Transcript Treatment of Osteoporosis: Applying the Evidence to Clinical Practice Chatlert Pongchaiyakul Division of Endocrinology and Metabolism Department of Medicine, Faculty of Medicine Khon Kaen University.

Treatment of Osteoporosis:
Applying the Evidence to
Clinical Practice
Chatlert Pongchaiyakul
Division of Endocrinology and Metabolism
Department of Medicine, Faculty of Medicine
Khon Kaen University
Expectations of an Agent for
Treatment of Osteoporosis
• Consistency across efficacy endpoints
• Increase in BMD at all sites
• Consistent fracture reduction
– Vertebral fracture (morphometric and clinical)
– Non-vertebral fracture
– Hip fracture
• Results reproducible and consistent across
– Subgroups
– Multiple trials
– Differing populations
• Established long-term efficacy and safety
What criteria should we consider
when making clinical decisions?
• Well conducted randomized placebo controlled
clinical trials
• Direct comparison of drugs in the same class to
demonstrate equal or superior efficacy
• Rigorous well defined meta-analysis (…pitfalls of
garbage in, garbage out)
• Clinical experience
• Physician/patient decision making
Data that can be misleading when
making clinical decisions
• Retrospective analysis
• Non pre-specified analysis
• Per-protocol vs. ITT
• Subgroup analyses
• Post-Hoc analyses
• Non-randomized, non-controlled
• Historical controls
• Anecdotal clinical experience
Downs SH, Black N; J Epidemiol Community Health 1998; 52:377-384
Hauselmann HJ, Rizzoli R, Osteo International 2003; 14:2-12 / Freemantle, BMJ 2001, ; 322:989-991
Assman SF, et al:Lancet 2000;355:1064-1069
Sackett DL,et al; Evidence Based Medicine Second Edition Harcourt Publishers Limited,London UK 2000.
Meta-analyses of Therapies for
Postmenopausal Osteoporosis
Endocrine Reviews 2002;23:495-578
Evidence-based Review of
Osteoporosis Trials
• Calcium & Vitamin D
• HRT
• SERMs
– Raloxifene
• Calcitonin
• Bisphosphonates
– Alendronate
– Risedronate
Orag Cranney et al Endocrine reviews 2002
Hauselmann et al Osteopororosis Intnl 2003
Hochberg MC et al; Arthritis Rheumatism 1999
Calcium & Vitamin D
Reduction in Hip & Other Nonvertebral Fractures
Calcium and Vitamin D
Other Nonvertebral Fracture
Cumulative Probabilities
of Fracture
Hip Fracture
0.09
0.09
P = 0.040
0.06
0.06
0.03
0.03
0.00
0.00
12
6
Months
18
P = 0.015
6
12
18
Months
Elderly institutionalized patients with high prevalence of subclinical vitamin D deficiency
Chapuy, MC etal, N Engl J Med 1992.
— Placebo
— Calcium and Vit D
Evidence of Fracture Efficacy from Randomized
Clinical Trials for Calcium and Vitamin D Analogs
Radiographic
Fractures
Spine
Clinical Fractures
Hip
Spine
Nonspine
Calcium & Vit D analogs
Calcitrol, other Vit D analog
+/–
ND
ND ND
Calcium alone
ND
ND
ND
Vit D analogs + calcium ND
+*
ND
+*
Vit D analogs alone
NS
NS
NS
ND
NS
+ = Significant risk reduction in 1 trial;
+/– = Inconsistent effect;
ND = No published data;
NS = Not significant;
* Nursing home population with high prevalence of vit D deficiency and low calcium intake
Hochberg MC. Drugs & Aging 17: 317-30,2000
HRT
Relative Risk For Vertebral Fractures After Treatment With HRT
Favours HRT
Favours Control
(n= 75)
Lufkin 0.63 (0.28,1.43)
(n=193)
Greenspan 0.70 (0.06, 7.55)
(n=32)
Wimalawansa 0.4 (0.09, 1.80)
(n=2763)
Hulley 0.69 (0.34, 1.38)
Alexandersen 2.78 (0.12, 65.1)
(n=52)
Mosekilde, 2.01(0.61,6.63)
(n= 1006)
(n=16,608)
WHI 0.65 (0.44, 0.97)
Pooled RR 0.70 (0.52, 0.94)
0.01
(p=0.02)
Wells Endo Reviews 2002
N=20,729
0.1
1
10
100
•SERMS
-Raloxifene
Efficacy at the SPINE
Effect of Raloxifene on Radiographic Vertebral
Fractures (MORE)
Percent of Patients with
Incident Vertebral Fracture
Radiographic Vertebral Fractures
25
Substudy 1 (n=4,524)
20
(BMD-2.5 and no pre-existing
vertebral fractures)
15
Substudy 2 (n=2,304)
(BMD-2.5 and pre-existing
vertebral fractures)
RRR
30%
10
5
0
RRR
50%
Placebo Raloxifene
60 mg/d
JAMA, August 18, 1999--Vol 282, No. 7, pp 637-645
Placebo Raloxifene
60 mg/d
Efficacy at the HIP
Percent of Patients with Incident
Non-Vertebral Fractures
Effect of Raloxifene on Non-Vertebral and Hip Fracture
MORE Pooled Data (60 mg and 120 mg)
Non-Vertebral Fractures
Hip Fractures
15
3
Placebo
10
2
Raloxifene
Pooled
5
Raloxifene
Pooled
1
Placebo
0
0
0
6
12
18
24
Months
JAMA. 1999;282:637–645
30
36
0
6
12
18
24
Months
30
36
Relative Risk for Vertebral and
Non-Vertebral Fracture After Raloxifene
Treatment
Favors
Raloxifene
Favors
Control
Vertebral Fractures
Ettinger 0.60 (0.50 to 0.70)
Lufkin 1.16 (0.77 to 1.76)

