1. New Perspective of SERM in Postmenopausal Women Health Daniel Thiebaud MD, Medical Fellow, Global Osteoporosis Strategy, Eli Lilly, Australia

2. Case Study
63 year old woman presents with a history of acute low back pain.
Menopause at 44 years of age, but never received postmenopausal HRT.
Reported a history of a Colles’ fracture at age of 60 years.
What additional questions would you ask?
Lumbar spine films reveal a recent vert fracture (L1)
DXA of the hip shows a BMD T-score of –1.8 SD, and of -2.7 at LS (L2-L4).
How should her case be managed?

3. Case Study : How should it be managed?
What other questions should you ask?
What other tests would you like to know?
What general advice would you give ?
What treatment would you consider?

4. The Osteoporosis Cascade
When to suspect and investigate for osteoporosis?
VERT FRACTURES ARE OFTEN NOT RECOGNISED
Radiologists often do not mention vertebral fractures in reporting chest x-rays
Clinicians often fail to recognize or act on x-ray reports of fractures
Two thirds of new vertebral fractures are not diagnosed
This slide illustrates the clinical impact of vertebral fractures. Recurrent fractures can cause spinal deformity (such as thoracic kyphosis), shortened stature, and disability. Anatomical changes of the chest wall due to multiple fractures may also lead to pain, respiratory compromise, early satiety, and other difficulties.
When considering therapeutic management, it is important to understand the needs of the patient and her immediate as well as long-term risks. 50
Menopausal
Experiencing vasomotor symptoms
55+ Postmenopausal
At greater risk for vertebral fracture than any other type of fracture
75+
Kyphotic
At risk for hip fracture & further Vertebral fracture
Gehlbach SH, et al. Osteoporos Int. 2000;11:
Delmas PD, et al. J Bone Miner Res. 2001;16(Suppl 1):S139.
Lindsay R. et. Al. JAMA 2001; 285;

5. Therapeutic options for osteoporosis
Inhibitors of bone resorption (Antiresorptives)
Bisphosphonates
Alendronate
Etidronate
Risedronate
Calcitonin
Estrogen ± progestin
Selective estrogen receptor modulators (SERMs)
Raloxifene
Stimulators of bone formation
(Fluoride)
Parathyroid hormone
Mixed mechanism of action
Active Vitamin D metabolites
Strontium ranelate
Recommended for all women at risk for osteoporosis
Calcium and vitamin D
Slide 34
Speaker Notes:
Over the last few years, many new therapeutic options have become available for the prevention and treatment of osteoporosis. Commonly used agents include a variety of estrogen and estrogen-plus-progestin preparations, selective estrogen receptor modulators (SERMs) (such as raloxifene), calcitonin, and bisphosphonates (such as etidronate, alendronate, and risedronate). Calcium and vitamin D are recommended for all women at risk for osteoporosis unless there are specific contraindications.

6. Selective Estrogen Receptor Modulator Concept of a SERM
Source:
Review:
Reviewer Memo:
Not an estrogen, progestin or other hormone
Binds to estrogen receptors
Has estrogen-like effects in some tissues
Blocks estrogen effects in some tissues
Slide Modified:
Memo:

7. Chemical Structures of Estradiol and Currently Available SERMs
Source:
Tamoxifen
prevention and treatment of breast cancer
Clomiphene
fertility induction
Toremifene
treatment of breast cancer
17b-estradiol
Review:
Reviewer Memo:
Raloxifene
post-menopausal osteoporosis
prevention and treatment
New SERMs in Phase 3 trials:
- Lasofoxifene
- Basedoxifene
- Arzoxifene
Slide Modified:
Memo:

8. Raloxifene versus Estrogen: Receptor Binding and Pharmacology
Source:
Review:
Raloxifene
Is not a hormone
Binds to estrogen receptors differently than does estrogen*
Induces conformational changes in the estrogen receptor that are distinct from those induced by estrogen*
Leads to different biological activities depending on the target tissue/organ*
Raloxifene does not accumulate in bone
Estradiol and Raloxifene Occupy the Same Ligand Binding Site
Raloxifene, Kd= 54 pM
Estradiol, Kd= 86 pM
Reviewer Memo:
Raloxifene versus Estrogen:Receptor Binding and Pharmacology
Reproduced with permission from Brzozowski AM et al. Nature 389:753-58, 1997;
*Katzenellenbogen BS. Science 2002;295:
Slide Modified:
Memo:

9. Tissue Dependent Action
Source:
Tissue Dependent Action
Review: N OH O HO S
Basic Side Chain
Benzothiophene
Reviewer Memo: ER
Antagonistic Effects
(uterus, breast)
Tissue Dependent Action
Agonistic Effects (bone)
Increase BMD and reduce
the risk of vertebral fractures
ER = Estrogen Receptor
BMD = Bone Mineral Density
Slide Modified:
Memo:

10. Multiple co-regulatory factors
Estrogen Receptor Signaling
Source:
Multiple co-regulatory factors
Multiple ligands
estrogens
SERMs
Multiple receptor
isoforms/variants  
Genomic*
Non- genomic**
Signal Transduction
MAP Kinase
ERK/Akt
NO synthase
Membrane ER?
Review:
Reviewer Memo:
Estrogen Receptor Signaling
How can we explain differences in biological effects between estrogen and SERMs, and between different SERMs? In the last 5-10 years, it has become clear that the molecular pathways behind estrogen receptor (ER)-mediated responses are multiple and complex. In the classical genomic pathway, estrogen or other ER ligand binding to the ER results in dimerization of the receptor and translocation to the nucleus. However, it is now clear that in addition to this “classical” pathway, there is multiplicity at various stages of this process that can contribute to tissue- and compound-specific differences in responses:
Multiple ER receptors. There exists both nuclear ERs (mediating genomic effects of estrogen) and membrane ERs (mediating non-genomic effects of estrogen). The membrane ER receptor has been implicated in some of estrogen’s rapid, non-genomic effects. There is also multiplicity among genomic ER, with the two major isoforms being ERa and ERb. Although the tissue distribution of a and b overlap considerably, some tissues express the b-isoform more abundantly than the a-isoform, including bone, prostrate, and hippocampus.
Multiple co-regulatory proteins. Once the ER is bound to the DNA, there are a variety of co-regulatory proteins that can interact with the ER:ligand complex. These co-regulatory proteins may be co-activators, which facilitate the ER:ligand complex interaction with the DNA or otherwise act to promote transcriptional activation, or they may be co-repressors, which act to prevent transcription by binding to the ER. The presence of different co-activators or co-repressors in various tissues may contribute to the multiplicity of action of estrogen and SERMs in various estrogen-responsive tissues.
Multiple genomic response sequences. Finally, there appears to be multiple genomic sequences, in addition to the classical estrogen response element (ERE), through which the ER:ligand complex may regulate transcription.
Thus, the presence of multiple ER types, multiple co-regulatory proteins, and multiple sites of genomic and non-genomic regulation by the ER:ligand complex, all may contribute to the tissue-specific action of SERMs, and likely form the basis for the differences in biological effects among SERMs.
1. McDonnell and Norris, Osteoporosis Int 1997;S29-4
2. Bryant HU, Reviews in Endocrine and Metabolic Disorders 2001;2:129-38
ERE
Other response elements
**Simoncini T et al. Steroids 67: , 2002
Multiple genomic sequences
* McDonnell and Norris, Osteoporosis Int 1997;S29-4 Bryant HU, Reviews in Endocrine and Metabolic Disorders 2:129-38, 2001
Slide Modified:
Memo:

11. Risk of New Clinical Vertebral Fractures at 1 Year
Women with and without
Prevalent Vertebral Fractures
Women with
Prevalent Vertebral Fractures
2.2
2.2
2.0
2.0
RR 0.34 (95% CI, )
1.8
1.8
1.6
1.6
1.4
1.4
66%
New Clinical Vertebral Fracture
% of Women with
1.2
1.2
1.0
1.0
RR 0.32 (95% CI, )
0.8
0.8
0.6
68%
0.6
0.4
0.4
0.2
0.2
0.0
0.0
Placebo
RLX 60
Placebo
RLX 60
Marici et al, Arch. Int med, 2002

12. Risk Reduction in Clinical Vertebral Fractures at 1 Year
69%
59%
p=.009
p<.03
68%
p=.01
MORE1 Raloxifene
FIT-I/FIT-II2 Alendronate
VERT-MN/VERT-NA3 Risedronate*
*Clinical vertebral fractures derived from pooled post-hoc analysis of VERT-NA/VERT-MN. 1. Ettinger B, et al. JAMA. 1999;282(7): Black DM, et al. J Clin Endocrinol Metab. 2000;85(11): Data on file, Procter & Gamble.

