SERM Prof.Dr.Hakan SEYİSOĞLU İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi Kadın Hastalıkları ve Doğum Anabilim Dalı 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;281:2189-97

S elektif E strojen R eseptör M odulatörü SERM kavramı Concept of a SERM Selective estrogen receptor modulators (SERMs) are non-hormonal agents that bind to estrogen receptors, but produce estrogen agonist effects in some tissues while blocking the effect of estrogen in other tissues. Östrojen değildir Östrojen reseptörlerine bağlanır Bazı dokularda östrojen benzeri etki Bazı dokularda östrojenin etkisini bloke eder

Östrojenik etki farklılık nedenleri Doku reseptör konsantrasyon farklılıkları Dimerizasyon proteinleri konsantrasyon farklılıkları Farklı dimerlerin farklı hücrelerde farklı DNA bölgelerine (ERE) bağlanması AF1 ve AF2 (Aktivasyon fonksiyonu) reseptör bölgelerinin dokulara göre farklılık göstermesi 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;281:2189-97

Çeşitli dokularda östrojen reseptör dağılımı Santral sinir sistemi  ve  Kemik  ve  Kan damarları  ve  Kalb  ve  Akciğer  Karaciğer  Meme  ve  Böbrek  Mesane  Barsak  Over  ve  Uterus  ve  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;281:2189-97

SERM grubu maddeler Trifeniletilen türevleri Tetrahidronaftalinler Klomifen Tamoksifen Tamoksifen deriveleri Droloksifen Toremifen TAT-59 Idoksifen Tetrahidronaftalinler Lasofoksifen Sentkroman enantiomerleri Ormeloksifen Levormeloksifen Benzotiofen türevleri Raloksifen LY353381 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;281:2189-97

Tamoksifen Osteoklastik aktiviteyi inhibe eder (Antirezorptif) IGF-1 üzerine pozitif etkili (Formasyon arttırıcı) KMY de 5 yılda %2 artış olmasına karşın kırık üzerine yapılan çalışma sonuçları olumsuz Genç postmenopozal olgularda kırığın arttığına dair veriler var Endometriumdaki olumsuz etkisi nedeni ile tek başına osteoporozda kullanımı yoktur 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;281:2189-97 Love RR, et al. Arch Intern Med,1994 Manassiev N, et al. The Management of the Menopause, 2000

Raloksifen Benzotiofen derivesidir İlk çalışmaları meme kanseri üzerinedir Endometrium ve uterus üzerine etkisi yoktur Büyüme faktörleri ve sitokinler üzerine etki ederek osteoblastik aktiviteyi destekler Osteoklastların yaşam süresini kısaltır ve osteoklastik aktiviteyi inhibe eder Postmenopozal tedaviler arasındadır 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;281:2189-97

5 Yılda KMY’de Normalden Osteopeniye İlerleme Oranı* Osteopenili hasta oranı (%) 5 10 15 20 25 Plasebo RLX 60 RR = 0.32 95% CI (0.08 , 0.78) RR = 0.64 95% CI (0.26 , 1.5) Lumbar Total kalça * Başlangıçta osteopeni ya da osteoporozu olmayan hastalarda Bjarnason et al. NOF, March 6, 2002 68% 36% Among women who had normal BMD at baseline, 5 years of treatment with RLX 60 mg/day led to significantly fewer women developing osteopenia of the lumbar spine (vs. placebo).

5 Yılda KMY’de Osteopeniden Osteoporoza İlerleme Oranı* Osteoporozlu hasta oranı (%) 5 10 15 20 25 Plasebo RLX 60 RR = 0.17 95% CI (0.05, 0.49) Lumbar Total kalça * Başlangıçta osteopenisi olan hastalarda Bjarnason et al. NOF, March 6, 2002 NONE 83% Among women who had osteopenia at baseline, 5 years of treatment with RLX 60 mg/day led to significantly fewer women developing osteoporosis of the lumbar spine (vs. placebo).