(N = 6828)
( N = 133)

Non-Vertebral Fractures
Ettinger 0.92 (0.79 to 1.07)
Lufkin 0.52 (0.12 to 2.18)


( N = 6828)
(N= 133)
0.1
1
10
* All Trials Secondary Treatment
Vertebral fracture results from Lufkin trial based on 15% cutoff in reduction of vertebrae
(baseline to 1 year)
Raloxifene: Summary
• Reduces vertebral fracture risk
• No effect on hip or non-vertebral
fractures
Calcitonin
Calcitonin Nasal Spray
Prevent Recurrence of Osteoporotic Fractures (PROOF)
Number of patients
Mean Age
Mean T-Score
New Vertebral Fx
Study Design
Drug
Calcium/Vitamin D
Primary Endpoint
Dropout rate
1,255
Most (79%) had 1 to 5 Vertebral Fx
378 (30%) completed the study
68 (postmenopausal)
< –2.0
1–5
5 year, randomized, double-blind,
placebo-controlled
Placebo (n = 311), 100 IU (n = 316),
200 IU (n = 316, marketed dose) or
400 IU (n = 312)
1000 mg/400 IU daily
Spine BMD and new VFX
59% lost to follow-up
Chesnut CH et al., Am J Med. 2000, 109: 267-276.
PROOF
Effect of nasal calcitonin on risk of vertebral
fractures
Women with
new fractures
Decreased
risk
Placebo
26%
-
100 IU
22%
15%
No
200 IU
18%
33%
Yes
400 IU
22%
16%
No
Dose
p<0.05?
Non-vertebral fracture and hip fracture
No consistent trend with dose
Non-significant reductions at the approved dose (200 IU)
Chesnut CH et al., Am J Med. 2000, 109: 267-276.
Trial quality is very important
What PROOF Proves about
Calcitonin and Clinical Trials
Steven R. Cummings, MD
Roland D. Chapurlat, MD
Editorial from: Am J Med 109: 330-331, Sept 2000
Calcitonin
Summary
• Morphometric vertebral fracture
– Small reduction in vertebral fracture rate
– No consistent trend with dose
• No reduction in non-vertebral or hip fracture
• Minimal effect on BMD and biomarkers
• Trial Issues
– High drop out rate
– Investigators and patients were not blinded to
important outcomes (e.g., BMD)
• Effectiveness of nasal calcitonin not proven
•Bisphosphonates
•Alendronate
•Risedronate
•Alendronate
Efficacy at the SPINE
Alendronate Vertebral Fracture Study1
(Patients with pre-existing vertebral fractures)
Reduction in Vertebral Fractures at Year 3
Radiographic
Clinical
16
Multiple
Radiographic
% of Patients
with Fracture
47%
12
Reduction
P < 0.001
8
55%
Reduction
P < 0.001
4
90%
Reduction
P < 0.001
0
n=
1Black
PBO
965
ALN
981
PBO
965
DM. Lancet. 1996;348:1535-1541.
ALN
981
PBO
965
ALN
981
Alendronate Reduced the Risk of Hip Fractures
in women with or without existing vertebral fracture
Rate per 100 PYR
2
1,5
Reduction = 56%
p = 0.044
Reduction = 51%
p = 0.047
Placebo
1
Alendronate
0,5
0
Without (T < -2.5)
With (T < -1.6)
Vertebral Fracture Status at Baseline
Cummings SR, et al. JAMA. 1998; 280:2077-2082.
Black DM, et al. Lancet. 1996; 348:1535-1541.
Evidence-Based Review of OP Trials:
Effect of Alendronate in Reducing
Vertebral Fractures
Prevention Trials
Favors alendronate

