Download from Slide 1 Update on Alendronate and Raloxifene in Osteoporosis EFficacy of Fosamax ™ vs. Evista ® Comparison

Slide 1

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Update on Alendronate and Raloxifene in OsteoporosisUpdate on Alendronate and Raloxifene in Osteoporosis

EFficacy of EFficacy of FosamaxFosamax™™ vs. Evista vs. Evista®® Comparison Trial (EFFECT)Comparison Trial (EFFECT)

FOSAMAX (alendronate) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. EVISTA (raloxifene) is a registered trademark of Eli Lilly and Company, Indianapolis, IN.

Slide 2


Osteoporosis Is an Increasingly Important Health Issue Worldwide

Osteoporosis is a progressive disease characterized by age-related decline in BMD– Bone loss accelerates rapidly after menopause– Bone loss accelerates rapidly in postmenopausal women

after cessation of hormone replacement therapy Loss of bone mass increases fracture risk and associated

morbidity/mortality 40% lifetime risk of fracture for women over 50 worldwide Incidence/impact expected to increase in the future with

the aging population Several therapies available for treatment of osteoporosis

BMD=bone mineral density

Adapted from Riggs BL, Melton LJ III Bone 1995;17(5 suppl):505S-511S; International Osteoporosis Foundation. Available at: http://www.osteofound.org/osteoporosis/about_osteoporosis.html. Accessed June 11, 2003; Melton LJ III et al J Bone Miner Res 1992;7:1005-1010; Tremollieres FA et al Osteoporos Int 2001;12:385-390.

Slide 3


Current Knowledge of Alendronate and Raloxifene

Both alendronate and raloxifene are used for postmenopausal osteoporosis

Meta-analyses of clinical data for each agent have recently been performed [Cranney A et al Endocr Rev 2002;23(4):570-578]

No head-to-head fracture trial data currently available– Requires large patient population (tens of thousands)– Long duration (>3 years)

One study assessed the individual and additive effects of alendronate and raloxifene [Johnell O et al J Clin Endocrinol Metab 2002;87(3):985-992]

EFFECT was conducted to provide head-to-head data for alendronate once weekly vs. raloxifene in postmenopausal osteoporosis

RCT=randomized clinical trial

Adapted from Cranney A et al Endocr Rev 2002;23(4):570-578; Cranney A et al Endocr Rev 2000;23(4):496-507; Johnell O et al J Clin Endocrinol Metab 2002;87(3):985-992; Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

Slide 4


Meta-Analyses of RCT Data for Raloxifene and Alendronate

Raloxifene BMD increases at spine

(2.5%), combined hip (2.1%), forearm (0.65%), and total body (1.3%) (1–3 yrs)

40% risk reduction in vertebral fractures

No effect on nonvertebral fractures

Alendronate BMD increases at spine

(7.5%), combined hip (4.2%), forearm (2.1%), total body (2.7%) (10–40 mg, 2–4 yrs)

48% risk reduction in vertebral fractures (5–40 mg)

49% risk reduction in nonvertebral fractures(10–40 mg)

Adapted from Cranney A et al Endocr Rev 2002;23(4):570-578.

Slide 5


Placebo Raloxifene Alendronate Alendronate + raloxifene(n=82) (n=82) (n=83) (n=84)

Johnell O et al, J Clin Endocrinol Metab 2002;87(3):985-992

Randomized, double-blind, 12-month study Postmenopausal women with osteoporosis (FN –2.0 or lower), N=331 Greater spine and FN increases with alendronate than raloxifene Similar tolerability

*p≤0.05 alendronate vs. raloxifene

FN=femoral neck (T-score); NTx/Cr=ratio of N-telopeptide to creatinine; BSAP=bone-specific alkaline phosphatase

Adapted from Johnell O et al J Clin Endocrinol Metab 2002;87(3):985-992.

