downloaded from 1 alendronate vs. risedronate comparison trial

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Alendronate vs. RisedronateAlendronate vs. RisedronateComparison TrialComparison Trial

Alendronate vs. RisedronateAlendronate vs. RisedronateComparison TrialComparison Trial

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Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison Trial

AimTo compare the efficacy of alendronate 70 mg once weekly with risedronate 5 mg daily (alternate meal dosing) in postmenopausal women with osteoporosis

Primary EndpointRate of bone resorption (urine NTx) at 3 months

Secondary Endpoints• Change in BMD at spine and hip at 6 and 12 months• Rate of bone turnover (NTx and BSAP) at 6 and 12 months• Safety and tolerability profile at 12 months

NTx = N-telopeptides of type 1 collagen BSAP = bone-specific alkaline phosphataseHosking et al Curr Med Res Opin 2003;19(5):383-394.

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• First head-to-head study comparing alendronate and risedronate for treatment of osteoporosis

• Endpoints– Biochemical markers of bone turnover

– BMD at spine and hip

• First head-to-head study comparing alendronate and risedronate for treatment of osteoporosis

• Endpoints– Biochemical markers of bone turnover

– BMD at spine and hip

Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison Trial

OverviewOverview

Hosking et al Curr Med Res Opin 2003;19(5):383-394.

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ParticipantsParticipants

• Women aged 60-90, N = 549

• At least 2 years postmenopausal at baseline

• 38 centers in 10 countries

• No vertebral fractures

• T score 2.5 (LS or hip) or

• T score 2.0 (LS and hip)

Hosking et al Curr Med Res Opin 2003;19(5):383-394. LS = Lumbar spine

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Alendronate Risedronate Placebo

Mean SD Mean SD Mean SD

Age ( years ) 69.2 6.6 68.9 5.9 69.6 7.0

Years sincemenopause 20.8 8.3 20.3 8.0 20.6 8.5 BMI (kg/m2) 24.8 3.5 25.3 3.7 25.3 3.6

LS BMD (g/cm2) 0.71 0.08 0.72 0.08 0.73 0.07(Hologic)

LS = Lumbar Spine BMI = Bone mineral index BMD = Bone mineral density SD = Standard deviationHosking et al Curr Med Res Opin 2003;19(5):383-394.

Baseline CharacteristicsBaseline Characteristics

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Randomized, double-blind, multicenter, multinational, placebo-controlled study 3 months: bone turnover 6- and 12-month extensions: BMD

549 postmenopausal women (age > 60) with osteoporosis

T-score < -2.5 at either lumbar spine or total hip orT-score < -2.0 at both lumbar spine and total hip

Treatments (using approved dosing regimens) Alendronate 70 mg OW (standard AM dosing) n=219 Risedronate 5 mg daily (post-meal dosing) n=222 Placebo n=108

Randomized, double-blind, multicenter, multinational, placebo-controlled study 3 months: bone turnover 6- and 12-month extensions: BMD

549 postmenopausal women (age > 60) with osteoporosis

T-score < -2.5 at either lumbar spine or total hip orT-score < -2.0 at both lumbar spine and total hip

Treatments (using approved dosing regimens) Alendronate 70 mg OW (standard AM dosing) n=219 Risedronate 5 mg daily (post-meal dosing) n=222 Placebo n=108

Alendronate vs. Risedronate Comparison Trial Alendronate vs. Risedronate Comparison Trial Study DesignStudy Design

Hosking et al Curr Med Res Opin 2003;19(5):383-394. OW = Once weekly

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Alendronate vs. Risedronate Comparison Trial Alendronate vs. Risedronate Comparison Trial Dosing RegimensDosing RegimensAlendronate vs. Risedronate Comparison Trial Alendronate vs. Risedronate Comparison Trial Dosing RegimensDosing Regimens

• FOSAMAX (alendronate sodium) 70 mg once weekly

At least 1/2 hour before the first food, beverage, or medication of the day, upon arising for the day

• ACTONEL (risedronate) 5 mg dailyAt least 2 hours from any food or drink at any other time of the day, and at least 30 minutes before going to bed

• FOSAMAX (alendronate sodium) 70 mg once weekly

At least 1/2 hour before the first food, beverage, or medication of the day, upon arising for the day

• ACTONEL (risedronate) 5 mg dailyAt least 2 hours from any food or drink at any other time of the day, and at least 30 minutes before going to bed

† Registered Trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA

‡ Trademark of Procter & Gamble, Cincinnati, OH


®†

™‡

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Risedronate 30 mg BioavailabilityRisedronate 30 mg BioavailabilityRisedronate 30 mg BioavailabilityRisedronate 30 mg Bioavailability

EUSPC for ACTONEL™ 2003.

