2011 Tibolone 新共識陳述與更年期治療路徑

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1 2011 Tibolone 新共識陳述與更年期治療路徑 台大醫院婦產部主治醫師張廷禎醫師

2 Introduction: What is tibolone? A Selective Tissue Estrogenic Activity Regulator (STEAR) indicated for relief of climacteric symptoms and prevention of osteoporosis in postmenopausal women Has a tissue-specific mode of action different to that of conventional HRT: - Prevents oclimacteric symptoms obone loss - Does not stimulate obreast tissue oendometrium

3 Estradiol and testosterone

4 Metabolism of tibolone 3 - HSD HO OH 3 -OH-tibolone Sulfotransferase Sulfatase Pool of Sulfated compounds OH HO 3 - HSD-Isomerase O Tibolone OH O 4 -isomer 3 -HSD 3 -HSD-Iso 3 -HSD-Iso HO 3 -OH-tibolone

5 各種荷爾蒙接受體 Tibolone 及其活性代謝物之對各種荷爾蒙接受體作用之分析 ER PR AR Tibolone - +/- +/- 3 -OH tibolone OH tibolone isomer Adapted from Markiewicz et al., J Steroid Biochem Mol Biol 1990

6 Tibolone 的組織選擇性作用 Tibolone 活性代謝物 Receptor 活化作用 Sulfatase 抑制作用 代謝作用 Bone (Brain, CVS, Vagina) 沒有具活性 Estrogenic compounds Breast 4 -isomer Endometrium 組織刺激作用 沒有組織刺激作用

7 Common symptoms of Taiwanese women 請問您在 45 歲後, 您的身體較常出現哪些明顯類似更年期的情形?( 可複選 ) 1 熱潮紅熱潮紅 冒汗感覺不適, 冒汗感覺不適 43.5 疲倦 三不五時經常疲憊 42.5 失眠 失眠 42.0 月經不規則 月經不規則 41.3 腰酸背痛 腰痠背痛 40.3 情緒起伏大, 心情容易低落鬱悶 37.6 情緒起伏大, 心情鬱悶陰道乾澀 32.6 陰道乾澀頻尿頻尿 25.9 其他 其他 6.5 不知道 / 拒答 不知道拒答 0.2 0% % % 30% % % 女性更年期身心健康調查,

8 絕大多數的婦女認為嚴重的更年期症狀還是需要被治療的 Treatment vs. accepting the symptoms Base: All respondents (N=150) Don't know 1% 3% Total Disagree strongly 1% 6% years Disagree slighty 8% 9% 8% 6% Agree slightly 41% 45% 43% 32% years Agree strongly 48% 47% 46% 55% years Severe menopausal symptoms need to be treated instead of accepting them just as they are. Do you...???

9 90% 的台灣更年期婦女聽過 HRT, 但普遍整體認為 HRT 是較負面的, 導致目前整體使用率偏低 Heard, seen or read anything about menopause treatments Base: All respondents (N=150) General feeling about HRT Base: Respondents who heard about HRT (N=135) Don't know 9% HRT 90% Very positive 4% Natural or herbal treatments Anti-depressants 35% 32% Somewhat positive Somewhat negative 29% 52% None 7% Very negative 7% TCM 1% Treatment currently using or ever used Base: Respondents who heard about any menopause treatments (N=139) 80% 73% 60% 54% 40% 33% 20% 17% 0% 10% 14% 4% 1% 4% 3% HRT Natural or Antidepressants TCM None of these herbal treatments Ever used Currently using

10 Development of consensus recommendations 1 on use of tibolone A panel of experts from 11* Asian Pacific countries have developed recommendations for the use of tibolone based on evidence from clinical studies (in Asian and Western women) published since to provide a practical approach to the use of tibolone in Asian postmenopausal women - to address the needs of Asian postmenopausal women - to encourage informed, evidence-based menopause symptom management * Taiwan, Korea, Australia, China, Philippines, Malaysia, India, Thailand, Vietnam, Singapore, Indonesia 1 Huang, K-E and Baber, R. Climacteric 2010 ;13;