Favors control
(n = 355)
McClung 0.34 (0.04 to
(n = 1355)

Treatment Trials


(n = 157)

(n = 478)

(n = 516)



Pooled Estimate 0.52 (0.43 to 0.65)
(n = 184) Bone 0.68 ( 0.21 to 2.18)

(n = 2027)
Chesnut 0.25 (0.03 t
L
Liberm
Black 0.53 (0.41 to 0.69)
Cummings 0.51
(n = 4432)
(n = 8005)
(n = 9360)
48% reduction
0.01
0.1
1
10
Adami and Hoskings trials not included in figure due to low vertebral fracture incidence.
Evidence-Based Review of OP Trials:
Effect of Alendronate in Reducing
Non-Vertebral Fractures
Cranney et al, Endocrine Reviews 23 (4):508-516; 2002
Favors Alendronate
Favors Control
Prevention Trials
(n =267)

McClung 0.79 (
Treatment Trials
(n = 211)

(n = 125)

Liber
(n = 1908)
Pols 0.47 (0.26 to 0.83)
Rosen 0.35 (0.15 to
(n =420)
Pooled Treatment Estimate 0.49 (0.36 to 0.67)

(n = 3456)
Pooled Estimate 0.51 (0.38 to 0.69)

(n = 3723)
0.01
0.1
L
(n =412)


Chesnut 0.43 (0
(n = 380)


