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

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Presentation on theme: "New Perspective of SERM in Postmenopausal Women Health Daniel Thiebaud MD, Medical Fellow, Global Osteoporosis Strategy, Eli Lilly, Australia."— Presentation transcript:

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 75+ Kyphotic At risk for hip fracture & further Vertebral fracture 55+ Postmenopausal At greater risk for vertebral fracture than any other type of fracture 50 Menopausal Experiencing vasomotor symptoms When to suspect and investigate for osteoporosis? 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 diagnosedTwo thirds of new vertebral fractures are not diagnosed Gehlbach SH, et al. Osteoporos Int. 2000;11:577-582. Delmas PD, et al. J Bone Miner Res. 2001;16(Suppl 1):S139. Lindsay R. et. Al. JAMA 2001; 285; 320-23 VERT FRACTURES ARE OFTEN NOT RECOGNISED

5 Therapeutic options for osteoporosis 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 Inhibitors of bone resorption (Antiresorptives) Bisphosphonates –Alendronate –Etidronate –Risedronate Calcitonin Estrogen ± progestin Selective estrogen receptor modulators (SERMs) –Raloxifene

6 S S elective E E strogen R R eceptor M odulator Concept of a SERM Not an estrogen, progestin or other hormoneNot an estrogen, progestin or other hormone Binds to estrogen receptorsBinds to estrogen receptors Has estrogen-like effects in some tissuesHas estrogen-like effects in some tissues Blocks estrogen effects in some tissuesBlocks estrogen effects in some tissues

7 Chemical Structures of Estradiol and Currently Available SERMs Raloxifene post-menopausal osteoporosis prevention and treatment Tamoxifen prevention and treatment of breast cancer Clomiphene fertility induction Toremifene treatment of breast cancer 17  -estradiol New SERMs in Phase 3 trials: - Lasofoxifene - Basedoxifene - Arzoxifene

8 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 Raloxifene versus Estrogen: Receptor Binding and Pharmacology *Katzenellenbogen BS. Science 2002;295:2380-2381 Raloxifene, K d = 54 pMEstradiol, K d = 86 pM Reproduced with permission from Brzozowski AM et al. Nature 389:753-58, 1997; http:www.nature.com/ Estradiol and Raloxifene Occupy the Same Ligand Binding Site

9 Tissue Dependent Action Antagonistic Effects (uterus, breast) Agonistic Effects (bone) Basic Side Chain Benzothiophene ER = Estrogen Receptor BMD = Bone Mineral Density ER Increase BMD and reduce the risk of vertebral fractures

10 Estrogen Receptor Signaling Other response elements ERE Multiple genomic sequences **Simoncini T et al. Steroids 67:935-939, 2002 * McDonnell and Norris, Osteoporosis Int 1997;S29-4 Bryant HU, Reviews in Endocrine and Metabolic Disorders 2:129-38, 2001

11 Women with and without Prevalent Vertebral Fractures Women with Prevalent Vertebral Fractures Placebo RLX 60 % of Women with New Clinical Vertebral Fracture 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 RR 0.32 (95% CI, 0.13 - 0.79) PlaceboRLX 60 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 RR 0.34 (95% CI, 0.11 - 0.77) 66% 68% Risk of New Clinical Vertebral Fractures at 1 Year Marici et al, Arch. Int med, 2002

12 Risk Reduction in Clinical Vertebral Fractures at 1 Year 59% p<.03 69% p=.009 p=.01 68% MORE 1 Raloxifene FIT-I/FIT-II 2 Alendronate VERT-MN/VERT-NA 3 Risedronate* *Clinical vertebral fractures derived from pooled post-hoc analysis of VERT-NA/VERT-MN. 1. Ettinger B, et al. JAMA. 1999;282(7):637-645. 2. Black DM, et al. J Clin Endocrinol Metab. 2000;85(11): 4118-4124. 3. Data on file, Procter & Gamble.

13 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 Ettinger B et al. JAMA 282:637-45, 1999 Cummings SR et al. JAMA 281:2189-97, 1999 MORE Multiple Outcomes of Raloxifene Evaluation

14 Cumulative Incidence of New Clinical Vertebral Fractures in the First Year of MORE 7705 postmenopausal women with osteoporosis *P=0.007 in the first 6 months for each raloxifene group compared with placebo Qu Y, et al. CMRO, 2005, 21 (12): 1955-59. Clinical Vertebral Fracture (%)

15 0.44% (n=10) Effect of Raloxifene on New Clinical Vertebral Fractures at 6 Months Qu Y, et al. CMRO, 2005, 21 (12): 1955-59.