0

10

20

30

40

50

60

70

80

90

100

4 Hoursbefore

breakfast

1 Hourbefore

breakfast

1/2 Hourbefore

breakfast

2 Hoursafter

dinner

Mean absolute bioavailability with 30 mg tablet = 0.63%

Rel

ativ

e b

ioav

aila

bilit

y (%

of

mea

n a

bso

lute

)

Risedronate 30 mg daily

Alendronate 70 mg once weekly

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Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialMarkers of Bone Turnover at 1 and 3 MonthsMarkers of Bone Turnover at 1 and 3 Months

p< 0.001: Alendronate vs. risedronate + p< 0.001: Alendronate vs. placebo

Mea

n pe

rcen

t cha

nge

Placebo, n = 108

RIS 5 mg daily, n = 222ALN 70 mg once weekly, n = 219

BSAP 20

10

0

-10

-20

-30

-40

Months0 1 3

*

Urine NTx

Months

20

0

-10

-20

-30

-40

-50

-60

-70

-80

0 1 3

* *+ +

*+

+

Hosking et al Curr Med Res Opin 2003;19(5):383-394. ALN = Alendronate RIS = Risedronate

10

*

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Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison Trial BSAP at 3, 6, and 12 Monthsat 3, 6, and 12 MonthsAlendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison Trial BSAP at 3, 6, and 12 Monthsat 3, 6, and 12 Months

Placebo, n = 108 RIS 5 mg daily, n = 222 ALN 70 mg once weekly, n = 219

Months

-40

-60

-20

0

0 3 6 12

Mea

n p

erce

nt

chan

ge

p<0.001: Alendronate vs. risedronate

+ p<0.001: Alendronate vs. placebo

* *

+

+

+


*

*

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Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison Trial Urine NTxAlendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison Trial Urine NTx

0

-20

-40

-60

1 3 6 12

Mea

n pe

rcen

t ch

ange

p<0.001: Alendronate vs. risedronate

+ p<0.001: Alendronate vs. placebo Hosking et al Curr Med Res Opin 2003;19(5):383-394.

++

++

**

*

*

Placebo, n = 336

RIS 5 mg dailyn = 490

ALN 70 mg once weekly, n = 616

Months*

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Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison Trial Urine NTx Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison Trial Urine NTx

Placebo, n = 108 RIS 5 mg daily, n = 222 ALN 70 mg once weekly, n = 219

Months

-40

-60

-20

0

0 3 6 12

Mea

n p

erce

nt

chan

ge

* p<0.001: Alendronate vs. risedronate + p<0.001: Alendronate vs. placebo

*

+

+

+


*

*


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Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialLumbar Spine BMDLumbar Spine BMDAlendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialLumbar Spine BMDLumbar Spine BMD

Months p<0.001: Alendronate vs. risedronate p<0.001: Alendronate vs. placebo Hosking et al Curr Med Res Opin 2003;19(5):383-394.

Mea

n pe

rcen

t ch

ange

1

-1

2

0

3

4

5

6

-260 12

ALN 70 mgOnce weeklyn = 219

RIS 5 mg daily n = 222

Placebon = 108

*

+

*

+*

+

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Months p<0.001: Alendronate vs. risedronate+ p<0.001: Alendronate vs. placebo

6

1

-1

2

0

3

4

5

6

-20 12

ALN 70 mgOnce weeklyn = 219

RIS 5 mg Dailyn = 222

Placebon = 108

Mea

n pe

rcen

t ch

ange *+

Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialHip Trochanter BMDHip Trochanter BMDAlendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialHip Trochanter BMDHip Trochanter BMD

*+


*

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p<0.001: Alendronate vs. risedronate+ p<0.001: Alendronate vs. placebo

Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialTotal Hip BMDTotal Hip BMDAlendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialTotal Hip BMDTotal Hip BMD

