Ms. Y Updates of SERMs and Estrogen Steven R. Cummings, MD, FACP San Francisco Coordinating Center CPMC Research Institute and UCSF Support from Lilly, Pfizer, Berlex 55 y.o. woman with mild hypertension treated with HCTZ Had a hysterectomy for fibroids No hot flushes Mother: breast cancer and kyphosis BMD FN T-score = -.3; spine -.9 Low bone mass / osteopenia GI upset with alendronate Gynecologist recommended Premarin.65 mg daily for osteopenia Outline SERMS Bone Breast cancer New SERMs Postmenopausal estrogen therapy Bone Recent findings about other risks and benefits 4 years of raloxifene decreases the risk of vertebral fracture % with fracture 36% 43% Placebo RLX 6 RLX
In women with low BMD, nonvertebral fractures are the most important 4 years of raloxifene did not decrease the risk of non-spine fractures % of days of disability due to fractures 5 RR =.93 (.8,.6) Nonvertebral fractures 9% 8% % with fractures 5 Placebo Raloxifene Clinical vertebral fractures 6 8 4 3 36 Cummings, JAMA 6;96:6 Months Reduction in Risk of Breast Cancer Summary of 3 Raloxifene Trials Incidence of Invasive Breast Cancer per Woman-Years 6 5 4 3 Placebo Raloxifene 44% 7% RUTH MORE CORE 56% FDA approved indications for prevention of breast cancer Raloxifene is indicated for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis for postmenopausal women at high risk for invasive breast cancer
5- year risk of invasive breast cancer Breast density and risk of breast cancer Age 45 55 65 75 Family history.6.4 3. 3.4 No family history.7..5.6 Odds Ratio for Breast Cancer 5 4 3 3 4 3... 4. 3 4 BI-RADS Grade Cummings, et al. JNCI 9;:384 Bazedoxifene and raloxifene had similar effects on spine BMD 6,847 women, 55-85 years old, with osteoporosis 3 years Bazedoxifene Silverman et al, JBMR 8 3
Bazedoxifene and raloxifene reduced vertebral fracture ~4% Bazedoxifene was not effective for nonvertebral fracture 6,847 women, 55-85 years old, with osteoporosis 3 years Silverman JBMR 8;3:93 Combining a SERM with estrogen Bazedoxifene plus Conjugated Estrogen TSEC Might have more potent estrogenic effects on bone than the SERM alone However, the SERM may inhibit the effect of estrogen on bone Tested in the SMART Trial 3,397 postmenopausal women with spine or hip T-scores above -.5 4
Annualized Improvement in Spine BMD Versus Placebo Premarin + Bazedoxifene Bazedoxifene appears to blunt the improvement in BMD At low doses, stronger than raloxifene at ~4 mg of bazedoxifene, effects are similar Will the combination decrease fracture risk any more than the SERM alone? Safety? (Stroke? Breast cancer?) Plus Premarin.65 mg Lindsay et al. Fertil Steril 9;9:45 Lasofoxifene SERMs you won t see Reduced the risks of Vertebral and nonvertebral fracture Breast cancer Stroke Coronary heart disease Increased Venous thromboembolism Hot flushes, leg cramps Rarely lung cancers?? 5
Arzoxifene Summary More potent than raloxifene on bone resorption and BMD mice Large fracture trial showed Decreased risk of vertebral fracture Decreased risk of breast cancer No decrease in risk of nonvertebral fracture Numerical increase in risk of endometrial cancer Will not apply to FDA for approval Raloxifene reduces the risk of vertebral fractures Consider raloxifene (or tamoxifen) for women with high risk of breast cancer Over 6, family history, high breast density HRT and All Fractures ET/HT 5 HR.76 (.69,.85) Placebo E+P 5 3 4 5 6 7 Time (years) 6