13. MORE Multiple Outcomes of Raloxifene Evaluation
Source:
Review:
Multicenter, double-blind, placebo-controlled trial
25 countries, 180 centers, 3 years with 1 year extension
7705 postmenopausal women with osteoporosis
Mean age 66.5 years
Raloxifene 60 mg =Evista, 120 mg, or placebo
All patients given daily calcium (500 mg) and vitamin D (600 IU)
Primary endpoints: radiographic vertebral fracture, BMD, safety
Secondary endpoints: all osteoporotic fractures, cardiovascular health, breast cancer, cognitive function
Reviewer Memo:
MORE: Multiple Outcomes of Raloxifene Evaluation
The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a large, multicenter, double-blind, placebo controlled trial of postmenopausal women with osteoporosis, enrolling 7705 women at 180 sites in 25 countries.1,2 The trial consisted of a 3-year core treatment phase with a 1-year extension phase. Women were randomly assigned to receive placebo or raloxifene 60 mg/day (Evista), or raloxifene 120 mg/day. All women also received supplemental calcium (500 mg/day) and vitamin D (400 – 600 IU/day).
The primary endpoints of the MORE trial were the incidence of new vertebral fractures and bone mineral density of the lumbar spine and femoral neck. Secondary endpoints included all osteoporotic fractures, serum lipids and other markers of cardiovascular risk, cognitive function, breast cancer, and safety. Major criteria for exclusion from the study included a history of breast or endometrial cancer or the presence of abnormal uterine bleeding.
The dose of raloxifene approved for the prevention and treatment of postmenopausal osteoporosis is 60 mg/day, and effects observed with raloxifene 120 mg/day were comparable to those observed with 60 mg/day. Thus, unless noted otherwise, the data in the subsequent slides will focus on the raloxifene 60 mg/day group compared with placebo.
1. Ettinger B et al. JAMA 1999; 282:637-45
2. Cummings SR et al., JAMA 1999;281:
Ettinger B et al. JAMA 282:637-45, 1999
Cummings SR et al. JAMA 281: , 1999
Slide Modified:
Memo:

14. Cumulative Incidence of New Clinical
Vertebral Fractures in the First Year of MORE
7705 postmenopausal women with osteoporosis
Months 2 4 6 8 10 12 14 16
0.0
0.2
0.4
0.6
0.8
1.0
Placebo
Raloxifene 60 mg/d
Raloxifene 120 mg/d
Clinical Vertebral Fracture (%)
*P=0.007 in the first 6 months for
each raloxifene group compared with placebo
Qu Y, et al. CMRO, 2005, 21 (12):

15. Effect of Raloxifene on New Clinical Vertebral Fractures at 6 Months
0.44%
(n=10)
Qu Y, et al. CMRO, 2005, 21 (12):

16. Effect of raloxifene on clinical fractures in Asian (China, Japan) women with osteoporosis
Baseline Characteristics a
Japan (N=284)b
China (N=204)c
Age (years)
64.8±6.3
65.3±6.0
Years Postmenopausal
15.2±6.5
16.9±7.3
Body Mass Index (kg/m2)
21.8±2.8
23.0±2.9
Prevalent Vertebral Fracture (%)
26.4
13.7
Lumbar Spine BMD (g/cm2) T-score
0.63± ±0.46
0.69± ±0.51
a : Mean ± standard deviation for continuous variables presented b : N=97 for placebo ; N=92 for raloxifene 60 mg/d ; N=95 for raloxifene 120 mg/d c : N=102 for placebo ; N=102 for raloxifene 60 mg/d
T.Nakamura et al.JBMM, 24: , 2006

17. New Clinical Vertebral Fractures Combining the Japan and China Studies
（%） 6 5
＊:p<0.01 vs. placebo
＊＊:p<0.002 vs. placebo 4
3.5%
（n=7） 3 2 0%
（n=0） * 0%
（n=0） ** 1
Placebo
Raloxifene
60mg/day
Raloxifene
Pooled
N=199
N=194
N=289
T.Nakamura et. Al, JBMM; 24: ; 2006

18. Any New Clinical Fractures Combining the Japan and China Studies
（%） 9
RR：0.11（ ） 8 7
RR：0.17（ ）
＊:p<0.01 vs. placebo 6
＊＊:p<0.001 vs. placebo 5
6.0%
（n=12） 4 3 *
1.0%
（n=2）
0.7%
（n=2） ** 2 1
Placebo
Raloxifene
60mg/day
Raloxifene
Pooled
T.Nakamura et. al.JBMM; 24: , 2006

19. % of Women with at least 1 New Nonvertebral Fracture
Raloxifene Reduces Risk of at least 1 New Nonvertebral* Fracture in Women with Severe Fracture
MORE Trial - 3 Years
P=0.046 20
RH=0.53 (95% CI 0.29, 0.99) 15
47%
% of Women with at least 1 New Nonvertebral Fracture 10 5
Placebo
Raloxifene 60 mg/d
*Clavicle, humerus, wrist, pelvis, hip, leg
Delmas PD et al. Bone 2003;33;4:

