3

RALOXIFENE

The first SERM to be approved for the prevention and the treatment of postmenopausal osteoporosis

Estrogen agonist in bone (Prevents bone loss)

Estrogen antagonist in the breast and the uterus

4

Effect of Raloxifene on Spine andFemoral Neck BMDMORE Trial - 48 Months

Months0 12 24 36 48

-2

-1

0

1

2

3

4

** * *

Placebo Raloxifene 60 mg/d

Months0 12 24 36 48

-2

-1

0

1

2

3

4

** *

*

Femoral NeckLumbar Spine

1.91.3

2.1 2.1

2.0 2.6 2.7 2.6

5

0

5

10

15

20

25

30

35

40

Effects of Raloxifene onNew Vertebral Fractures

MORE Trial - 48 Months

% o

f W

omen

With

In

c ide

nt V

erte

bra l

Fra

c tur

e

With Prevalent Vertebral Fractures

Without Prevalent Vertebral Fractures

RR 0.51(95% CI = 0.35-0.73)

RR 0.66(95% CI = 0.55-0.81)

PlaceboRaloxifene 60 mg/d

49%

34%

6

Wrist

Ankle

Hip

Any nonvertebral

No. (%) of Women

Placebo

(N=2576)

Raloxifene(pooled)(N=5129)

0.9 (0.7-1.1)

0.6 (0.4-1.0)

1.1 (0.6-1.9)

0.9 (0.8-1.1)

Effect of Raloxifene on Nonvertebral FracturesMORE Trial - 3 Years

151 (2.9)

34 (0.7)

40 (0.8)

437 (8.5)

86 (3.3)

28 (1.1)

18 (0.7)

240 (9.3)

Relative Risk(95% CI)

Fractures

7

BCPT: Relative Risk of Fracture by Tamoxifen use

• HIP• Spine• Radius, Colles• Other• Total

<49 years at entry >50 years at entry

0.55 (0.25-1.15)

0.74 (0.41-1.32)

0.61 (0.29-1.23)

1.05 (0.73-1.51)

0.81 (0.63-1.05)

0.88 (0.46-1.68)

0.79 (0.60-1.05)

RR (95% CI)

Fisher B, et al. JNCI 1998;90:1371-88.

8

Prevent vertebral fracturesNo effect on other clinical fracturesPrevent Breast Cancer in average risk women

? High Risk Women (STAR)No effect on endometrium? Prevent CVD in high risk women: RUTHIncrease in VTE

Long-term effects: CORE–Increase in ER(-) tumors?–Immunity to anti-estrogen effects ?

Summary: Raloxifene

9

Bisphosphonates

• Alendronate (Fosamax®)

• Risedronate (Actonel®)

• Zoledronic Acid (Zometa®) (not FDA approved)

• Pamidronate (Aredia®) (not FDA approved)

-2

0

2

4

6

8

10

0 12 24 36

Months

Per

cen

t C

han

ge

in L

S-B

MD

Rel

ativ

e to

Bas

elin

e

RIS 5 mg RIS 2.5 mg Placebo

-2

0

2

4

6

8

10

12 24 36

Months

Per

cen

t C

han

ge

in L

S-B

MD

Rel

ativ

e to

Bas

elin

e

ALN 5 mg ALN 10 mg Placebo

* p<0.05

Results from Separate Risedronate and Alendronate BMD Trials

Lumbar Spine BMDLumbar Spine BMD

Mean Change vs. Baseline Mean Change vs. BaselineRisedronateRisedronate

Lumbar Spine BMDLumbar Spine BMDMean Change vs. BaselineMean Change vs. Baseline

AlendronateAlendronate

* *

*

**

*

* * *

*

** *

*

11

Efficacy at the Spine: Radiographic Vertebral Fractures at 3 years

15

8

0

4

8

12

16

Placebo Alendronate

16.3

10

0

4

8

12

16

Placebo Risedronate

Alendronate (n=2027; 71y)+ Risedronate (n=2458; 69y)*

47% reduction

p<0.001

41% reduction

p=0.003

+Black et al. Lancet 1996. *Harris S. JAMA 1999.