En az 1 yeni vertebral kırık olan kadın %si * Osteopeni: total kalça T-skoru –1 ile –2.5, NHANES referans veritabanı, önceden vertebral kırığı olmayan kadın hastalar Kanis, Bone 33 (2003) 293-300 1 2 3 4 Radiografik En az 1 yeni vertebral kırık olan kadın %si RR 0.55 (95% CI = 0.32-0.95) 45% Klinik RR 0.25 (95% CI = 0.05-0.81) 75% Plasebo RLX 60 mg/g Postmenopozal Osteopenik Kadınlarda Raloksifenin Yeni Vertebral Kırık Riskine Etkisi* MORE Çalışması Effect of Raloxifene on the Risk of New Vertebral Fractures in Postmenopausal Women with Osteopenia: MORE Trial – 3 Years When the MORE trial was designed, the manufacturer’s reference database was used for calculating T-scores for the hip and spine. In 1995 (and subsequently in 1998), NHANES III published databases that have become the standard for calculating hip T-scores.1 Young-adult reference BMD values from NHANES are lower than other published values, mainly due to selection and recruitment differences. The NHANES sample was more diverse than the healthy volunteer samples used in most other databases and patients have higher T-scores using NHANES. As a result, as in other trials such as FIT22, some patients who were enrolled in MORE no longer had osteoporosis at the total hip using the new reference database. The mean (SD) T-scores of this group of women without preexisting vertebral fractures and with total hip T-scores –1 to -2.5 (osteopenia group, N=2338) were –1.80 (0.39) at the total hip and –2.31 (1.04) at the lumbar spine. In this group of women with osteopenia, raloxifene 60 mg/d for 3 years significantly reduced the risk of of new radiographic vertebral fracture 45% and decreased the risk of new painful clinical vertebral fracture 70%. 1. Looker AC, et al. Osteoporos Int. 8:468-489, 1998. 2. Cummings SR, et al. JAMA 280:2077-2082., 1998 N=2338

Kırığı Olan ve Olmayan Kadınlarda Raloksifen’in Etkisi MORE Çalışması Raloksifen 60 mg/g Plasebo % vertebral kırığı olan kadınlar 5 10 15 20 25 Prevalan vertebral kırık yok Prevalan vertebral kırık var RR 0.45 (95% CI = 0.29, 0.71) RR 0.70 (95% CI = 0.56, 0.86) 30% 55% Effect of Raloxifene Treatment on New Vertebral Fractures (MORE Trial-3 Years) This slide summarizes the fracture results from the core 3-year treatment phase of the MORE trial, showing the incidence of new vertebral fractures in women with no preexisting vertebral fractures at baseline (without prevalent vertebral fracture) or with 1 or more preexisting vertebral fractures at baseline (with prevalent vertebral fracture). Women assigned to placebo are represented by the white bars and those assigned to raloxifene 60 mg/d are represented by the yellow bars.   Confirming previous studies, women with 1 or more existing fractures at baseline were at a 5-fold higher risk of experiencing a subsequent vertebral fracture compared with women with no vertebral fractures at baseline. In women without prevalent vertebral fractures, raloxifene 60 mg/day significantly decreased the risk of new vertebral fractures by 55% at 3 years, compared with placebo. In women with prevalent vertebral fractures, who are at greater risk of subsequent fracture, raloxifene 60 mg/day significantly decreased the risk of new vertebral fractures by 30% at 3 years, compared with placebo. The reduction in risk of new vertebral fracture with raloxifene therapy was similar in the following subgroups, as defined according their baseline characteristics: tertiles of age, tertiles of baseline lumbar spine or femoral neck BMD, prior hysterectomy, and prior hormone replacement therapy Ettinger B et al. JAMA 1999; 282:637-45 Lufkin et al. Rheum Dis Clin No Amer 2001;27:163-185 Ettinger et al. JAMA 1999; 282:637-45. Lufkin et al. Rheum Dis Clin No. Amer. 2001; 27:163-185

Raloksifen 60 mg/gün 3 Yılda Kemik Döngüsünü Premenopozal Düzeylere İndirir Premenopozal aralık1 1Garnero et al. J Bone Miner Res, 1996: 11; 1531-8 2Delmas et al. New Engl J Med 1997; 337: 1641-7. 3Johnston et al. Arch Int Med 2000; 160: 3444-50. Başlangıç Sonlanım 300 200 100 400 Avrupa2 Uluslararası3 C-telopeptid / Kr Tip I kolajen Raloxifene Decreases Bone Turnover to Premenopausal Range through 3 Years The reference range for C-telopeptide/creatinine, a biochemical marker of bone resorption, was determined to be 189 + 88 mg/mmol (mean + standard deviation) in normal healthy premenopausal women.1 The pink area in this diagram shows the premenopausal reference range + 1 SD. In the European2 and in the International3 prevention trials with raloxifene, the mean baseline values for C-telopeptide (red circles) were approximately 300 mg/mmol, corresponding to levels above the upper limit of the premenopausal range. After raloxifene 60 mg/day treatment, the mean endpoint values for C-telopeptide (green squares) were approximately 200 mg/mmol, within the normal premenopausal range. The observed steady state levels of C-telopeptide/creatinine in postmenopausal women after raloxifene treatment was within the range observed in normal healthy premenopausal women. Garnero P et al., J Bone Miner Res 1996;11:337-49. Delmas et al. New Engl J Med 1997; 337: 1641-7. Johnston et al. Arch Int Med 2000; 160: 3444-50.