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±6.365.3±6.0 Years Postmenopausal 15.2±6.516.9±7.3 Body Mass Index (kg/m 2 ) 21.8±2.823.0±2.9 Prevalent Vertebral Fracture (%) 26.413.7 Lumbar Spine BMD (g/cm 2 ) T-score 0.63±0.05 -3.77±0.46 0.69±0.07 -3.52±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, 24:414-418, 2006

17 New Clinical Vertebral Fractures Combining the Japan and China Studies Raloxifene Pooled 3 2 1 0 (%)(%) 3.5% ( n=7 ) 0% ( n=0 ) PlaceboRaloxifene 60mg/day 4 5 6 0% ( n=0 ) *** ** :p<0.002 vs. placebo * :p<0.01 vs. placebo N=199N=194N=289 T.Nakamura et. Al, JBMM; 24:414-418; 2006

18 Raloxifene Pooled 7 6 5 4 3 2 1 0 (%)(%) 6.0% ( n=12 ) 1.0% ( n=2 ) 0.7% RR : 0.11 ( 0.03 - 0.51 ) RR : 0.17 ( 0.04 - 0.75 ) PlaceboRaloxifene 60mg/day 8 9 ** * ** :p<0.001 vs. placebo * :p<0.01 vs. placebo Any New Clinical Fractures Combining the Japan and China Studies T.Nakamura et. al.JBMM; 24:414-418, 2006

19 Raloxifene Reduces Risk of at least 1 New Nonvertebral* Fracture in Women with Severe Fracture *Clavicle, humerus, wrist, pelvis, hip, leg Delmas PD et al. Bone 2003;33;4:522-532 0 5 10 15 20 % of Women with at least 1 New Nonvertebral Fracture RH=0.53 (95% CI 0.29, 0.99) Placebo Raloxifene 60 mg/d 47% MORE Trial - 3 Years P=0.046

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 * Farrerons et al., CTI, 2003;72(4):391(P230) 0 10 20 30 40 % of Women With at Least 1 New non-Vertebral Fracture RR=0.69 (95% CI 0.48, 0.99) P<0.05 Placebo Raloxifene 31% * Clavicle, humerus, wrist, pelvis, hip, leg

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 CharacteristicRaloxifene (N=707) Alendronate (N=716) P-value Age (years)65.565.70.56 Caucasian (%)86.786.90.83 BMI (kg/m 2 )24.824.60.42 LS BMD (g/cm 2 ) 0.82 0.79 T-score-2.32-2.340.65 FN BMD (g/cm 2 ) 0.61 0.98 T-score-2.39 0.77 Hip BMD (g/cm 2 ) 0.71 T-Score-1.99-2.010.64

23 EVA trial : Ralo vs Alendronate BMD changes after 2 years Recker R et al, ASBMR 2005, J Bone Miner Res. 2005;20(suppl 1):S97, Bopne in press 2007 Lumbar SpineFemoral 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)

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=713 N=699 Age, yrs 65.7± 7.865.5± 7.7 0.56 Vert or Non Vert 22 (3.1)20 (2.9) 0.84 Vertebral 8 (3.1) 5 (1.9) 0.53 Moderate/Severe4 (1.6) 0 0.04 Clinical Vertebral3 (0.4) 0 0.1 NonVertebral 14 (2.0) 15 (2.2) 0.86 Nonvertebral-Six b 11 (1.5) 10 (1.4) 0.89 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 (%) EventRLX (N=707) ALN (N=716) P-Value Colonoscopy 1 (0.14)8 (1.12)0.04 Diarrhea11 (1.56)27 (3.77)0.01 Nausea22 (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 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 0 5000 10000 15000 20000 1,764 7,705 4,011 10,101 19,747 Number of Enrolled Women Osteoporosis Prevention MORECORERUTHSTAREVA 1,400 Large-Scale Raloxifene Clinical Trials

28 Rationale for the RUTH Trial Coronary outcomes, based on: –favorable impact of raloxifene on cardiovascular risk markers 1 –evidence from observational studies that treatment with estrogen was associated with a reduced risk of CHD in postmenopausal women 2,3 Invasive breast cancer, based on: –anti-estrogenic effects of raloxifene in the breast 4 –72% reduction in invasive breast cancer in a secondary analysis of data from the MORE trial 5 RUTH was designed to determine the effect of raloxifene on: 1 Blumenthal R et al. Am Heart J 2004 2 Stampfer MJ et al. Prev Med 1991 3 Grady D et al. Ann Intern Med 1992 4 Brzozowski AM et al. Nature 1997 5 Cauley J et al. Breast Cancer Res Treat 2001

29 Relevant Clinical Trial Findings After RUTH Commenced 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 disease 1 –WHI trial: Early increase in risk of coronary events with estrogen plus progestin therapy and estrogen alone in healthy postmenopausal women 2,3 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 1 Hulley et al, JAMA 1998 2 Writing Group for the Women's Health Initiative Investigators, JAMA 2002 3 Anderson GL et al. JAMA 2004 4 Barrett Connor et al, JAMA 2002

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. Vogel et al, JAMA, 2006; 295, June 2006 2. Fisher B, et al. J Natl Cancer Inst 1998; 90:1371- 1388.

