Outline. Estrogens and SERMS The forgotten few! How Does Estrogen Work in Bone? Its Complex!!! 6/14/2013

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1 Outline Estrogens and SERMS The forgotten few! Clifford J Rosen MD rosenc@mmc.org Physiology of Estrogen and estrogen receptors Actions of estrogen on bone BMD, fracture, other off target effects Cohort and randomized trials of E2 Role of SERMS in bone diseases Raloxifene Bazedoxifene Summary The signal transduction pathways available to estrogen or a selective estrogen receptor modulator (SERM) to initiate gene transcription. How Does Estrogen Work in Bone? Its Complex!!! Oxford University Press Jordan V C et al. JNCI J Natl Cancer Inst 2001;93:

2 Modes of Action of Estrogen on Bone- Adults Anti-resorptive Inhibit RANKL Apoptosis of Osteoclasts Inhibit NFkB signaling Anabolic Stimulates bone formation in rodents Humans unlikely- suppresses formation Other Stimulates ATGL in fat cells- reduction in adipocytes Bone Remodeling Targets for E2 NTx D-Pyr CTx RANK OSTEOCLAST H + Collagen α v β 3 RANK-L(OPGL) Proteases Osteocyte M-CSF Calcium Osteocalcin IGF-I IGFBPs Matrix OSTEOBLAST - Sclerostin OPG IGF-I IGF-2 IGF-BPs Activation GH, TGF IL-1, PTH, IL-6, E2, IGF-I LRP5,6 Osteocalcin BSAP PICP Ovariectomy Induced Marrow Adiposity Resorption Formation 20 Days 100 Days 120 Days 2

3 Estrogen Treatment Works Like other Anti Resorptive Agents but generally Mechanism of Blocks Fracture the recruitment of osteoclasts Risk Reduction Bone Remodeling:Rankl/OPG Antiresorptive Therapy Reduce Bone Turnover Stabilize or Improve Microarchitecture Increase BMD Decrease in Fracture Risk Hormone Products Available for Rx Estrogen Dose Equivalents Estrogen Full doses of conjugated EE or estradiol Low doses EE Alternate routes of administration Progestins Micronized progesterone Progesterone orally- provera Progestin intrauterine device Vaginal estrogen Bioidentical hormones Soy products, isoflavinoids, genistein Estrogen Standard Low Dose CEE mg 0.3 mg Oral E2 1 mg 0.5 mg Transdermal E2 Ethinyl estradiol CEE = conjugated equine estrogen; E2 = estradiol. Graphic courtesy of Kathryn A. Martin, MD mg (50 µg) mg (25 µg) 5 µg 2.5 µg Ultra-Low Dose mg (14 µg) 3

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5 Wehrli, JBMR, 2010 Estrogen Use reduces non vertebral fractures Estorgen + Progesterone increases Spine BMD more than Alendronate 5

6 WHI From: Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial JAMA. 2002;288(3): doi: /jama From: Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial JAMA. 2002;288(3): doi: /jama Figure Legend: Figure Legend: HR indicates hazard ratio; nci, nominal confidence interval; andaci, adjusted confidence interval. Date of download: 5/29/2013 Copyright 2012 American Medical Association. All rights reserved. Date of download: 5/29/2013 Copyright 2012 American Medical Association. All rights reserved. Women s Health Initiative Estrogen and Progestin Arm: Absolute Excess Risk Women s Health Initiative: Estrogen Alone in Postmenopausal Women Compared to Placebo: Major Clinical Outcomes Excess CHD events: 7/10,000 woman-years Excess stroke events : 8/10,000 woman-years Excess pulmonary emboli: 8/10,000 woman-years Excess invasive breast cancer: 8/10,000 woman-years * * Favors Treatment Favors Placebo Source: Writing Group for the WHI Investigators Source: Adapted from WHI Steering Committee 2004 * P <