Months6

1

-1

2

0

3

4

5

-20 12

Mea

n pe

rcen

t ch

ange

Placebo, n = 108RIS 5 mg daily,ALN 70 mg once weekly,

6

*

n = 222n = 219

++*


*+

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ALN 70 mg once weekly, n = 219

Months6

1

-1

2

0

3

4

-20 12

Mea

n pe

rcen

t ch

ange

Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialFemoral Neck BMDFemoral Neck BMDAlendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialFemoral Neck BMDFemoral Neck BMD

*

p 0.05 : Alendronate vs. risedronate+ p < 0.001: Alendronate vs. placebo


Placebo, n = 108

RIS 5 mg daily, n = 222

++

*

*

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Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialAdverse ExperiencesAdverse ExperiencesAlendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialAdverse ExperiencesAdverse Experiences

Gastric or duodenal perforation, ulcer or bleed

Adverse Experiences

Placebo n=108

ALN 70 mg

once weekly n=219

RIS 5 mg daily

n=222

% of patients

Any clinical adverse experience

70 77 76

Any upper GI 27 28 27.5

Esophageal 0 2 2

PUB 0 0 0.5

Similar tolerability seen in all three groups*


*

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Significantly greater increases in BMD at both the hip and spine with alendronate compared to risedronate over 12 months(p ≤ 0.001)

70% greater at the lumbar spine (4.75% vs. 2.8%) 266% greater at the hip trochanter (3.3% vs. 0.9%) 200% greater at the total hip (2.7% vs. 0.9%)

Significantly greater increases in BMD with alendronate seen early (6 months) at spine, trochanter, and total hip (p ≤ 0.001)

Significantly greater increases in BMD at both the hip and spine with alendronate compared to risedronate over 12 months(p ≤ 0.001)

70% greater at the lumbar spine (4.75% vs. 2.8%) 266% greater at the hip trochanter (3.3% vs. 0.9%) 200% greater at the total hip (2.7% vs. 0.9%)

Significantly greater increases in BMD with alendronate seen early (6 months) at spine, trochanter, and total hip (p ≤ 0.001)

Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialSummarySummaryAlendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison TrialSummarySummary


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Alendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison Trial Summary Cont’dSummary Cont’dAlendronate vs. Risedronate Comparison TrialAlendronate vs. Risedronate Comparison Trial Summary Cont’dSummary Cont’d

Significantly greater effect on markers of bone resorption with alendronate compared to risedronate (months 3, 6, and 12) (p < 0.001)

Greater decrease in resorption marker urine NTx with alendronate seen early (at one month)

Similar tolerability was seen between alendronate and risedronate, including upper gastrointestinal adverse experiences

Significantly greater effect on markers of bone resorption with alendronate compared to risedronate (months 3, 6, and 12) (p < 0.001)

Greater decrease in resorption marker urine NTx with alendronate seen early (at one month)

Similar tolerability was seen between alendronate and risedronate, including upper gastrointestinal adverse experiences


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ConclusionsConclusionsConclusionsConclusionsIn this first head-to-head double-blind comparison of alendronate and risedronate for treatment of osteoporosis in postmenopausal women:

In this first head-to-head double-blind comparison of alendronate and risedronate for treatment of osteoporosis in postmenopausal women:

• Alendronate produced significantly greater increases in BMD at both spine and hip sites as early as 6 months (p ≤ 0.001)

• Alendronate produced significantly greater reduction in bone resorption at 3, 6, and 12 months (p < 0.001)

• Differences seen early, with greater effects of alendronate seen at 1 month for resorption marker urine NTx, and 6 months for

BMD

These differences may be due to superior efficacy of alendronate, reduced bioavailability of risedronate resulting

from post-meal dosing, or both.

• Alendronate produced significantly greater increases in BMD at both spine and hip sites as early as 6 months (p ≤ 0.001)

• Alendronate produced significantly greater reduction in bone resorption at 3, 6, and 12 months (p < 0.001)

• Differences seen early, with greater effects of alendronate seen at 1 month for resorption marker urine NTx, and 6 months for

BMD

These differences may be due to superior efficacy of alendronate, reduced bioavailability of risedronate resulting

from post-meal dosing, or both.Hosking et al Curr Med Res Opin 2003;19(5):383-394.