11 Recent international randomized controlled trials (RCT) of tibolone Study Primary objectives N OPAL Bots et al. Eur Heart J 2006 THEBES Archer et al. J Clin Endocrinol Metab 2007 TOTAL Hammar et al. Br J Obstet Gynaecol 2007 Compare effects of tibolone, CEE/MPA & placebo on carotid artery IMT and CVD risk factors Confirm endometrial safety of tibolone vs. CEE/MPA Compare tolerability and vaginal bleeding between tibolone and low-dose HT (E2/NETA) 886 3, STEP Nijland et al. Maturitas 2007; Delmas et al. Osteoporos Int 2008 Compare effects of tibolone and raloxifene on BMD 308 LISA Nijland et al. J Sex Med 2008; Nijland et al. Climacteric 2009 LIFT Cummings et al. NEJM 2008 LIBERATE Kenemans et al. Lancet Oncol 2009 Compare improvements in sexual dysfunction of tibolone with transdermal E2/NETA Test hypothesis that tibolone reduces risk of vertebral fractures Breast cancer recurrence rate in women with climacteric symptoms 403 4,538 3,148

12 Climacteric and urogenital symptoms and tolerability Evidence

13 Median Number of hot flashes TOTAL : Vasomotor symptoms Tibolone (n=242) E2/NETA (n=263) Months Hammar ML et al. BJOG 2007;114:

14 Mean Mean TOTAL: Effects on vaginal tissue Karyopyknotic Index Maturation Index 20 Tibolone 2.5 mg E2/NETA Baseline week 48 Baseline week 48 Hammar ML et al. BJOG 2007;114:

15 Percentage of women TOTAL: Prevalence of bleeding per 12-week period Tibolone 2.5 mg (N=242) E2/NETA (N=263) ** * Month 1-3 Month 4-6 Month 7-9 Month **P < between groups; *P < 0.01 between groups Hammar ML et al. BJOG 2007;114:

16 Sexual interest TOTAL: Sexual interest Mean Tibolone (N = 242) E2/NETA (N = 263) ** * Baseline week 12 week 24 week 48 *P<0.05 between treatment groups **P=0.003 between treatment groups Hammar ML et al. BJOG 2007;114:

17 Consensus statements 1 : Climacteric, urogenital symptoms and tolerability Tibolone is as effective as currently used EPT/ET regimens in the management of climacteric symptoms 2 Tibolone treats vaginal atrophy and alleviates local vaginal symptoms 2,3 Tibolone has a positive effect on sexual well-being, and is more effective than oral EPT/ET in some respects namely arousal, desire, and satisfaction 2,4 1 Huang, K-E and Baber, R. Climacteric 2010; 2 Hammar ML et al. BJOG 2007;114: ; 3 Nijland E et al. Climacteric 2009;12: Nijland E et al. J Sex Med 2008;5:

18 Bone density and fractures: Evidence

19 % Change LIFT: BMD lumbar spine Percentage change from baseline in BMD (g/cm 2 ) in lumbar vertebrae (L1 L4) Tibolone Placebo Year 1 Year 2 * P < compared to placebo Year 3 Year 4 BMD: Bone mineral density Cummings SR, et al. N Engl J Med 2008;359: * * * *

20 % Change LIFT: BMD total hip Percentage change from baseline in BMD (g/cm 2 ) in total hip Tibolone Placebo Year 1 year 2 Year 3 Year 4 * P < compared to placebo Cummings SR, et al. N Engl J Med 2008;359: * * * *

21 % with new fracture LIFT: Fractures 15 Placebo (N=2,257) Tibolone 1.25mg (N=2,249) 10 RR 0.55 (95% CI = 0.4, 0.7) RR 0.74 (95% CI = 0. 6, 0.9) 26% 5 45% 0 Vertebral Fracture Non-Vertebral Fracture Cummings SR, et al. N Engl J Med 2008;359:

22 % change STEP: BMD in lumbar vertebrae Percentage change from baseline in BMD (g/cm 2 ) in vertebrae (L1 L4) P < Week 52 Week 104 Delmas PD, et al. Osteoporosis Intl. 2008:19; P < Tibolone 1.25 mg (N=115) Raloxifene (N=120) Intent-To-Treat group

23 % change STEP: BMD in hip Percentage change from baseline in BMD (g/cm 2 ) in total hip week 52 week 104 * P < 0.02 compared to raloxifene * Tibolone 1.25 mg (N=115) Raloxifene (N=120) Delmas PD, et al. Osteoporosis Intl. 2008:19; Intent-To-Treat group

24 Consensus statements 1 : Bone density and fractures Tibolone prevents bone loss and is: - as effective as standard doses of EPT/ET - more effective than raloxifene 2 Tibolone reduces the risk of vertebral and non-vertebral fractures in older osteoporotic women - The absolute reduction was greater among women who had already had a vertebral fracture than among those who had not 3 1 Huang, K-E and Baber, R. Climacteric 2010; 2 Delmas PD, et al. Osteoporosis Intl. 2008:19; ; 3 Cummings SR, et al. N Engl J Med 2008;359:

25 Breast: Evidence

26 Mammographic density study E 2 /NETA Tibolone Placebo results Before Six months treatment Lundström E et al., Am J Obstet Gynecol 2002 ; 186:

27 Mammographic density and menopause treatments Women with increase in mammographic density after 6 months treatment (using Wolfe Scale) 50% * 40% 30% 20% 10% 0% Placebo * P < vs. placebo Tibolone 2.5 mg (N=83) E 2 /NETA 2 mg/1mg (N=83) Lundström et al. Am J Obstet Gynecol 2002;186:

28 TOTAL and LISA: Incidence of breast tenderness Tibolone N = 242 E 2 /NETA N = 263 Breast tenderness 3.2%** 9.8% Hammar ML et al. BJOG 2007;114: ** P < vs. E 2 /NETA Breast tenderness 4%* 11% Nijland E et al. Climacteric 2009;12: P = vs. E 2 /NETA

29 Consensus statements: 1 Breast tissue and symptoms Tibolone does not increase mammographic density 2 Tibolone causes less breast tenderness and less mastalgia than EPT 2,3 1 Huang, K-E and Baber, R. Climacteric 2010; 2 Lundström et al. Am J Obstet Gynecol 2002;186: ; 3 Hammar ML et al. BJOG 2007;114: ; 4 Nijland E et al. Climacteric 2009;12:

30 LIFT: Breast cancer risk Relative hazard: % CI: P = 0.02 Cummings SR, et al. N Engl J Med 2008;359:

31 LIFT: Incidence of primary breast cancer (0.8%) (0.3%) 0 Placebo Tibolone 2.25 mg (N=2,249) Placebo (N = 2,257) Hazard Ratio [95% CI]: 0.32 [0.13,0.80] P = Cummings SR, et al. N Engl J Med 2008;359:

32 LIBERATE: Breast cancer recurrence (ITT) Kenemans P, et al. Lancet Oncol. 2009:10;

33 LIBERATE: Breast cancer recurrence (ITT) Aromatase inhibitor use at baseline (N = 202) Kenemans P, et al. Lancet Oncol. 2009:10;

34 LIBERATE: Breast cancer recurrence (ITT) Tamoxifen use at baseline (N = 2,068) Kenemans P, et al. Lancet Oncol. 2009:10;

