1 ipriflavone in the treatment of postmenopausal osteoporosis randomized placebo-controlled, 4-year...
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RALOXIFENE
The first SERM to be approved for the prevention and the treatment of postmenopausal osteoporosis
Estrogen agonist in bone (Prevents bone loss)
Estrogen antagonist in the breast and the uterus
4
Effect of Raloxifene on Spine andFemoral Neck BMDMORE Trial - 48 Months
Months0 12 24 36 48
-2
-1
0
1
2
3
4
** * *
Placebo Raloxifene 60 mg/d
Months0 12 24 36 48
-2
-1
0
1
2
3
4
** *
*
Femoral NeckLumbar Spine
1.91.3
2.1 2.1
2.0 2.6 2.7 2.6
5
0
5
10
15
20
25
30
35
40
Effects of Raloxifene onNew Vertebral Fractures
MORE Trial - 48 Months
% o
f W
omen
With
In
c ide
nt V
erte
bra l
Fra
c tur
e
With Prevalent Vertebral Fractures
Without Prevalent Vertebral Fractures
RR 0.51(95% CI = 0.35-0.73)
RR 0.66(95% CI = 0.55-0.81)
PlaceboRaloxifene 60 mg/d
49%
34%
6
Wrist
Ankle
Hip
Any nonvertebral
No. (%) of Women
Placebo
(N=2576)
Raloxifene(pooled)(N=5129)
0.9 (0.7-1.1)
0.6 (0.4-1.0)
1.1 (0.6-1.9)
0.9 (0.8-1.1)
Effect of Raloxifene on Nonvertebral FracturesMORE Trial - 3 Years
151 (2.9)
34 (0.7)
40 (0.8)
437 (8.5)
86 (3.3)
28 (1.1)
18 (0.7)
240 (9.3)
Relative Risk(95% CI)
Fractures
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BCPT: Relative Risk of Fracture by Tamoxifen use
• HIP• Spine• Radius, Colles• Other• Total
<49 years at entry >50 years at entry
0.55 (0.25-1.15)
0.74 (0.41-1.32)
0.61 (0.29-1.23)
1.05 (0.73-1.51)
0.81 (0.63-1.05)
0.88 (0.46-1.68)
0.79 (0.60-1.05)
RR (95% CI)
Fisher B, et al. JNCI 1998;90:1371-88.
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Prevent vertebral fracturesNo effect on other clinical fracturesPrevent Breast Cancer in average risk women
? High Risk Women (STAR)No effect on endometrium? Prevent CVD in high risk women: RUTHIncrease in VTE
Long-term effects: CORE–Increase in ER(-) tumors?–Immunity to anti-estrogen effects ?
Summary: Raloxifene
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Bisphosphonates
• Alendronate (Fosamax®)
• Risedronate (Actonel®)
• Zoledronic Acid (Zometa®) (not FDA approved)
• Pamidronate (Aredia®) (not FDA approved)
-2
0
2
4
6
8
10
0 12 24 36
Months
Per
cen
t C
han
ge
in L
S-B
MD
Rel
ativ
e to
Bas
elin
e
RIS 5 mg RIS 2.5 mg Placebo
-2
0
2
4
6
8
10
12 24 36
Months
Per
cen
t C
han
ge
in L
S-B
MD
Rel
ativ
e to
Bas
elin
e
ALN 5 mg ALN 10 mg Placebo
* p<0.05
Results from Separate Risedronate and Alendronate BMD Trials
Lumbar Spine BMDLumbar Spine BMD
Mean Change vs. Baseline Mean Change vs. BaselineRisedronateRisedronate
Lumbar Spine BMDLumbar Spine BMDMean Change vs. BaselineMean Change vs. Baseline
AlendronateAlendronate
* *
*
**
*
* * *
*
** *
*
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Efficacy at the Spine: Radiographic Vertebral Fractures at 3 years
15
8
0
4
8
12
16
Placebo Alendronate
16.3
10
0
4
8
12
16
Placebo Risedronate
Alendronate (n=2027; 71y)+ Risedronate (n=2458; 69y)*
47% reduction
p<0.001
41% reduction
p=0.003
+Black et al. Lancet 1996. *Harris S. JAMA 1999.