20. Raloxifene prevents Non Vertebral Fracture in Women with 2 Prevalent Vertebral Fractures (n= 1369, mean age 69y MORE Trial - 3 Years – pooled raloxifene
Nonvertebral Fracture *
RR=0.69 (95% CI 0.48, 0.99)
P<0.05 40 30
% of Women With at Least 1 New non-Vertebral Fracture 20
31%
In the small subgroup of women with SQ grade 3 prevalent vertebral fractures, raloxifene 60 mg/d significantly decreased the relative risk of new vertebral fractures by 27% compared with placebo. The corresponding number-needed-to-treat to prevent 1 new vertebral fracture (NNT) was 10.
In addition, raloxifene 60 mg/d significantly decreased the relative risk of new nonvertebral fractures by 47% compared with placebo. The corresponding number-needed-to-treat to prevent 1 new nonvertebral fracture was 18.
NNT (Number-needed-to-treat) = number of women needed to be treated to prevent a fracture event. 10
Placebo
Raloxifene
* Clavicle, humerus, wrist, pelvis, hip, leg
Farrerons et al., CTI, 2003;72(4):391(P230)

21. EVA Trial (Evista Versus Alendronate)
First ever head-to-head fracture outcome trial
Compare the osteoporotic fracture risk reduction efficacy of raloxifene and alendronate
Approximately 2000 postmenopausal women with osteoporosis
Double-blind, randomized, controlled, 1-3 year trial with raloxifene 60 mg/d vs alendronate 10 mg/d
Calcium 500 mg/d + vitamin D 400 IU/d to all patients
Sites in US, Canada, and Puerto Rico
Recker RR, et al. J Bone Miner Res. 2005;20(suppl 1):S97, Bone in press 2007.

22. Baseline Characteristics
Raloxifene
(N=707)
Alendronate
(N=716)
P-value
Age (years)
65.5
65.7
0.56
Caucasian (%)
86.7
86.9
0.83
BMI (kg/m2)
24.8
24.6
0.42
LS BMD (g/cm2)
0.82
0.79
T-score
-2.32
-2.34
0.65
FN BMD (g/cm2)
0.61
0.98
-2.39
0.77
Hip BMD (g/cm2)
0.71
T-Score
-1.99
-2.01
0.64

23. EVA trial : Ralo vs Alendronate BMD changes after 2 years
Lumbar Spine Femoral Neck Total Hip
P<0.0001 *
P= 0.002
P=0.041 * * * * *
Age 65 yrs, BMD LS Tscore = -2.3, Hip FN Tscore = -2.4
* Significant change compared with baseline (P<0.05)
Recker R et al, ASBMR 2005, J Bone Miner Res. 2005;20(suppl 1):S97, Bopne in press 2007

24. EVA Trial: Incidence of VFx and Non-V Fx
Women with ≥1 new Fx, n(%)
Type of Fracture ALN, 10mg/d RLX 60mg/d P value
N= N=699
Age, yrs ± ±
Vert or Non Vert 22 (3.1) 20 (2.9)
Vertebral (3.1) 5 (1.9)
Moderate/Severe 4 (1.6)
Clinical Vertebral 3 (0.4)
NonVertebral (2.0) (2.2)
Nonvertebral-Sixb 11 (1.5) (1.4)
b Includes the clavicule, humerus, wrist, pelvis, hip and leg.
Recker R et al, ASBMR 2005, Abstract in JBMR 2005, 20,Suppl 1,S97, Bone in press 2007

25. Adverse Events: All no significant difference Incidence Significantly Different Between Raloxifene and Alendronate
No. of Patients (%)
Event
RLX
(N=707)
ALN
(N=716)
P-Value
Colonoscopy
1 (0.14)
8 (1.12)
0.04
Diarrhea
11 (1.56)
27 (3.77)
0.01
Nausea
22 (3.11)
38 (5.31)
0.047
R.Recker et al : ASBMR 2005