35 Tibolone and breast cancer Breast cancer increased in Liberate trial RR 1.40 ( ) (80% on adjuvant endocrine therapy) Breast cancer decreased in LIFT trial RR 0.32 ( ) Breast cancer not increased in S/ P pooled clinical trial data RR 0.68 ( ) Breast Cancer not increased in GPRD Observational study RR 0.86 ( ) Breast Cancer increased in MWS Observational study RR 1.45 ( ) Kenemans P et al Lancet Oncology 2009;10: Cummings S et al N Eng J Med 2008;359: Opatrny L et al Br J Obstet Gynaecol. 2008;115:

36 Consensus statements: 1 Breast cancer risk Tibolone, taken by women with a personal history of breast cancer, is associated with an increased risk of recurrence 2. therefore ongoing BC remains the counter-indicator for all HRT treatment. The evidence of tibolone use and increased risk of breast cancer from observational studies remains inconclusive 3 Tibolone 1.25 mg does not increase breast cancer risk in older osteoporotic women with no history of breast cancer 4 1 Huang, K-E and Baber, R. Climacteric 2010 May 5 e pub; 2 Kenemans P, et al. Lancet Oncol 2009;10: ; 3 Opatrny L, et al. Br J Obstet Gynaecol 2008;115:169 75; 4 Cummings SR, et al. N Engl J Med 2008;359:

37 Cardiovascular health: Evidence

38 % change from baseline OPAL: Change in CVD risk factors lipids Tibolone CEE/MPA Placebo Total Cholesterol LDL HDL Triglycerides Bots ML, et al. Eur Heart J 2006;27:

39 Change from Baseline (mm) OPAL: Mean common CIMT over time Tibolone CEE + MPA Placebo Bots ML, et al. Eur Heart J 2006;27: CIMT: carotid intima media thickness

40 LIFT: Cumulative incidence of stroke Cummings SR, et al. N Engl J Med 2008;359: Mean age (years) = 68.3

41 Consensus statements: 1 Cardiovascular health There are still no hard endpoint data on the effect of tibolone on cardiovascular health 2 Tibolone has different effects on lipids compared with EPT/ ET 2 Tibolone increases CIMT in a manner similar to EPT 2 Tibolone increases CVD risk of elder patients 2. 1 Huang, K-E and Baber, R. Climacteric 2010; 2 Bots ML, et al. Eur. Heart J 2006;27:

42 Endometrial safety: Evidence

43 THEBES: Endometrial hyperplasia and cancer Parameter Tibolone 1.25 mg (N = 637) Tibolone 2.5 mg (N = 671) CE/MPA (N = 1,320) Women-years of exposure Endometrial hyperplasia Endometrial cancer 1,179 1,223 2,415 0 (0.0%) 0 (0.0%) 2 (0.2%) 0 (0.0%) 0 (0.0%) 1 (0.08%) # Evaluable subjects (90 days treatment and biopsy taken) # Endometrial stromal sarcoma, not hormone-sensitive Archer DF et al. J Clin Endocrinol Metab 2007;92:

44 1 Huang, K-E and Baber, R. Climacteric 2010; 2 Hammar ML, et al. BJOG 2007;114: ; 3 Archer DF, et al. J Clin Endocrinol Metab 2007;92:911-8; 4 Nijland EA, et al. Climacteric 2009;12:114-21; 5 Beral V, et al. Lancet 2005;365: ; 6 de Vries CS, et al. Drug Saf 2005;28: Consensus statements 1 Endometrial Safety Tibolone did not stimulate the endometrium or induce endometrial hyperplasia or carcinoma in postmenopausal women in randomized controlled clinical trials and has a low incidence of bleeding. 2,3,4 In observational studies, an increased relative risk of endometrial cancer has been shown 5, 6

45 Who may benefit from tibolone 1 Any symptomatic post menopausal woman A switch from HRT to Tibolone may be considered in those women who experience: - an increase in breast pain despite HRT dose adjustment - increased breast density that resulted in an unreadable mammogram - low libido - mood disorders - persistent bleeding problems (providing no histopathological reasons exist) 1 Huang, K-E and Baber, R. Climacteric 2010

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47 Thank You!!