% w
ith
frac
ture
% w
ith
frac
ture
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Efficacy of Oral Bisphosphonates on Hip Fracture
• Alendronate+
– Women with vertebral fractures: 50% reduction, p<0.05
– Women without vertebral fractures:T< -2.5: 56% reduction, p<0.05T> -2.5: Not significant
• Risedronate*Age 70 – 79– Women with osteoporosis (t-score < -2.5)
39% reduction (p=0.02)– Women with vertebral fractures
58% reduction (p<0.01)Age 80+– Women with osteoporosis (t-score < -2.5)
25% reduction, p=0.14– Women with risk factors
Not significant
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Once-Weekly Alendronate for the Treatment of Osteoporosis: Effect on BMD
0
1
2
3
4
5
6
6 12
% C
hang
e fr
om B
asel
ine
ALN 10mg Daily`
ALN 35 mg TwiceWeekly
ALN 70 mg OnceWeekly
Month
Lumbar Spine
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Effects of Zoledronic Acid on BMD in Lumbar Spine
Month of Scan
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Bisphosphonates: Alendronate and Residronate
–Prevent vertebral fractures–Prevent clinical fractures
• Alendronate: Hip Fracture indication
–Both approved for weekly administration–RCTs >3 years duration–No other systemic effects–Long term effect
• Alendronate :10 years of use: BMD
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PTH: Mode of Delivery Determines Bone Activity
• Intermittent doses of PTH are anabolic and lead to increased bone formation whereas continuous exposure to PTH leads to increased bone resorption and a net bone loss.
Tam et al. Endocrinology 1982
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Effect of rhPTH(1-34) on the Risk of New Vertebral Fractures
*p <0.001 vs. Placebo
Ris
k R
edu
ctio
n (
RR
)
Placebo(n=448)
rhPTH 20(n=444)
rhPTH 40(n=434)
64 22 19100%
75%
50%
0%
25%
% o
f Wo
men
8
0
246
101214
RR 0.31 (95% CI, 0.19 to 0.50)*
RR 0.35 (95% CI, 0.22 to 0.55)*
65% 69%
No. of women who had > 1 fracture
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Effect of rhPTH(1-34) on the Risk of Nonvertebral Fragility Fractures
* p = 0.02 vs. Placebo** p = 0.01 vs. Placebo
0
1
2
3
4
5
6
7
Placebo rhPTH 20 rhPTH 40
% o
f W
om
en
30 14 14
53% 54%
(n=544) (n=552)(n=541)
No. of women who had > 1 fragility fracture
RR 0.46 (95% CI, 0.25 to 0.86)**
RR 0.47 (95% CI, 0.25 to 0.88)*
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Effect of rhPTH(1-34) on BMD
% Change from Baseline to Last Visit ( + SD )
rhPTH 20 rhPTH 40
• Lumbar Spine9.7 ± 7.4* 13.7 ± 9.7*
• Femoral Neck 2.8 ± 5.7* 5.1 ± 6.7*
• Total Hip 2.6 ± 4.9* 3.6 ± 5.4*
*p <0.001 vs. Placebo
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WHO SHOULD BE TREATED WITH WHAT?
HOT FLASHES HIP FRACTURES
ESTROGEN???? ALENDRONATERISEDRONATE
RALOXIFENE, ALENDRONATE, RISEDRONATE
FIRST VERTEBRAL FRACTURE
CALCITONIN??
50 807060
AGE
25
Anti-fracture Efficacy of Selected Therapies
• Alendronate +++ ++• Calcitonin + 0• Etidronate + 0• Fluoride + -• HRT + +++• PTH +++ ++• Raloxifene +++ 0• Risedronate +++ ++• Vit D derivatives + 0
Drug Vertebral F x Hip fx
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