Adami 0.36 (0.07 to
1
49% reduction
10
The Effect of Alendronate on Hip Fracture
Favors Alendronate
Primary
Fracture
Studies
Favors PBO
Black: vertebral osteo
Cummings: T < -2.5
Karpf: Osteoporosis
BMD
Primary
Endpoint
Pols:Osteoporosis
Long Term Care
Osteoporosis
All Studies
Test for homogeneity: p = 0.996
52% (p = 0.001)
0.1
T < 2.0
Quandt S., Annals Rheum Disease 2000, 59; 83
0.3
0.5
0.8 1
Relative Risk
2
Long-Term Effects of Bisphosphonates
Alendronate 10 Year Efficacy Data
Mean Percent Change  SE
Lumbar Spine BMD
ALN 5 mg
ALN 10 mg
ALN 20 mg/ALN 5 mg/Placebo
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
0
12
24
36
48
60
72
Month
Emkey et al. J Bone Miner Res 2002;17 (Suppl 1):S139
84
96
108
120
Alendronate 10 Year Efficacy Data
Mean Percent Change  SE
Trochanter BMD
ALN 5 mg
ALN 10 mg
ALN 20 mg/ALN 5 mg/Placebo
12
11
10
9
8
7
6
5
4
3
2
1
0
0
12
24
36
48
60
Month
72
84
96
108 120
Percent of Patients with
Non-vertebral Fractures
Years 8 to 10
15
10
5
*Liberman 1995, NEJM
g
10
m
AL
N
5m
g
AL
N
20
/5
yr)
AL
N
PB
O
(+7
LN
All
A
/PB
O
0
Pla
ce
bo
Percent of Patients
Years 1 to 3*
Annual Height Loss
Mean Height Loss (mm/year)
Years 1 to 3*
2.0
1.5
1.0
0.5
0
*Liberman 1995, NEJM
P=0.005
Years 5 to 10
Alendronate
Summary
• Most robust, consistent efficacy in reducing
fractures at all sites
• Largest number of trials performed for the longest
period of time across the entire spectrum of
osteoporosis
• Long term 10 year data evidence of continued safety
and efficacy
Effect of alendronate on trabecular
microstructure
UNTREATED
Hu et al. Bone Nov 2002
ALENDRONATE
Alendronate Increases Trabecular Connectivity in
Elderly Osteoporotic Women
Masarachia P, Howard T, Santora A, Yates J, Rodan
GA, Recker RR, and Kimmel, DB
ASBMR Poster M326
MicroCT Analysis of Transilial Biopsy Specimens
from Alendronate (ALN) Phase III Studies
Masarachia P, Chavassieux P, Arlot M, Meunier PJ,
Santora A, Yates J, Rodan GA and Kimmel DB
ASBMR Poster M325
Monday 22 September 2003
m-CT Images representing
respective BV/TVs for PBO and
ALN Groups
PBO Specimen 1618; BV/TV 13.9%; BMD, 119.8 mg/cc; Euler# 2.3
ALN Specimen 1776; BV/TV 19.0%; BMD 156.1 mg/cc; Euler# 3.1
Alendronate Increases Trabecular
Connectivity in Elderly Osteoporotic Women
Table 3. m-CT unique Endpoints (69±6yo)
PBO
ALN
BMD (mg/cc)
112.0 ± 55.4
146.2 ± 53.1
Euler #
3.29 ± 1.7
4.89 ± 2.33*
DMB g/cc bone
7.96 ± 2.34
8.29 ± 1.03
• ALN patients
have higher
Euler#
• ALN patients
have higher
Euler#
• ALN patients
trend higher but without
• ALN patients trend higher but without statistically significant
statistically
significant
PBO, for BMD or DMB
differences
from differences
PBO, for BMDfrom
or DMB.
Hip fractures are correlated to the number and width of
haversian canals (cortical porosity) in femoral cortical bone
Bell et al. Bone, 2000
Alendronate Reduces
Cortical Porosity
Iliac Crest Biopsy
Cortical Porosity (%)
10
8
6
4
2
PBO
ALN
0
Roschger et al, Bone, 2001
All patients had NTx levels above the lower limit of
the normal premenopausal range (n=1023)
Garnero, JBMR 1996;11:337-349
Alendronate Data on File, Protocol 118
Risedronate
Risedronate Vertebral Fracture Studies (VERT)
(Patients with pre-existing vertebral fracture)
% of Patients with Fracture
Radiographic Vertebral Fractures at Year 3
30
25
20
49%
Reduction
P < 0.003
15
10
5
0
n=
PBO
678
RIS
696
NA(1)
1Harris
et al. JAMA. 1999;282:1344–1352.
JY. Osteoporos Int. 2000;11:83–91.
2Reginster
Reduction
P < 0.001
41%
PBO
346
RIS
344
MN(2)
Risedronate Non-Vertebral Fracture Studies
(VERT)
% of Patients with Fracture
Non Vertebral Fractures at Year 3
33%
15 39%
Reduction
12 P =0.02
9
6
3
0
PBO
RIS
NA(1)
1Harris
et al. JAMA. 1999;282:1344–1352.
JY. Osteoporos Int. 2000;11:83–91.
2Reginster
Reduction
NS (0.063)
PBO/ RIS
RIS
MN(2)
Risedronate hip fracture efficacy data in
postmenopausal women with osteoporosis
With Prior VFx=39%
Hip T-score –3.0 w/ risk factors
or Hip T-score–4.0
Age Range=70-79
With Prior VFx=45%
Age Range=80+
40%
% of patients with fracture
2.5 mg 50% s.s
5 mg 30% n.s
HIP (80+)2
5
reduction
at Year 3
p=0.009
4
3
2
reduction
at Year 3
p=0.35
5
4
3
2
1
0
(20%)
% of patients with fracture
Group 1 by dosage
HIP (70-79)2
1
PBO
RIS
n=1,821
n=3,624
0
PBO
RIS
n=1,313 n=2,573
1. ACTONEL® [package insert]. Cincinnati, OH: Procter & Gamble Pharmaceuticals and Kansas City, MO: Aventis Pharmaceuticals, Inc.; 2000.
2. McClung MR, et al. NEJM. 2001;344(5):333–340.
§ The percentages are based on the number of women for whom vertebral-fracture status was known.
Evidence-Based Review of OP Trials:
Effect of Risedronate in Reducing Vertebral
Fractures
•
Cranney et al, Endocrine Reviews 23(4):517-523; 2002
Relative Risk with 95% CI
(Final Year, All Doses)
Favors Risedronate
Favors control
Prevention Trials