Raloksifende hasta uyumu Çok Yakınılan Yan Etkiler Bırakma Oranı (Tedaviye Başladıktan Ortalama 7 Ay Sonra) Tedavi Yan etki oranı ET/EPT 40% 22% 27% Alendronat 27% 13% 21% Raloksifen 30% 8% 14% Adherence to Osteoporosis Therapies Ettinger and colleagues conducted a study based on interviews with 576 postmenopausal women who had received bone density results of –1 SD or below. Ninety percent of the patients stated that they initiated therapy ET/EPT, alendronate, or raloxifene) due to osteoporosis concerns. After a mean of 7 months of treatment, 27%, 21%, and 14% of patients had discontinued ET/EPT, alendronate, and raloxifene respectively.1 The incidence of very or extremely bothersome side effects was also lowest in the raloxifene-treated group. Raloxifene is generally well tolerated and induces few nuisance side effects. In order to obtain maximum therapeutic effect (ie, fracture reduction), the patient must take the product properly and stay on it for the long term. 1. Ettinger B, et al. IBMS and ECTS meeting 2001 Ettinger B et al. Bone 28 (Suppl 5); S76, 2001

Raloksifen ve stroke (RUTH) Framingham Stroke Risk Skoru : <13 HR 1.08 (95% CI 0.49-2.37) anlamlı fark yok >13 HR 1.75 (95% CI 1.01-3.02) anlamlı yüksek Bu nedenle yüksek riskli hastalarda Raloksifen kullanımı risklidir. 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;281:2189-97 Barrett-Connor E, Am J Med , 2009

Lasofoksifen Tetrahidronaftalin grubundandır Minimal gastrointestinal glukuronidasyonu nedeni ile oral alımda biyoyararlanımı yüksektir Raloksifen ve Tmx e göre reseptör afinitesi 10 kat yüksektir Selektivitesi 100 kat fazladır Ortalama yarılanma ömrü 165 saattir Doz 0.25 – 0.50 mg/gün 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;281:2189-97

Lasofoksifen Lipid metabolizması üzerine etkileri Raloksifene göre daha olumludur Vajinal maturasyonu güçlendirip vulvovajinal yakınmaları azaltır Venöz tromboz açısından diğer SERM lerle aynı olmasına karşın (Plaseboya göre 2 kat) stroke anlamlı olarak azdır 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;281:2189-97

Lasofoksifen ve lipid metabolizması vs. Raloksifen ve Plasebo LDL %20.6 %12.1 %3.2 p<0.05 TK (Apo) B-100 (Apo) A-1 HDL TG Fibrinojen AT III Lasofoksifenin Raloksifen ile karşılaştırma çalışması CORAL henüz açıklanmamıştır Lewiecki, EM. Ther Clin Risk Manag, 2009

Postmenopausal Evaluation And Risk-reduction with Lasofoxifene PEARL Trial Lasofoksifen 0.25 mg dozda vertebral kırıklar üzerinde anlamlı koruyucu olmasına karşın nonvertebral kırıklar üzerine etkisi anlamsızdır. Doz 0.50 mg a çıkılırsa her iki lokalizasyonda kırığı anlamlı ölçüde azaltır.

Bazedoksifen Vertebral kırıklarda azalma sağlıyor. Nonvertebral kırıklarda ise sadece yüksek fraktür riski taşıyan hastalarda olumlu sonuç veriyor. Doz 20 – 40 mg/gün Östrojenler ile birlikte uygulandığında memedeki proliferasyonu en güçlü antagonize edebilen SERM 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;281:2189-97

Bazedoksifen GENEL Morfometrik vertebral kırıkta %39 azalma (HR 0.61 95% CI 0.43-0.86) Tüm klinik kırıklarda %16 azalma (HR 0.84 95% CI 0.67-1.06) FRAX YÜKSEK RİSK Morfometrik vertebral kırıkta %51 azalma (95%CI 21-69%) Tüm klinik kırıklarda %33 azalma (95%CI 7-51%) 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;281:2189-97 Kanis JA, et al. Bone 2009

Doku Selektif Östrojen Kompleksi TSEC (Tissue Selective Estrogen Complex) 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;281:2189-97

TSEC AMAÇ Yaşam kalitesi parametreleri üzerine olumlu etki sağlamak ve SERM in bu yöndeki etkisini önlemek SERM olumlu etkilerini potansiyalize etmek SERM lerin yetersizliği olan nonvertebral kırıklarda etkinliği arttırmak Meme üzerinde proliferasyona antagonist etki sağlamak Endometrium güvenliğini sağlamak ve progestin kullanımını devreden çıkarmak Hem temel hormon Östrojeni vermek ve hem de bunun olası yan etkilerini en aza indirgemek.