26. Evista Safety Daniel Thiebaud MD, Medical Fellow, Global Osteoporosis Strategy, Eli Lilly, Australia

27. Large-Scale Raloxifene Clinical Trials
Source:
Review:
19,747
20000
15000
10,101
Reviewer Memo:
Number of Enrolled Women
10000
7,705
4,011
5000
1,400
1,764
Completed and Ongoing Large-Scale Raloxifene Clinical Trials
This slide summarizes the number of women who have been and are currently being studied in large-scale clinical trials of raloxifene. Approximately 1700 women without osteoporosis and 7700 women with osteoporosis have been studied in osteoporosis prevention and treatment trials, respectively. The MORE trial has ended. However, approximately 4000 women originally enrolled in MORE continue to receive raloxifene treatment and will be followed for an additional 4 years as part of the CORE (Continuing Outcomes Relevant to Evista) trial. The RUTH trial completed enrollment in August 2000 with 10,101 women enrolled, with first results available The STAR trial will eventually enroll approximately 19,000 women; over 15,000 women have been enrolled in STAR as of January 2003.
In addition to these ongoing clinical trials, there have been an estimated 2 million patient-years of therapy with raloxifene worldwide since EVISTA was introduced to the market in January of 1998.
STAR: Enrollment as of 3/1/04 was 18,005
EVA: 757 Enrolled as of 1/28/04
Osteoporosis
Prevention
MORE
CORE
RUTH
STAR
EVA
MORE, Multiple Outcomes of Raloxifene Evaluation; CORE, Continuing Outcomes Relevant to EVISTA; RUTH, Raloxifene Use for The Heart; STAR, Study of Tamoxifen and Raloxifene; EVA, EVISTA-Alendronate Comparison
Slide Modified:
Memo:

28. Rationale for the RUTH Trial
Source:
RUTH was designed to determine the effect of raloxifene on:
Coronary outcomes, based on:
favorable impact of raloxifene on cardiovascular risk markers1
evidence from observational studies that treatment with estrogen was associated with a reduced risk of CHD in postmenopausal women2,3
Invasive breast cancer, based on:
anti-estrogenic effects of raloxifene in the breast4
72% reduction in invasive breast cancer in a secondary analysis of data from the MORE trial5
Review:
Reviewer Memo:
RUTH was NOT designed based on the post hoc findings from MORE (reduction in risk of cardiovascular events in women at increased risk for CV events)
1Blumenthal R et al. Am Heart J 2004
2Stampfer MJ et al. Prev Med 1991
3Grady D et al. Ann Intern Med Brzozowski AM et al. Nature Cauley J et al. Breast Cancer Res Treat 2001
Slide Modified:
Memo:

29. Relevant Clinical Trial Findings After RUTH Commenced
Source:
Estrogen and Estrogen Plus ProgestinTherapy
HERS trial: Estrogen plus progestin did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease1
WHI trial: Early increase in risk of coronary events with estrogen plus progestin therapy and estrogen alone in healthy postmenopausal women2,3
Raloxifene
MORE trial results suggested no overall effect of raloxifene on cardiovascular (CV) events, and a reduced risk for CV events in the subset of postmenopausal women retrospectively defined as at increased CV risk (post hoc analysis)4
Review:
Reviewer Memo:
RUTH was NOT designed based on the post hoc findings from MORE (reduction in risk of cardiovascular events in women at increased risk for CV events)
1Hulley et al, JAMA 1998
2Writing Group for the Women's Health Initiative Investigators, JAMA 2002
3Anderson GL et al. JAMA 2004
4Barrett Connor et al, JAMA 2002
Slide Modified:
Memo:

30. STAR Results: Invasive Breast Cancer
The number of invasive breast cancers in the tamoxifen group (163 cases of 9,726) versus the raloxifene group (168 cases of 9,745) were statistically equivalent.
Tamoxifen is known to reduce breast cancer risk by 50%, and STAR shows that raloxifene produces similar results.
STAR= Study of Tamoxifen and Raloxifene
Vogel et al, JAMA , 2006; 295, June Fisher B, et al. J Natl Cancer Inst 1998; 90:

31. MORE plus CORE Study Design
Source:
MORE plus CORE Study Design
Review:
Gap
MORE Conclusion
CORE Screening
MORE (N=7705)
CORE (n=4011)
Three Treatment
Two Treatment
Groups
Groups
Placebo
Placebo
Reviewer Memo:
Raloxifene HCl 60 mg/day
Raloxifene HCl 60 mg/day
Raloxifene HCl 120 mg/day
As the 4 years of the MORE trial were concluding, it was decided to enroll as many of these women as possible into the CORE trial– for an additional 4 years, thus providing 8-year data. Of the original 7,705 MORE participants, 4,011 chose to continue in the CORE trial.
Women continuing in CORE were not re-randomized but the randomization assignment from MORE was carried forward into CORE.
The MORE trial, compared 3 treatment groups - placebo, raloxifene 60 mg/d, and raloxifene 120 mg/day for 4 years. The CORE trial compared 2 treatment groups – raloxifene 60mg/d and placebo. Women assigned to raloxifene 60mg/d or 120 mg/d in MORE were assigned to 60 mg/d in CORE. Women assigned to placebo in MORE were assigned to placebo in CORE.
Raloxifene 60mg/d was chosen as the dose for CORE because it is the dose approved for prevention and treatment of osteoporosis and because the reduction in incidence of breast cancer observed in the MORE trial was similar for both doses.
Similar to the MORE trial, twice as many women were assigned to the raloxifene group as to the placebo groups
Median time between the end of MORE and enrollment in CORE was 10.6 months. For approximately 95% of those assigned to raloxifene and 94% of those assigned to placebo the interval between the end of MORE and enrollment in CORE was less than 2 years.
Year 1 2 3 4 5 6 7 8
8 Years Total Follow-up
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):
Slide Modified:
Memo:

32. Incidence of Invasive Breast Cancer
Source:
Incidence of Invasive Breast Cancer
8 Years of MORE plus CORE (N=7705)
Review:
4.0
Placebo
4.2 per 1000 Women-Yrs
HR 0.34 (95% CI = )
3.0
Reviewer Memo:
p <0.001
Cumulative Incidence (%)
66%
2.0
1.0
8-year MORE plus CORE Results N=7705
This slide shows the Kaplan-Meier curve for the cumulative breast cancer incidence plotted against time over the 8 years of the MORE plus CORE trials beginning at randomization in MORE to the end of CORE
Over the 8-year period, raloxifene reduced the incidence of invasive breast cancer by 66% (p value < .001) compared with placebo.
A total of 98 cases of invasive breast cancer (58 in the placebo group and 40 in the Raloxifene group) were reported and confirmed by adjudication.
Absolute risk in the placebo group was 4.2 cases per 1000 woman-years and 1.4 cases for the raloxifene group. Thus, in the raloxifene group there was an absolute risk reduction of 2.8 cases per 1000 women-years.
Raloxifene
1.4 per 1000 Women-Yrs
0.0 1 2 3 4 5 6 7 8
Years in Study
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):
Slide Modified:
Memo:

33. Summary of Adverse Outcomes over the 8 Years of MORE-CORE (N=4011)
%Percentage of participants who experienced event (n)
P-value
Placebo
(N=1286)
Raloxifene
(N=2725)
Mortality
2.3 (29)
1.7 (47)
0.27
All cancers†
8.6 (110)
5.7 (156)
0.001
All cancers† excluding breast cancer
6.3 (81)
4.6 (126)
0.027
Hospitalization
40.9 (526)
38.8 (1057)
0.21
Treatment-emergent AEs
99.0 (1273)
98.6 (2688)
0.45
Treatment-emergent serious AEs
45.5 (585)
42.3 (1154)
0.07
Study discontinuation CORE due to AE
2.4 (31)
1.9 (53)
0.35
Over the 4 years of CORE, and the combined 8 years of MORE plus CORE, there was no increase in mortality associated with raloxifene therapy. This is in agreement with the results of the MORE trial.
Raloxifene was associated with a reduced incidence of all cancers, even when breast cancer was excluded from the analysis. This reduction in cancer incidence (when breast cancer excluded) was not due to an effect of raloxifene on any specific cancer. The clinical significance of this finding, if any, remains to be determined.
†Excluding non-melanoma skin cancers
Martino S et al. Curr Med Res Opin 2005

34. Summary of Gynecological AE Data over 8 Years of MORE-CORE (N=4011)
Source:
Martino S et al. Curr Med Res Opin 21; , 2005
%Percentage of participants
who experienced event (n)
P-value
Placebo
(N=1286)
Raloxifene
(N=2725)
Uterine cancer†‡
0.39 (4)
0.32 (7)
0.75
Endometrial hyperplasia‡
0.29 (3)
0.37 (8)
>0.99
Ovarian cancer
0.16 (2)
0.11 (3)
0.66
Postmenopausal bleeding‡§
5.4 (55)
5.5 (120)
0.87
Uterine polyps‡
1.9 (19)
3.2 (70)
0.028
Vulvovaginal signs and symptoms
5.8 (75)
5.0 (135)
0.26
Review:
discl #MEPN-6E9SHA appr
Reviewer Memo:
These 8-year MORE-CORE findings are similar to those reported from MORE and other studies of shorter duration. No increased incidence of ovarian cancer, uterine cancer, endometrial hyperplasia, or postmenopausal bleeding associated with raloxifene treatment. These uterine data support a neutral effect of raloxifene on the uterus.
Uterine polyps were more common in the raloxifene treatment group over the 8-year period. They were more frequently reported during the MORE trial period versus the CORE period (79 versus 9 events), presumably as a result of the uterine surveillance plan in place during MORE but not CORE. None of the uterine polyps diagnosed in the raloxifene treatment group were associated with an increase in reported bleeding or diagnosis of endometrial cancer over the 8 years, and most likely would not have been identified in a normal clinical setting, as demonstrated in CORE. The increased incidence of uterine polyps in the raloxifene group versus placebo during MORE may in part be related to an increased sensitivity of ultrasound in the active treatment group due to the presence of endometrial fluid. Raloxifene has previously been associated with an increase in endometrial cavity fluid, and it is feasible that this could have aided detection of these benign endometrial changes. Moreover, it is presumed that the greater incidence of endometrial biopsy in the raloxifene treatment group during the MORE period is at least in part the result of this increase in detection of benign endometrial changes during ultrasound in the raloxifene treatment group.
Martino S et al. Curr Med Res Opin 21; , 2005
Slide Modified:
Memo:
SCA: Sherie Dowsett
copyright permission received for graphs

