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


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.


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.


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.


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


EFficacy 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.


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)



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



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



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



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



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


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


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)


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


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.


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



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


ORAG 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



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


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.


Bibliography

Ascott-Evans BH, Guanabens N, Kiviven S et al. Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy. Arch Intern Med 2003;163:789-794.

Black DM, Cummings SR, Karpf DB et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:1535-1541.

Bone H, Greenspan SL, Miller P et al. EFficacy of Fosamax® vs. Evista® Comparison Trial (EFFECT): Results of a randomized, multicenter study. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.

Cranney A, Guyatt G, Griffith L et al. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23(4):570-578. Cranney A, Tugwell P, Wells G et al. I. Systematic reviews of randomized trials in osteoporosis: Introduction and methodology. Endocr Rev

2000;23(4):496-507. Cummings SR, Black DM, Thompson DE et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral

fractures. Results from the Fracture Intervention Trial. JAMA 1998;280(24):2077-2082. Ettinger B, Black DM, Mitlak BH et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene.

Results from a 3-year randomized clinical trial. JAMA 1999;282(7):637-645. Garnero P, Sornay-Rendu E, Chapuy M-C et al. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J

Bone Miner Res 1996;11(3):337-349. Hochberg MC, Greenspan S, Wasnich RD et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures

that occur during treatment with antiresorptive agents. J Clin Endocrinol 2002;87:1586-1592. International Osteoporosis Foundation. What is osteoporosis? Available at: www.osteofound.org/

osteoporosis/about_osteoporosis.html. Accessed June 11, 2003. Johnell O, Scheele WH, Lu Y et al. Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in

postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002;87(3):985-992. Kanis JA, Oden A, Johnell O et al. Uncertain future of trials in osteoporosis. Osteoporos Int 2002;13(6):443-449. Looker AC, Bauer DC, Chesnut CH III et al. Clinical use of biochemical markers of bone remodeling: Current status and future directions.

Osteoporos Int 2000;11:467-480. Melton LJ III, Chrischelles EA, Cooper C et al. How many women have osteoporosis? J Bone Miner Res 1992;7:1005-1010. Riggs BL, Melton LJ III. The worldwide problem of osteoporosis: Insights afforded by epidemiology. Bone 1995;17(5 suppl):505S-511S. Sambrook P, Geusens P, Keraudren V et al. Efficacy of Fosamax vs. Evista Comparison Trial (EFFECT–International): Results at 6 and 12 months.

Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003. Tremollieres FA, Pouilles J-M, Ribot C. Withdrawal of hormone replacement therapy is associated with significant vertebral bone loss in

postmenopausal women. Osteoporos Int 2001;12:385-390.


Update on Alendronate and Raloxifene in Osteoporosis

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manufacturers’ prescribing information.

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