% C

han

ge

at 1

2 m

on

ths

*

*

–1

0

1

2

3

4

5

6

Spine Femoral neck*

*

–80

–60

–40

–20

0

20

NTx/Cr BSAP

BMD Bone Turnover

% C

han

ge

at 1

2 m

on

ths

Slide 6

Download from www.fosavance.aeEFficacy of Fosamax™ (alendronate) vs. Evista® (raloxifene) Comparison Trial (EFFECT–International)

Rationale– Alendronate once weekly and raloxifene are

prescribed for postmenopausal osteoporosis but have not been compared in a large-scale RCT

Objective– Compare effects of alendronate 70 mg once weekly

vs. raloxifene 60 mg once daily on improvements in BMD and inhibition of bone resorption in postmenopausal women with osteoporosis

Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

Slide 7


EFFECT–International Study Design

Randomized, double-blind, double-dummy, active-comparator–controlled, 12-month study

50 sites in 16 countries (non-US)

BMD and bone turnover evaluated before treatment and at months 6 and 12

487 patients randomized to alendronate 70 mg once weekly plus raloxifene placebo once daily (n=246) or raloxifene 60 mg once daily plus alendronate placebo once weekly (n=241)


Slide 8


EFFECT–International Entry Criteria

Community-dwelling, ambulatory women

≥40 years of age and ≥6 months postmenopausal

Osteoporosis defined by a BMD T-score –2.0 or lower at either lumbar spine or total hip

No estrogen, estrogen analogue, SERM, bisphosphonate, or PTH taken within the previous year

No history of breast or uterine cancer

No contraindications as stated in the product labels (e.g., venous thromboembolic disease, esophageal motility disorders)

SERM=selective estrogen-receptor modulator; PTH=parathyroid hormone


Slide 9


Primary– Percent change from baseline in lumbar spine BMD

at 12 months Secondary

– Percent change from baseline in • Total hip BMD at 12 months• Hip trochanter BMD at 12 months• Lumbar spine, total hip, hip trochanter BMD at

6 months – Percentage of patients who maintained or increased

spine BMD– Percent change in markers of bone turnover (NTx/Cr

and BSAP) – Tolerability, including upper GI and vasomotor events

EFFECT–International Study Endpoints


Slide 10


EFFECT–International Baseline Characteristics

Alendronate Raloxifene70 mg 60 mg

once weekly once daily Overall(n=246) (n=241) (N=487)

Age (years) 62 62 62Race (%)

White 80 78 79Multiracial 9 9 9Hispanic 8 8 8Asian 3 5 4

Body mass index (kg/m2) 25 25 25Years since last menses 15 15 15BMD T-score

Lumbar spine –2.89 –2.86 –2.88Total hip –1.55 –1.55 –1.55


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EFFECT–International Lumbar Spine BMD


Pe

rce

nt

cha

ng

e fr

om

b

ase

line

(m

ea

n ±

SE

)

Months

4.8

2.2

0

1

2

3

4

5

6

0 6 12

Alendronate (n=226)

Raloxifene (n=219)

p<0.001

p<0.001

Slide 12



EFFECT–International Total Hip BMD

Months

2.3

0.8

0

1

2

3

4

0 6 12

Alendronate (n=224)

Raloxifene (n=220)

Pe

rce

nt

cha

ng

e fr

om

b

ase

line

(m

ea

n ±

SE

)

p<0.001

p<0.001

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EFFECT–International Hip Trochanter BMD


Months

2.9

1.0

0

1

2

3

4

0 6 12

Alendronate (n=224)

Raloxifene (n=220)

Pe

rce

nt

cha

ng

e fr

om

b

ase

line

(m

ea

n ±

SE

)

p<0.001

p<0.001

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Premenopausal rangePremenopausal range

EFFECT–International Markers of Bone Turnover: Absolute Values

17.7

38.8

0

10

20

30

40

50

60

0 6 12

Months Months

8.1

13.5

0

5

10

15

20

0 6 12

Ab

solu

te v

alu

e (n

mo

l/m

mo

l)

NTx/Cr BSAP

Alendronate (n=161)Raloxifene (n=154)

N values refer to month 12

Adapted from Garnero P et al J Bone Miner Res 1996;11(3):337-349.

Ab

solu

te v

alu

e (n

g/m

l)

p<0.001 p<0.001p<0.001 p<0.001

Alendronate (n=175)Raloxifene (n=166)

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EFFECT–International Safety and Tolerability Profiles


Percent of patientsAlendronate Raloxifene

70 mg 60 mgAdverse once weekly once dailyExperience (AE) (n=246) (n=241) p Value

Any AE 63 65 NS

Drug-related* AE 23 27 NS

Discontinued due to AE 6 8 NS

Upper GI AE 15 22 NSDrug related 9 16 0.029

Vasomotor AE 4 10 0.010Drug related 2 8 0.007

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EFFECT–International Summary

Alendronate produced two to three times greater increases in hip and spine BMD than did raloxifene at 12 months (p<0.001)– Differences were significant at 6 months (p<0.001)

Alendronate reduced bone turnover significantly more than raloxifene at 12 months (p<0.001)– Differences were significant at 6 months (p<0.001)

Alendronate decreased markers of bone turnover to well within the premenopausal ranges

Similar tolerability observed with alendronate and raloxifene

Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003; Garnero P et al J Bone Miner Res 1996;11(3):337-349.