(N = 111)
Treatment Trials

(N =1374)

(N = 132)

(N = 297)

(N = 690)

Pooled Estimate 0.64 (0.54 to 0.77)
0.1
36% reduction
(N =2604)
1
10
Evidence-Based Review of OP Trials:
Effect of Risedronate in Reducing Non-Vertebral
Fractures
•
Cranney et al, Endocrine Reviews 23(4):517-523;
2002
Relative Risk with 95% CI (Final Year, All Doses)
Favors Risedronate
Favors Control
Prevention Trials

(N = 111)
Treatment Trials

Harris
(N = 1627 )


(N=132)
(N = 9331)

(N =297)

(N =812 )

McClung (1999) 0.71 (0.36 to 1.40)
(N=648)

Pooled Estimate 0.73 (0.61 to 0.87)
0
0.5
(N =12958 )
1
1.5
2
27% reduction
2.5
10
The Effect of Risedronate on Hip Fracture
Favors RIS
Favors PBO
McClung: 70 -79 Osteoporosis (Group I)
Primary
Hip Study
McClung: Over 80 with T < -2.5 (Group II)
Harris (with VFX)
Primary
VFX Study
Reginster (with VFX)
30% (p = 0.015)
All Studies
0.1
Test for homogeneity: p = 0.440
T < 2.0
Quandt S., Annals Rheum Disease 2000, 59; 83
0.3
0.5
Relative Risk
0.8
1
2
Risedronate
Summary
• Reduction in vertebral fracture
• Reduction in non-vertebral fractures in
North American cohort
• Reduction in hip fracture shown in
women 70-79 years of age
• 7 year data show sustained effect on
vertebral fracture reduction
Meta Analysis Summary:
Antifracture Efficacy -Vertebral Fractures
Intervention
Alendronate
Risedronate
Raloxifene
Number of
Trials
Relative Risk
(Patients)
(95% CI)
8 (9360)
5 (2604)
0.52 (0.43 to 0.65)
0.64 (0.54 to 0.77)
2 (6961) 0.65 (0.56 to 0.76)
Relative
Risk p Heterovalue geneity
< 0.01
0.01
0.01
0.99
0.89
0.01
Etidronate
9 (1076)
0.63 (0.44 to 0.92)
0.02
0.87
Calcitonin
4 (1404)
0.46 (0.25 to 0.87)
0.02
0.01
Vitamin D
8 (1130)
HRT
3 (300)
0.63 (0.45 to 0.88) < 0.01
0.16
0.57 (0.29,1.13)
0.12
0.86
Calcium
5 (576)
0.77 (0.54 to 1.09)
0.14
0.40
Fluoride (4yrs)
5 (646)
0.67 (0.38,1.19)
0.17
0.01
ORAG
Meta-Analysis Summary:
Antifracture Efficacy -Non-vertebral Fractures
Alendronate
Risedronate
Calcitonin
Calcium
Etidronate
Fluoride
HRT
Raloxifene
Vitamin D
6 (3723)
7 (12958)
3 (1481)
2 (222)
7 (867)
5 (950)
5 (3936)
2 (6961)
6 (6187)
0.51 (0.38, 0.69)
0.73 (0.61, 0.87)
0.50 (0.22, 1.23)
0.86 (0.43, 1.72)
0.99 (0.69, 1.42)
1.46 (0.92, 2.32)
0.67 (0.43, 1.05)
0.91 (0.79, 1.06)
0.77 (0.57, 1.04)
< 0.01
< 0.01
0.14
0.66
0.97
0.11
0.10
0.24
0.09
0.89
0.81
0.08
0.54
0.94
0.06
0.57
0.43
0.09
Are there direct
comparisons with
anti-resorptive agents in
assisting the physicians’
clinical decision?
Combination Therapy with Hormone
Replacement and Alendronate for
Prevention of Bone Loss in Elderly Women
Greenspan SL et al
JAMA 2003 289, 2525-2523
Combination Treatment of Raloxifene &
Alendronate in PM Osteoporosis
•
•
•
•
% change at 12 months
Randomized, double-blind, 12 month study
Postmenopausal women with osteoporosis (FN -2.0), n=331
Greater spine and FN increases with ALN than RLX
Similar tolerability
6
5
4
20
*
0
*
3
2
Placebo
Raloxifene
Alendronate
RLX + ALN
1
-20
-40
-60
0
-1
*
*
-80
Spine
Femoral Neck
* P≤0.05 ALN vs. RLX
NTx/Cr
BSAP
Johnell et al., JCEM 2002
EFFECT-International
EFficacy of Fosamax® vs. Evista®
Comparison Trial
Sambrook et al, Calcif Tissue Int 2003
EFFECT – International
Study Design