35. Adverse Events Reported During MORE Plus CORE – 8 Years
Source:
Adverse Events Reported
During MORE Plus CORE – 8 Years
Review:
Number (%)
Placebo Raloxifene p-value
(n=1286) (n=2725)
Reviewer Memo:
Flushing (hot flushes) 89 (6.9) 342 (12.6) <0.001
Leg cramps 152 (11.8) 407 (14.9) 0.008
Peripheral edema 120 (9.3) 288 (10.6) 0.240
This slide shows the incidences of hot flushes, leg cramps, and peripheral edema, adverse events known to be associated with raloxifene therapy over the 8 years of the MORE plus CORE trials.
For the 8 years of MORE plus CORE, hot flushes and leg cramps, but not peripheral edema, were reported significantly more often in the raloxifene group than in the placebo group.
Raloxifene dose is 60mg/d in CORE and 60mg/d or 120 mg/d in MORE.
P values based on 2-sided Fisher’s exact test.
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):
Slide Modified:
Memo:

36. Therapeutic options for osteoporosis
Inhibitors of bone resorption
Bisphosphonates
Alendronate
Etidronate
Risedronate
Calcitonin
Estrogen ± progestin
Selective estrogen receptor modulators (SERMs)
Raloxifene
Stimulators of bone formation
(Fluoride)
Parathyroid hormone
Mixed mechanism of action
Vitamin D and metabolites
Strontium ranelate
Recommended for all women at risk for osteoporosis
Calcium and vitamin D
Slide 34
Speaker Notes:
Over the last few years, many new therapeutic options have become available for the prevention and treatment of osteoporosis. Commonly used agents include a variety of estrogen and estrogen-plus-progestin preparations, selective estrogen receptor modulators (SERMs) (such as raloxifene), calcitonin, and bisphosphonates (such as etidronate, alendronate, and risedronate). Calcium and vitamin D are recommended for all women at risk for osteoporosis unless there are specific contraindications.

37. Shifting the Osteoporosis Paradigm NIH Consensus Statement 2000
Bone Strength
NIH Consensus Statement 2000
Bone
Strength
Bone
Quality
Bone
Density
and
Architecture and geometry
Turnover/ remodeling rate
Degree of Mineralization
Damage Accumulation
Properties of collagen/mineral matrix
According to the NIH Consensus Statement, bone strength reflects the integration of bone quality and bone density. Bone density is expressed as grams of mineral per area or volume. Bone quality refers to architecture, turnover, damage accumulation, and mineralization.1
1NIH Consensus Development Panel. JAMA. 2001;285:
NIH Consensus Development Panel on Osteoporosis. JAMA 285 (2001):

38. Older, relatively highly Adapted from David Dempster, Ph.D.
Antiresorptive Agents Increase BMD by Decreasing Remodeling Space and Prolonging Mineral Acquisition
High Turnover
Older, relatively highly
Mineralized bone
Antiresorptive Agent
Low Turnover
Remodeling space
New relatively under-mineralized bone
Adapted from David Dempster, Ph.D.

39. Markers of collagen degradation and synthesis in women treated with raloxifene or alendronate
Resorption
Formation
Stepan J, Vokrouhlicka J, CCA 288, 1999,
Stepan et al, ASBMR 2002