7 Number of CHD Events Estrogen Alone Did Not Effect CHD Events in WHI; After Cessation of Estrogen, Younger Women Who Had Taken CEE Had Fewer CHD Events 56 * 33 CEE: conjugated equine estrogen Source: Anderson 2004; LaCroix Placebo CEE.625 mg Age at Initiation of CEE (Average 5.9 years of use and 10.7 years of follow up) * Statistically significant difference Low-Dose Estrogen HOPE Trial Women s Health, Osteoporosis, Progestin, Estrogen (HOPE) trial postmenopausal women with uterus, treated for 2 years 8 treatment groups and placebo CEE mg/d ± MPA 2.5 mg/d CEE 0.45 mg/d ± MPA 2.5 mg/d CEE 0.45 mg/d + MPA 1.5 mg/d CEE 0.3 mg/d ± MPA 1.5 mg/d Placebo Endpoints: vasomotor symptoms, BMD, endometrial safety CEE = conjugated equine estrogen; MPA = medroxyprogesterone acetate; BMD = bone mineral density. Utian WH, et al. Fertil Steril. 2001;75:1065. Change Spine BMD (%) CEE and Spine BMD HOPE Trial Month CEE = conjugated equine estrogen; BMD = bone mineral density. Reprinted from Lindsay R, et al. JAMA. 2002;287:2668, with permission from the American Medical Association. Placebo CEE 0.3 mg CEE 0.45 mg CEE mg Percentage Hot Flash Frequency (Mean) CEE and Hot Flashes HOPE Trial Week Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065, with permission from Elsevier. CEE 0.3 mg/d Placebo CEE 0.45 mg/d CEE mg/d 7

8 Ultra Low-Dose Estrogen ULTRA trial: Ultra low-dose Transdermal Estradiol Assessment 1 Transdermal E2 (0.014 mg/day) vs placebo x 2 years N = 417 women, mean age 67 Asymptomatic population no effect on hot flashes 2 Effective for hot flashes in trials of younger women (N = 425) 3 Ultra Low-Dose Estrogen and BMD ULTRA Trial BMD increased more in spine (2%) and hip (1.2%) vs placebo 1 Greater bone effect with lower endogenous E 2 1. Yaffe K, et al. Arch Neurol. 2006;63: Diem S, et al. Menopause. 2006;13: Bachmann GA, et al. Obstet Gynecol. 2007;110: Ettinger B, et al. Obstet Gynecol. 2004;104: Huang AJ, et al. J Bone Miner Res. 2007;22:1791. Discontinuation of ERT and Risk of Osteoporotic Fracture Raloxifene: A selective estrogen receptor modulator 8

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10 Graphical depiction of femoral neck trabecular bone analyses. Are there non- BMD effects of the SERMS On Bone Strength? Allen M R et al. Endocrinology 2007;148: by Endocrine Society Significant alterations of trabecular bone material-level biomechanical properties with raloxifene. Raloxifene alters energy to failure and toughness of cortical bone through changes in postyield displacement by Endocrine Society Allen M R et al. Endocrinology 2007;148: by Endocrine Society Allen M R et al. Endocrinology 2007;148:

11 Significant Risk Reduction from Bazedoxifene for Non Vert Frx 11

12 Summary Estrogens are very effective in raising BMD and reducing vert and non-vert fracture risk Off-target effects of estrogen limit clinical utility (breast cardiovascular, thrombosis) SERMS are protective to the skeleton At least one SERM has non-vert fracture risk reduction There may be beneficial off-target effects; e.g. protection vs breast cancer Mean percent change (± se) in BMD of the lumbar spine with alendronate (ALN)+HRT (shaded bars) or placebo (PBO)+HRT. ***, P < between groups. Lindsay R et al. JCEM 1999;84: by Endocrine Society 12

13 Molecular structures of the endogenous estrogen 17β-estradiol and of tamoxifen, 4-hydroxytamoxifen, raloxifene, ICI 182,780 (fulvestrant), toremifene, R,R-cis-diethyl-THC, and genistein. Heldring N et al. Physiol Rev 2007;87: by American Physiological Society 13

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15 Raloxifene has less effect on BMD than alendronate Changes in bone mineral density (BMD) from baseline to 12 months (N=107) with GC. Changes in bone markers from baseline to 12 months (N=107). Mok C C et al. Ann Rheum Dis 2011;70: Mok C C et al. Ann Rheum Dis 2011;70: by BMJ Publishing Group Ltd and European League Against Rheumatism 2011 by BMJ Publishing Group Ltd and European League Against Rheumatism 15

16 Bazedoxifene 16