Konjuge Östrojenin meme hücreleri üzerindeki proliferatif etkisinin SERM ler tarafından antagonize edilmesi Bazedoksifen+CE > Raloksifen+CE > Lasofoksifen+CE Bu nedenle kombinasyon Bazedoksifen ile yapılmakta CE nin meme MCF-7 hücre proliferasyon ölçümleri ile yapılan çalışmalarda, Bazedoksifenin CE nin memedeki etkisini antagonize eden en güçlü SERM olduğu gösterilmiştir. Chang KC, et al. J Steroid Biochem Mol Biol, 2009

Bazedoksifen + CE (QoL-seksüel fonksiyon ve uyku) Semptomatik kadınlar üzerinde yapılan 12 haftalık randomize kontrollü çalışma (n=652) BAZ 20 mg + CE 0.45 mg ; BAZ 20 mg ; Plasebo ASEX (The Arizona Sexual Experiences) ve MENQOL (Menopause-Specific Quality of Life) skalaları ile değerlendirilmiş Seksüel fonksiyon, lubrikasyon skoru, emosyon, uyku ve vazomotor yakınma açısından: BAZ+CE vs. Plasebo (p<0.05) BAZ+CE vs. BZA (p<0.001) Bachmann G, et al. Climacteric, 2009

Bazedoksifen + CE (QoL-vazomotor yakınma) BAZ 20 mg (CE 0.45 ve 0.625 mg) – Vazomotor Yakınma 1.Dozda gerileme %51.7 2.Dozda gerileme %85.7 Plasebo %17.1 Her iki grup plaseboya göre anlamlı Lobo RA et al, Fertil Steril, 2009

Bazedoksifen + CE (QoL-uyku) Semptomatik kadınlar üzerinde yapılan 12 haftalık randomize kontrollü çalışma (n=318) BAZ 20 mg + CE 0.45 mg ; BAZ 20 mg + CE 0.625 mg ; Plasebo MOS (Medical Outcomes Study) Uyku Skalası ve MENQOL (Menopause-Specific Quality of Life) skalaları ile değerlendirilmiş Uykusuzluk, uykuya geçiş, uyku kalitesi, ve uyku yeterliliği açısından: BAZ+CE vs. Plasebo (p<0.001) Utian W, et al. Maturitas, 2009

Bazedoksifen + CE (Endometrium güvenilirliği) Kümülatif Amenore oranları: (13 ay) 0-13 ay %83 10-13 ay %93 (Archer DF, Pickar JH, et al. Fertil Steril, 2009) Endometrial güvenilirlik: (n=3.397 – 2 yıl) Hiperplazi oranı < %1 ns vs. plasebo (Pickar JH, Speroff L, et al. Fertil Steril, 2009) ** PROGESTIN-FREE MENOPAUSAL THERAPY**

Sonuç

SERM etkinlik ve güven karşılaştırılması Lasofoksifen Vertebral ve Nonvertebral frx VTE riski EU Meme kanseri riski Vajinal kanama Vulvojinal yakınmalar Vertebral frx VTE riski EU Meme kanseri riski Meme kanseri riski Fatal stroke riski USA Bazedoksifen Adherence to Osteoporosis Therapies Ettinger and colleagues conducted a study based on interviews with 576 postmenopausal women who had received bone density results of –1 SD or below. Ninety percent of the patients stated that they initiated therapy ET/EPT, alendronate, or raloxifene) due to osteoporosis concerns. After a mean of 7 months of treatment, 27%, 21%, and 14% of patients had discontinued ET/EPT, alendronate, and raloxifene respectively.1 The incidence of very or extremely bothersome side effects was also lowest in the raloxifene-treated group. Raloxifene is generally well tolerated and induces few nuisance side effects. In order to obtain maximum therapeutic effect (ie, fracture reduction), the patient must take the product properly and stay on it for the long term. 1. Ettinger B, et al. IBMS and ECTS meeting 2001 Raloksifen Lewiecki, EM. Ther Clin Risk Manag, 2009

SERM grubu ilaçlar büyük oranda osteoporoz üzerine etkindir Nonvertebral kırık önleme etkileri zayıftır Klasik menopozal yakınmaları arttırırlar Venöz tromboemboli riskleri vardır Meme üzerindeki koruyucu etkileri olumludur 3. kuşak SERM ler endometrium açısından emniyetlidir Bu etkileri nedeni ile östrojen kombinasyonlarında (TSEC) progestin kullanımına gerek yoktur Östrojen ile kombinasyonlar, östrojenin etkisinden de faydalanmayı sağlamaktadır

SERM Prof.Dr.Hakan SEYİSOĞLU İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi Kadın Hastalıkları ve Doğum Anabilim Dalı 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;281:2189-97