Slide 17


EFFECT–International Conclusions

Alendronate 70 mg once weekly was significantly more efficacious than raloxifene 60 mg

– Increases in spine and hip BMD two to three times greater with alendronate vs. raloxifene (p<0.001) at 12 months

– Alendronate produced greater reductions in bone turnover than raloxifene at 12 months (p<0.001)

– Alendronate was similarly well tolerated


Slide 18


Meta-Analyses of Percent Change from Baseline BMDin Separate RCTs of Alendronate or Raloxifenea

aThese are not head-to-head data. Data shown together for ease of comparison; bp<0.01 vs. baseline; cp=0.01 vs. baseline; dhip and femoral neck

ORAG=Osteoporosis Research Advisory Group


7.5b

4.2b

2.1b2.7b

2.5b

2.1b

0.71.3c

0

1

2

3

4

5

6

7

8

Spine Combined hipd Forearm Total body

Mea

n %

ch

ang

e

Alendronate Raloxifene

NS

n=1613 n=6053 n=1443 n=6033 n=565 n=359 n=469 n=511

ORAG Meta-Analyses:BMD Changes Reported for Alendronate and Raloxifene

Slide 19

Download from www.fosavance.aeORAG Meta-Analyses: Fracture Risk Reductions Reported for Alendronate and Raloxifene

–48b –49b

–40c

–9

–60

–50

–40

–30

–20

–10

0Vertebral Nonvertebral

Mea

n %

ch

ang

e

Meta-Analyses of Relative Risk of Fracture versus Placebo at 3 yearsa

NS

8 studies(n=9360)

1 study(n=6828)

6 studies(n=3723)

2 studies(n=6961)

Alendronated Raloxifene

aThese are not head-to-head data. Data shown together for ease of comparison; bp<0.01 vs. baseline; cp=0.01 at baseline; dAlendronate doses evaluated were 5–40 mg (vertebral fracture) and 10–40 mg (nonvertebral)

ORAG=Osteoporosis Research Advisory Group


Slide 20


Relative Risk Reductions for Vertebral and Nonvertebral Fractures

ORAG Meta-Analyses: Relative Risk Reductions with Therapies for Postmenopausal Osteoporosis

ORAG=Osteoporosis Research Advisory Group; V=vertebral; NV=nonvertebral

*Alendronate doses evaluated were 5–40 mg (vertebral fracture) and 10–40 mg (nonvertebral)


alendronate*(48% V, 49% NV)

alendronate*(48% V, 49% NV)

0

10

20

30

40

50

Rel

ativ

e ri

sk r

edu

ctio

n

in n

on

vert

ebra

l fra

ctu

res

vitamin D(37% V, 23% NV)

calcitonin(21% V, 20% NV)

calcium(23% V, 14% NV)

risedronate(36% V, 27% NV)

HRT (34% V, 13% NV)

raloxifene (40% V, 9% NV)raloxifene (40% V, 9% NV)

etidronate (37% V, 1% NV)

0 10 20 30 40 50 60

Relative risk reduction in vertebral fractures

Slide 21


Alendronate vs. Raloxifene:Overall Summary

Large-scale, head-to-head BMD trials can provide clinicians with useful information

EFFECT–International demonstrated – Alendronate 2–3 times more effective than raloxifene once

daily for increasing lumbar spine and hip BMD– Similar tolerability

Results from EFFECT–International consistent with independent meta-analyses – Alendronate outperformed raloxifene in increasing

BMD – In the ORAG meta-analysis, alendronate also outperformed

raloxifene in lowering risk of both vertebral and nonvertebral fractures

Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003; Cranney A et al Endocr Rev 2002;23(4):570-578.

Slide 22


Bibliography

Please see notes page.

Slide 23


Update on Alendronate and Raloxifene in Osteoporosis

Before prescribing any of the products mentionedin this slide presentation, please consult the

manufacturers’ prescribing information.

Copyright © 2003 Merck & Co., Inc., Whitehouse Station, NJ, USA.All rights reserved. 12-04 FSM 2003-W-6999-SS

VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com

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Download from Slide 1 Update on Alendronate and Raloxifene in Osteoporosis EFficacy of Fosamax ™ vs. Evista ® Comparison