Effect of HRT on Hip Fracture Risk Women s Health Initiative overall risk and benefit 3 E+P Placebo Only ~/6 had osteoporosis HR.66 (.45,.98) 3 4 5 6 7 Time (years) HT (E+P) Harm CHD.3 Stroke.4 P.E.. Breast Ca.3 Benefit Hip fracture.7 Colon cancer.6 ET (E only) Harm Stroke.4 Benefit Hip fracture.6 No significant effect CHD.9 P.E..3 Breast Ca.8 Colon Ca. Global Index net harm Who should receive estrogen for fracture prevention? Net harmful events per, ET and HT reduce risk of fracture Valuable for short-term use for hot flushes Is there a group of asymptomatic women for whom the benefits outweigh the risks? 7
The Young at Heart Theory The debate: is estrogen beneficial for early menopausal women? Estrogen prevents / slows atherosclerosis In atherosclerotic arteries, estrogen precipitates clots Therefore, estrogen therapy may protect against CVD in younger but increase risk in older women. NAMS Position The benefit-risk ratio is favorable for women who initiate HT close to menopause Analysis from WHI provide little support for the hypothesis of favorable effects among women who initiate HT soon after menopause for CHD or benefits vs. risks Menopause ;7:4 Prentice, et al. Am J Epidemiol 9;7: Does HT reduce CHD in 5-59 year olds? HT increased risk of lung cancer WHI analyses: No significant reduction in risk of CHD in women who started < years of menopause Increased risk in older women < years < years Toh, et al, Ann Intern Med ;5: ET did not increase risk of lung cancer Chlebowski Lancet 9;Sept :-9 8
Estrogen and the brain of women over age 65.8-fold increased risk of dementia HT decreased verbal memory; ET decreased spatial-rotational ability HT and ET shrunk the frontal cortex and hippocampus by ~ % Estrogen and skin Collagen production is stimulated by estrogen and this is necessary for skin to remain firm and wrinkle free Coker, et al. J Steroid Biochem Mol Biol ;8:34 From: www.wrinkledefense.info/images/menopausal-wrinkles Estrogen and skin: randomized blinded trial 485 women, ~ 5 years postmenopausal 5 or µg ethinyl estradiol/d for 48 weeks (plus norethindrone acetate) vs. placebo No significant differences in subjective or objective ratings of: wrinkling laxity / sagging dryness / texture Estrogen Update Don t prescribe hormone therapy for older women Valuable for bothersome hot flushes If an asymptomatic woman under age 6 has a high risk of fracture, consider bisphosphonates first Phillips, J Am Acad Dermatol 8;59:397 9
Ms. Y Ms. Y 55 y.o. woman with mild hypertension treated with HCTZ Had a hysterectomy for fibroids No hot flushes Mother: breast cancer and kyphosis BMD FN T-score = -.3; spine -.9 Low bone mass / osteopenia GI upset with alendronate Gynecologist recommended Premarin.65 mg daily for osteopenia 55 y.o. woman with mild hypertension treated with HCTZ Low risk of fracture; does not need treatment ~.4% 5 year risk of breast cancer Breast density? Consider raloxifene? The PEARL Trial Thank you 8556 women age 59 to 8 with osteoporosis Two daily doses (.5 mg or.5 mg) of lasofoxifene vs. placebo 5 years