• Randomized, double-blind, double-dummy, active-comparator controlled, 12
month study
• 50 sites in 16 countries
• Separate study conducted in the US
• Patients evaluated at screening, randomization,
3, 6, and 12 months
• Patients randomized 1:1 to:
– ALN 70 mg once weekly and RLX placebo daily
-or– RLX 60 mg daily and ALN placebo once weekly
• Key efficacy endpoints evaluated by central QA centers
(BMD – BioImaging; markers of bone turnover - Quest)
Sambrook et al, Calcif Tissue Int 2003
EFFECT – International
Endpoints
• Primary endpoint
– % change from baseline in lumbar spine BMD at
12 months
• Secondary endpoints
– % change from baseline in
• Total hip BMD at 12 months
• Hip trochanter BMD at 12 months
• BMD at 6 months
– Percentage of patients who maintained or increased BMD
– % change in markers of bone turnover (NTx and BSAP)
– Tolerability, including upper GI and vasomotor events
Sambrook et al, Calcif Tissue Int 2003
Alendronate-Raloxifene Comparison
12 Month Percent Change in BMD relative to baseline
P<0.001
ALN
RLX
Mean % Change in BMD
5
4.5
4
3.5
P<0.001
3
P<0.001
2.5
2
1.5
1
0.5
0
Lumbar Spine
Total Hip
Hip Trochanter
Sambrook et al ECTS 2003
EFFECT – International
Markers of Bone Turnover
% Change (95% CI)
NTx
BSAP
20
20
0
0
-12
-20
-29
-20
-40
-40
-51
-60
***
-80
Alendronate
Raloxifene
-100
0
-68
***
-60
***
***
6
12
-80
-100
6
Months
*** P<0.001 Alendronate vs. raloxifene
Sambrook et al, Calcif Tissue Int 2003
12
0
Months
EFFECT-International
Markers of Bone Turnover – Absolute Values
NTx
20
Alendronate
Raloxifene
60
Absolute Value
BSAP
50
15
13.5
40
38.8
10
30
8.1
20
***
10
*** 17.7
5
***
***
6
12
0
0
0
0
Months
6
*** P<0.001 Alendronate vs. raloxifene
Premenopausal range
Garnero et al, JBMR 1996
Sambrook et al, Calcif Tissue Int 2003
12
% below upper limit:
NTX
BSAP
Months
Alendronate
96%
96%
Raloxifene
60%
63%
EFFECT – International
Tolerability
ALN
70 mg OW
RLX
60 mg QD
N=246
N=241
Any AE
63
65
NS
Drug-related* AE
23
27
NS
Discontinued due to AE
6
8
NS
Upper GI AE
15
22
NS
9
16
0.029
4
10
0.010
2
8
0.007
% of patients
Drug-related*
Vasomotor AE
Drug-related*
*Possibly, probably or definitely drug-related as determined by the investigator
Sambrook et al, Calcif Tissue Int 2003
P-value
EFFECT – International
Summary
•
•
ALN produced 2-3 fold greater increases in hip and spine BMD than did
RLX at 12 months
ALN
RLX
–Spine
–Total hip
–Trochanter
4.8%
2.3%
2.9%
2.2%
0.8%
1.0%
•
More patients maintained or increased BMD with ALN than with RLX
•
ALN produced significantly greater increases in BMD than did RLX at the
early time point of 6 months
•
ALN decreased bone resorption (NTx) significantly more than did RLX at
6 and 12 months
•
The decreases in markers of bone turnover with alendronate were to the
middle of the premenopausal range
•
Overall tolerability of ALN and RLX was similar, with more patients
reporting vasomotor events on RLX
Sambrook et al, Calcif Tissue Int 2003
Alendronate vs.
Risedronate
Comparison Trial
Alendronate vs. Risedronate Comparison
Trial
Overview
• First head to head study comparing alendronate and
risedronate for treatment of osteoporosis
• Endpoints