% w

ith

frac

ture

% w

ith

frac

ture

12

Efficacy of Oral Bisphosphonates on Hip Fracture

• Alendronate+

– Women with vertebral fractures: 50% reduction, p<0.05

– Women without vertebral fractures:T< -2.5: 56% reduction, p<0.05T> -2.5: Not significant

• Risedronate*Age 70 – 79– Women with osteoporosis (t-score < -2.5)

39% reduction (p=0.02)– Women with vertebral fractures

58% reduction (p<0.01)Age 80+– Women with osteoporosis (t-score < -2.5)

25% reduction, p=0.14– Women with risk factors

Not significant

13

Once-Weekly Alendronate for the Treatment of Osteoporosis: Effect on BMD

0

1

2

3

4

5

6

6 12

% C

hang

e fr

om B

asel

ine

ALN 10mg Daily`

ALN 35 mg TwiceWeekly

ALN 70 mg OnceWeekly

Month

Lumbar Spine

14

Effects of Zoledronic Acid on BMD in Lumbar Spine

Month of Scan

15

Bisphosphonates: Alendronate and Residronate

–Prevent vertebral fractures–Prevent clinical fractures

• Alendronate: Hip Fracture indication

–Both approved for weekly administration–RCTs >3 years duration–No other systemic effects–Long term effect

• Alendronate :10 years of use: BMD

20

PTH: Mode of Delivery Determines Bone Activity

• Intermittent doses of PTH are anabolic and lead to increased bone formation whereas continuous exposure to PTH leads to increased bone resorption and a net bone loss.

Tam et al. Endocrinology 1982

21

Effect of rhPTH(1-34) on the Risk of New Vertebral Fractures

*p <0.001 vs. Placebo

Ris

k R

edu

ctio

n (

RR

)

Placebo(n=448)

rhPTH 20(n=444)

rhPTH 40(n=434)

64 22 19100%

75%

50%

0%

25%

% o

f Wo

men

8

0

246

101214

RR 0.31 (95% CI, 0.19 to 0.50)*

RR 0.35 (95% CI, 0.22 to 0.55)*

65% 69%

No. of women who had > 1 fracture

22

Effect of rhPTH(1-34) on the Risk of Nonvertebral Fragility Fractures

* p = 0.02 vs. Placebo** p = 0.01 vs. Placebo

0

1

2

3

4

5

6

7

Placebo rhPTH 20 rhPTH 40

% o

f W

om

en

30 14 14

53% 54%

(n=544) (n=552)(n=541)

No. of women who had > 1 fragility fracture

RR 0.46 (95% CI, 0.25 to 0.86)**

RR 0.47 (95% CI, 0.25 to 0.88)*

23

Effect of rhPTH(1-34) on BMD

% Change from Baseline to Last Visit ( + SD )

rhPTH 20 rhPTH 40

• Lumbar Spine9.7 ± 7.4* 13.7 ± 9.7*

• Femoral Neck 2.8 ± 5.7* 5.1 ± 6.7*

• Total Hip 2.6 ± 4.9* 3.6 ± 5.4*

*p <0.001 vs. Placebo

24

WHO SHOULD BE TREATED WITH WHAT?

HOT FLASHES HIP FRACTURES

ESTROGEN???? ALENDRONATERISEDRONATE

RALOXIFENE, ALENDRONATE, RISEDRONATE

FIRST VERTEBRAL FRACTURE

CALCITONIN??

50 807060

AGE

25

Anti-fracture Efficacy of Selected Therapies

• Alendronate +++ ++• Calcitonin + 0• Etidronate + 0• Fluoride + -• HRT + +++• PTH +++ ++• Raloxifene +++ 0• Risedronate +++ ++• Vit D derivatives + 0

Drug Vertebral F x Hip fx