey and Gosline, 1976 modified)

Ash density (degree of mineralization)

Stiffness(Young’s Modulus)

HighLow

Work to Failure　 (Toughness)

65 66 67 68 (%)

Effects of long-term anti-resorptive therapy

• increased bone mass• increased degree of mineralization

time dependent

increase bone strength

stiffer

decrease bone strength

brittle

Hypothetical Effects of Increasing Bone Mineralization

Percentage MineralizationPercentage Mineralization

ResistanceResistance to fracture to fracture forcesforces

Improved resistance to Improved resistance to bending = stiffnessbending = stiffness

Increasing brittlenessIncreasing brittleness

Normal =65-68%Normal =65-68%Normal =65-68%Normal =65-68%

Turnover Oversuppression

Beyond normal physiologic range

Increased Increased Fragility ?Fragility ?

Insufficient fatiguedamage repair

Microcrack accumulation Microcrack

propagation

Prolonged secondary mineralization

Hypermineralized + homogeneous bone

Sustained Efficacy of Raloxifene Occurrence of the First New Post-Baseline Vertebral Fracture

MORE Trial - 4 Years

Adapted from Delmas et al. J Clin Endocrinol Metab 87: 3609-17, 2002

Months of Exposure0 24 36 48

0

5

10

15

Inci

den

ce o

f Ne

w

Ve

rte

bra

l Fra

ctu

res

(%)

PlaceboRLX 60 mg/d

12

First Scheduled Radiograph

P<0.001

SERMs

Raloxifene

HT

Osteoporosis preventionT-score >–2.5

Osteoporosis treatment with or without

previous fracture

Osteoporosis treatment with multiple fractures and at

risk for hip fracture

50 55 60 65 70 75 80 85 90

Age (years)

Teriparatide

Bisphosphonates

Therapeutic Management of Postmenopausal Osteoporosis