– Biochemical markers of bone turnover
– BMD spine and hip
Alendronate vs. Risedronate Comparison
Trial Study Design
 Randomized, double-blind, multicenter, multinational,
placebo-controlled study
 3 months: bone turnover
 6 and 12 months: BMD
 549 postmenopausal women with osteoporosis age > 60
T-score < -2.5 at either lumbar spine or total hip or
T-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
Approved Dosing Regimens
• Alendronate sodium (Fosamax™)
At least 1/2 hour before the first food, beverage, or
medication of the day, upon arising for the day
• Risedronate (Actonel)*
At least 2 hours from any food or drink at any other
time of the day, and at least 30 minutes before going
to bed
*Post-meal dosing approved outside the
US
Risedronate Bioavailability
100
Relative Bioavailability (%)
90
80
70
60
50
40
30
20
10
0
4 Hour 1 Hour 1/2 Hour
Before Before Before
BreakfastBreakfastBreakfast
2 Hour
After
Dinner
Absolute Bioavailability 0.63%
Source: Actonel® [Risedronate] United States Product Circular
Alendronate-Risedronate Comparison
12 Month Percent Change in BMD relative to baseline
Alendronate
Risedronate
Placebo
6
% Change
5
***
4
***
3
***
*
2
1
0
-1
Lumbar Spine
Femoral Neck
Trochanter
*** p < 0.001; * p < 0.05 Alendronate v Risedronate
Hosking D I.O.F.meeting Lisbon 2002
Total Hip
Alendronate vs. Risedronate Comparison Trial
Markers of Bone Turnover
Urinary NTx
BSAP
Mean Percent Change
20
20
10
10
0
-10
0
-20
-30
-10
-40
Placebo
RIS 5 mg Daily
ALN 70 mg Once Weekly
-20
-30
-50
*
-60
*
*
-70
-80
-40
0
1
3
Month
* P<0.001: Alendronate vs. risedronate
0
1
3
Month
Alendronate vs. Risedronate Comparison Trial BSAP
Mean Percent Change
0
-20
†
-40
†
Placebo
RIS 5 mg Daily
ALN 70 mg Once Weekly
-60
0
† P<0.001:
†
3
Alendronate vs. Risedronate
6
Month
12
Alendronate vs. Risedronate Comparison Trial
Adverse Experiences
• Similar tolerability seen in all three groups
Placebo
N=108
ALN
N=219
RIS
N=222
Any clinical adverse
experience
70%
77%
76%
Any upper GI
27%
28%
27%
Esophageal
0%
2%
2%
0%
0%
0.5%
% of patients
†
PUB
†
Gastric or duodenal perforation, ulcer or bleed
Alendronate vs. Risedronate Comparison Trial
Summary
 Significantly greater increases in BMD at both the hip and spine with
alendronate compared to risedronate over 12 months
 70% greater at the lumbar spine (4.8% vs. 2.8%)
 3.7-fold greater at the hip trochanter (3.3% vs. 0.9%)
 3-fold 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
 Significantly greater effect on markers of bone resorption with alendronate
compared to risedronate
 Greater decrease in resorption with alendronate seen early (at one month)
 Similar tolerability was seen between alendronate and risedronate,
including upper gastrointestinal adverse experiences
Summary
Impact of Therapeutic Trials in Clinical
Decision Making
• Prescribe the drug that has the most significant
impact on reversing or stopping the consequences
of osteoporosis.
• Fracture is the most serious outcome of
osteoporosis: Use the drugs that reduce fractures at
all sites rapidly, consistently, and in a sustained
fashion. This will afford the physician and the
patient the best clinical benefit.