40. What Is the Optimal Reduction in Bone Turnover for an Antiresorptive Drug?
Insufficient turnover
Accumulation of microdamage
Increased brittleness due to excessive mineralization
Excessive turnover
Increase in stress risers (weak zones)
Increase in perforations
Loss of connectivity
Bone Strength
Bone Turnover
Physiological Range
The relationship between turnover and strength seems to have an inverted “U” shaped curve.
Accelerated (excessive) turnover increases bone fragility because of osteoid matrix accumulation, decreased time for adequate mineralization, and increased remodeling sites that cause temporarily weakened focal lesions in the trabeculae.
Absent (insufficient) turnover is also bad because some minimal amount of remodeling is necessary to repair fatigue microdamage, replace old or dead osteocytes, and restore bone hydration.
However, existing evidence suggests that there is a considerably wide safety margin of decreased bone turnover associated with increased bone strength.
Weinstein RS, J Bone Miner Res , 621.
Adapted from Weinstein RS, J Bone Miner Res 2000;

41. Mineralization of bone
Normal = 63-68% and heterogenous
Cortical bone
100 -
50 -
0 -
Primary mineralization
(3 months: during bone formation)
Secondary mineralization
(Years after bone formation)
　　 Maturation
Mineralization (%)
mineralization of newly formed BMU is separated into two periods.
The first period is called primary mineralization, in which about 50% of mineralization is completed during 3 months, formation period of bone remodeling sequence. Secondary mineralization starts after finishing bone remodeling and continue very slowly by years. The length of time required to completely mineralize an osteon is not known.
Time
Labels under epi-fluorescent microscope)

42. Effects of long-term anti-resorptive therapy
increased bone mass
increased degree of mineralization
increase bone strength
time dependent
decrease bone strength
brittle
stiffer
High
Low
Stiffness
(Young’s Modulus)
Work to Failure
　(Toughness)
(%)
Ash density (degree of mineralization)
(Adopted from Wainwright, Biggs, Currey and Gosline, 1976 modified)

43. Hypothetical Effects of Increasing Bone Mineralization
Improved resistance to bending = stiffness
Resistance
to fracture
forces
Increasing brittleness
Normal =65-68%
Percentage Mineralization

44. Beyond normal physiologic range
Turnover Oversuppression
Beyond normal physiologic range
Insufficient fatigue
damage repair
Microcrack
accumulation
propagation
Prolonged secondary
mineralization
Hypermineralized
+ homogeneous bone
When bone turnover is suppressed beyond the normal physiologic range, the normal cycle of fatigue damage repair will be inhibited leading to an accumulation of microcracks in bone. Oversuppression of bone turnover also leads to increased mineral content and a homogeneous distribution of mineral throughout the bone. This environment of increased mineralization could lead to the propagation of a microcracks resulting in a microfracture of the bone. These factors are likely to lead to increased bone fragility.
Note:
This is an interpretation of a hypothesis of the result of suppression of bone turnover beyond the normal physiologic range. This summary is one potential interpretation of the current literature, and data is not (yet) available to support some of the points made in this summary slide.
Increased
Fragility ?

45. Sustained Efficacy of Raloxifene
Source:
Sustained Efficacy of Raloxifene
Occurrence of the First New Post-Baseline Vertebral Fracture
MORE Trial - 4 Years
Review:
Placebo
RLX 60 mg/d 15
First Scheduled
Radiograph
Reviewer Memo:
P<0.001
Incidence of New Vertebral Fractures (%) 10 5
Sustained Efficacy of Raloxifene. Occurrence of the First New Post-Baseline Vertebral Fracture: MORE 4 Year (red lines are animated on slide)
This Kaplan-Meier plot shows the time to occurrence of the first new post-baseline vertebral fracture in patients with and without preexisting vertebral fractures (cumulative incidence). The plot shows the increasing incidence of new vertebral fractures with time in both the placebo (dotted) and raloxifene therapy groups, and continuing divergence between the raloxifene and placebo groups (as illustrated by the red arrows), supporting the sustained efficacy of raloxifene. The time to occurrence of the event was significantly different between the placebo and raloxifene 60mg/d treatment groups.
The following diagram explains the concept of sustained efficacy. The cumulative incidence of disease in the placebo (solid line) and Drug A (dotted line) treatment groups is illustrated :
If the solid and dotted lines continue to diverge, this is indicative of sustained efficacy of Drug A
If the lines become parallel, this is indicative of a reduced efficacy of Drug A
If the lines converge (and maybe eventually cross), this is indicative of a delayed harmful effect of Drug A 12 24 36 48
Months of Exposure
Adapted from Delmas et al. J Clin Endocrinol Metab 87: , 2002
Slide Modified:
Memo:

46. Therapeutic Management of Postmenopausal Osteoporosis
Osteoporosis prevention T-score >–2.5
Osteoporosis treatment with or without previous fracture
Osteoporosis treatment with multiple fractures and at risk for hip fracture
Bisphosphonates
Teriparatide HT
SERMs
Raloxifene
Therapeutic Management of Postmenopausal Osteoporosis
Age (years)