View
213
Download
1
Embed Size (px)
Citation preview
Slide 1
Update on Alendronate and Raloxifene in OsteoporosisUpdate on Alendronate and Raloxifene in Osteoporosis
EFficacy of EFficacy of FOSALANFOSALAN™™ vs. Evista vs. Evista®® Comparison Trial (EFFECT)Comparison Trial (EFFECT)
FOSALAN (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
EFficacy of FOSALAN™ (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)
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
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
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
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
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
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
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
Slide 11
EFFECT–International Lumbar Spine BMD
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
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
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 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
Slide 13
EFFECT–International Hip Trochanter BMD
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
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
Slide 14
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)
Slide 15
EFFECT–International Safety and Tolerability Profiles
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
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
Slide 16
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
Adapted from Sambrook P et al. Poster presented at the 2003 International Bone and Mineral Society meeting, Osaka, Japan, June 2–7, 2003.
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
Adapted from Cranney A et al Endocr Rev 2002;23(4):570-578.
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
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
Adapted from Cranney A et al Endocr Rev 2002;23(4):570-578.
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)
Adapted from Cranney A et al Endocr Rev 2002;23(4):570-578.
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