31 MORE plus CORE Study Design 012345678 Placebo Raloxifene HCl 60 mg/day Raloxifene HCl 120 mg/day Placebo Raloxifene HCl 60 mg/day Year 8 Years Total Follow-up MORE (N=7705) Three Treatment Groups CORE (n=4011) Two Treatment Groups Gap MORE Conclusion CORE Screening Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761

32 Incidence of Invasive Breast Cancer 8 Years of MORE plus CORE (N=7705) Years in Study 012345678 0.0 1.0 2.0 3.0 4.0 HR 0.34 (95% CI = 0.22-0.50) Placebo 4.2 per 1000 Women-Yrs Raloxifene 1.4 per 1000 Women-Yrs p <0.001 Cumulative Incidence (%) 66% Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761

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) Mortality2.3 (29)1.7 (47)0.27 All cancers † 8.6 (110)5.7 (156)0.001 All cancers † excluding breast cancer6.3 (81)4.6 (126)0.027 Hospitalization40.9 (526)38.8 (1057)0.21 Treatment-emergent AEs99.0 (1273)98.6 (2688)0.45 Treatment-emergent serious AEs45.5 (585)42.3 (1154)0.07 Study discontinuation CORE due to AE2.4 (31)1.9 (53)0.35 † 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) %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 cancer0.16 (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 symptoms5.8 (75)5.0 (135)0.26 Martino S et al. Curr Med Res Opin 21;1441-52, 2005

35 Flushing (hot flushes)89 (6.9)342 (12.6)<0.001 Leg cramps 152 (11.8) 407 (14.9)0.008 Peripheral edema120 (9.3) 288 (10.6)0.240 Adverse Events Reported During MORE Plus CORE – 8 Years Number (%) PlaceboRaloxifene p-value (n=1286)(n=2725) Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761

36 Therapeutic options for osteoporosis 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 Inhibitors of bone resorption Bisphosphonates –Alendronate –Etidronate –Risedronate Calcitonin Estrogen ± progestin Selective estrogen receptor modulators (SERMs) –Raloxifene

37 Bone Strength NIH Consensus Statement 2000 Bone Quality Bone Strength and Architecture and geometry Turnover/ remodeling rate Degree of Mineralization Damage Accumulation Properties of collagen/mineral matrix Shifting the Osteoporosis Paradigm Bone Density NIH Consensus Development Panel on Osteoporosis. JAMA 285 (2001): 785-95

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

39 Markers of collagen degradation and synthesis in women treated with raloxifene or alendronate Stepan J, Vokrouhlicka J, CCA 288, 1999, 121-135 ResorptionFormation Stepan et al, ASBMR 2002

40 What Is the Optimal Reduction in Bone Turnover for an Antiresorptive Drug? Adapted from Weinstein RS, J Bone Miner Res 2000; 15 621. Physiological Range Bone Strength Bone Turnover Excessive turnover Increase in stress risers (weak zones) Increase in perforations Loss of connectivity Insufficient turnover Accumulation of microdamage Increased brittleness due to excessive mineralization

41 Time 100 - 50 - 0 - Mineralization (%) Primary mineralization (3 months: during bone formation) Cortical bone Secondary mineralization (Years after bone formation) Maturation Labels under epi-fluorescent microscope) Mineralization of bone Normal = 63-68% and heterogenous

42 (Adopted from Wainwright, Biggs, Currey and Gosline, 1976 modified) Ash density (degree of mineralization) Stiffness (Young’s Modulus) HighLow Work to Failure (Toughness) 65 66 67 68 (%) Effects of long-term anti-resorptive therapy increased bone mass increased degree of mineralization time dependent increase bone strength stiffer decrease bone strength brittle

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

44 Turnover Oversuppression Beyond normal physiologic range Increased Fragility ? Insufficient fatigue damage repair Microcrack accumulation Microcrack propagation Prolonged secondary mineralization Hypermineralized + homogeneous bone

45 Sustained Efficacy of Raloxifene Occurrence of the First New Post-Baseline Vertebral Fracture MORE Trial - 4 Years Adapted from Delmas et al. J Clin Endocrinol Metab 87: 3609-17, 2002 Months of Exposure 0243648 0 5 10 15 Incidence of New Vertebral Fractures (%) Placebo RLX 60 mg/d 12 First Scheduled Radiograph P<0.001

46 SERMs Raloxifene HT Osteoporosis prevention T-score >–2.5 Osteoporosis treatment with or without previous fracture Osteoporosis treatment with multiple fractures and at risk for hip fracture 505560657075808590 Age (years) Teriparatide Bisphosphonates Therapeutic Management of Postmenopausal Osteoporosis


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