In women with low BMD, nonvertebral fractures are the most important % of days of disability due to fractures Nonvertebral fractures 6% 38% Five years of lasofoxifene improved BMD by 3% Lasofoxifene, mg/d.5.5 Spine BMD +3.% +3.% Femoral neck MD B +.9% +3.% Clinical vertebral fractures p. for all Cummings, JAMA 6;96:6 Cummings, NEJM (in press) Lasofoxifene reduced the risk of vertebral fractures The.5 mg dose also reduced the risk of nonvertebral fractures Cumulative % 8 6 4 9.5 3% (p <.) 4% (p <.) 6.9 5.7 Cumulative % 8 6 4.4 % (P =.9) 9.4 4% (p <.) 8. Pbo.5 mg.5 mg Lasofoxifene Cummings, NEJM (in press) Pbo.5 mg.5 mg Lasofoxifene Cummings, NEJM (in press)
Lasofoxifene.5 mg reduced the risk of major coronary heart disease HR (95% C.I.) Laso.5 mg.76 (.56,.3) Laso.5 mg.68 (.5,.93) Lasofoxifene HR (95% C.I.) Laso.5 mg.6 (.39,.96) Laso.5 mg.64 (.4,.99) Extension of the STAR trial Tamoxifen vs. Raloxifene Raloxifene or tamoxifen? Vogel, et al., Cancer Prev Res ;3:696
Extension of the STAR trial Tamoxifen vs. Raloxifene Effects of tamoxifen after stopping Reduction in risk of breast cancer continues for at least years Adverse effects stop when treatment stops year perspective: twice the benefit for the same 5-year risk Vogel, et al., Cancer Prev Res ;3:696 Benefits Persist 5 years of tamoxifen continues to reduce breast cancer risk and mortality for at least more years after stopping treatment Adverse effects (& costs) last 5 years* Thus, long-term benefit with short-term costs EBCT Group. Lancet 5;365:687 SF *IBIS- Coordinating Trial: J Cuzick, CenterJNCI 7;99:7 Breast cancer mortality Treat Off Cumulative Hazard....3.4 Estrogen alone: Total Breast Cancer Total Breast Cancer CEE Placebo HR =.8 (95% CI,.65-.4) P-value =. HR =.8 (95% CI..65-.4) P-value =. Time (years) 3 4 5 6 7 8 9 CEE 53 56 56 58 4989 496 446 844 357 484 Placebo 549 5353 57 58 58 4977 4479 9 443 63 Stefanick et al: JAMA 6; 95: 647-657 3
Women s Health Initiative overall risk and benefit Harm CHD.3 Stroke.4 P.E.. Breast Ca.3 Benefit Hip fracture.7 Colon cancer.6 HT (E+P) Relative Risk Estrogen alone seemed safer for women age 5 to 59..8.6.4. CHD.56.8 Global index.98.9.6.4 5 to 59 6 to 69 7 to 79 Age Group Rossouw et al. JAMA. 7;97:465 Estrogen therapy seemed beneficial for younger women (early after menopause) ET seemed safer early after menopause, until you consider stroke.5 CHD.5. CHD Stroke +7 Relative Risk.5.96. P=.5 Relative Risk.5.5...5.48.5.5-8 < to 9 ³ Years Since Menopause Rossouw et al. JAMA. 7;97:465 < to 9 ³ Years Since Menopause Rossouw et al. JAMA. 7;97:465 4
Coronary Calcification Estrogen and Coronary Calcification WHI: Estrogen only; 5-59 y.o. Coronary CT with calcification scores (CACS) 7.4 years after randomization.3 years after the end of the trial Estrogen and Coronary Calcification Estrogen and Coronary Calcification Mean CACS Estrogen 83 Placebo 3 CACS < Estrogen 65% Placebo 57% P =.4 At least 8% adherence CACS < Estrogen 68% Placebo 54% P <. 5
HT and ET increased risk of cognitive impairment in women 65 Symptomatic benefits of estrogen therapy Hot flushes Improved sleep and mood Decreased arthralgias and myalgias No effect on depression in women without hot flushes Shumaker JAMA 4;9:947 Half Dose Esterified Estrogen Improves BMD in Older Women What about low dose? Mean % Change +/- SEM 5 4 3.5.65.3 Placebo 6 8 Month 4 HK Genant et al, Arch Intern Med 57:69-65, 65, 997 6
3.5 3 Even lower Menostar patch also reduces hot flushes Spine p<. Mean % change from baseline.5.5 p<..%.%.6%.5.5%.6% Months 4 Months Placebo Estradiol.4mg 7