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Protocol 159 InvestigatorsProtocol 159 InvestigatorsProtocol 159 InvestigatorsProtocol 159 InvestigatorsS. Adami – Italy J. Kaufman – BelgiumR. Bartl – Germany B. Lindergård – SwedenL. Benhamou – France O. Ljunggren – SwedenM. Billsten – Sweden D. Mellström – SwedenJ. Cannata Andia – Spain M. Muñoz Torres – SpainC. Cooper – UK B. Nyhäll-Wåhlin – SwedenP. Delmas – France K. Obrant – SwedenJ. Devogelaer – Belgium J. Olmos Martinez – SpainO. Di Munno – Italy S. Radominski – BrazilH. Dobnig – Austria J. Reginster – BelgiumD. Felsenberg – Germany M. Rödén – SwedenJ. Fraser – UK C. Roux – FranceB. Freyschuss – Sweden M. Sääf – SwedenJ. Garcia Vadillo – Spain H. Schatz – GermanyP. Gillberg – Sweden J. Semler – GermanyJ. Gross – Sweden H. Sinclair – SwedenN. Guañabens Gay – Spain K. Thorsen – SwedenF. Hawkins Carranza – Spain G. Toss – SwedenD. Hosking – UK M. Välimäki – Finland


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AddendumAddendumAddendumAddendum

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““Agents that produce larger increases in BMD Agents that produce larger increases in BMD tend to provide greater reductions in both tend to provide greater reductions in both vertebral and nonvertebral fracture risk.” vertebral and nonvertebral fracture risk.”

M. HochbergM. Hochberg

““Agents that produce larger increases in BMD Agents that produce larger increases in BMD tend to provide greater reductions in both tend to provide greater reductions in both vertebral and nonvertebral fracture risk.” vertebral and nonvertebral fracture risk.”

M. HochbergM. Hochberg

Hochberg M et al J Clin Endocrin & Metab 2002;87(4):1586-1592.

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Meta-analyses of Percent Change from Baseline BMDin Separate RCTs of Alendronate or Risedronate*

* These are not head-to-head data. Data shown together for ease of comparison; **p<0.01 vs. baseline; ***hip and femoral neck

ORAG=Osteoporosis Research Advisory Group

RCTs = Randomized Clinical Trials

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

7.5**

4.2**

2.1**2.7**

4.5**

2.7**

0.7 0.0

0

1

2

3

4

5

6

7

8

Spine Combined hip*** Forearm Total body

Mea

n %

cha

nge

Alendronate 10 to 40 mgRisedronate 5 mg

NS

n=16135 Trials

n=21386 Trials

n=14435 Trials

n=23977 Trials

n=5652 Trials

n=6481 Trial

n=4692 Trials

ORAG Meta-analyses:ORAG Meta-analyses:BMD Changes Reported for Alendronate BMD Changes Reported for Alendronate and Risedronateand Risedronate

ORAG Meta-analyses:ORAG Meta-analyses:BMD Changes Reported for Alendronate BMD Changes Reported for Alendronate and Risedronateand Risedronate

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ORAG Meta-analyses:ORAG Meta-analyses: Fracture Risk Reductions Reported Fracture Risk Reductions Reported for Alendronate and Risedronate for Alendronate and Risedronate

ORAG Meta-analyses:ORAG Meta-analyses: Fracture Risk Reductions Reported Fracture Risk Reductions Reported for Alendronate and Risedronate for Alendronate and Risedronate

-48b -49b

-36c

–60

–50

–40

–30

–20

–10

0Vertebral Nonvertebral

Mea

n %

cha

nge

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

8 Trials(n=9360)

5 Trials(n=2604)

6 Trials(n=3723)

7 Trials(n=12,958)

Alendronated

Risedronate 5 mg

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

ORAG=Osteoporosis Research Advisory Group


-27b

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Relative Risk Reductions for Vertebral and Nonvertebral Fractures

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

ORAG Meta-analyses: ORAG Meta-analyses: Relative Risk Reductions with Therapies for Relative Risk Reductions with Therapies for Postmenopausal OsteoporosisPostmenopausal 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)

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Rel

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in n

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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)

etidronate (37% V, 1% NV)

0 10 20 30 40 50 60

Relative risk reduction in vertebral fractures

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Alendronate vs. Alendronate vs. Risedronate Comparison TrialRisedronate Comparison Trial

Alendronate vs. Alendronate vs. Risedronate Comparison TrialRisedronate Comparison Trial

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

manufacturers’ prescribing information.

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. 11-04 FSM 2003-W-7006-SS

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

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