Hormones Impact on Bone Health Throughout the Lifespan Meryl S. LeBoff, MD Director, Skeletal Health and Osteoporosis Chief, Calcium and Bone Section Brigham and Women s Hospital Professor of Medicine, Harvard Medical School Medical Society Lecture 4/21/17 Women s Health Forum: Hormones: Do They Define Us? Outline Sex differences in: Osteoporosis and fracture rates Secondary causes of osteoporosis The role of sex hormones on bone Effects of menopausal estrogen therapy and bone 1
Osteoporotic Changes in the Trabecular Architecture of Vertebrae Normal Bone Woman with Osteoporosis Loss of bone mass and horizontal trabeculae Borah, B et al., Anat Rec. 2001;265(2):101 10. Osteoporotic Fractures are Common It is estimated that up to 50% of women and 20% of men aged 50 years or older will suffer an osteoporosis related fracture in their remaining lifetime 2,000,000 Annual incidence of common diseases 2,000,000 1,500,000 1,000,000 500,000 300,000 hip 400,000 wrist 550,000 vertebral 135,000 pelvic 675,000 other sites 790,000 210,000 recurrent 580,000 new 795,000 185,000 recurrent 610,000 new 252,710 0 Osteoporotic Heart Attack Fractures Burge, R et al.,. J Bone Miner Res. 2007;22(3):465 75. Heart & Stroke Facts: 2017 Statistical Supplement, American Heart Assoc Cancer Facts & Figures 2017, American Cancer Society Stroke Breast Cancer (new cases) 2
Progression of Osteoporosis Across the Lifespan Bone Mineral Density (BMD) Measurement: Dual energy X ray absorptiometry (DXA) Predicts fracture risk Gold standard for BMD High precision, accuracy Low radiation exposure Rapidly measures spine, hip, forearm, total body Hologic Horizon A DXA System 3
Spine (PA) Bone Density by DXA Instant Vertebral Assessment (IVA) 75% of spine fractures are not clinically evident Fracture Patients with a spine fracture have a 5 fold increased risk of a spine and 2 fold risk of a hip fracture IVA is a rapid 10 second test with a bone density 4
Incidence of Fractures is Bimodal: Males vs. Females Geusens, P et al., Nat Rev Rheumatol. 2009 Sep;5(9):497 504. Why Are Fractures Less Common In Men Than Women? Bone Loss: No accelerated bone loss with menopause and slightly later onset of age related bone loss although at a similar rate Biomechanical Factors: Bones are bigger with greater cross sectional area, periosteal bone expansion and cortical thickness, which reduce fracture risk Other Factors: Higher androgen levels increase periosteal bone formation and the expansion of bone, greater muscle mass, and growth factors. 5
Biomechanical Factors: In Men Bones Bigger, Greater Cross sectional Area and Periosteoum MALE FEMALE YOUNG OLD Serum Estradiol and Testosterone in Pubertal Girls and Boys Yilmaz, D et al., J Bone Miner Metab. 2005;23(6):476 82. 6
Serum DHEA, ACTH, and cortisol in pubertal girls and boys Apter, D et al. Acta Paediatr Scand. 1979 Jul;68(4): 599 604. Interconversion to Androgens and Estrogen Modified from: Buster and Casson, 1999 7
Significant Relationships between Circulating Levels of Hormone and Bone Density Estrogen is important for the female AND male skeleton: Women Men Total estrogen + + a Bioavailable estrogen + + DHEA + a Bioavailable testosterone + b + a Except UD radius b UD radius Greendale, GA et al., J Bone Miner Res. 1997 Nov;12(11):1833 43.; Khosla, S et al., J Clin Endocrinol Metab 1998 Jul;83(7):2266 74. Effects of Estrogens and Androgens on Bone Remodeling Black Posi ve effects Red Ⱶ Negative effects Black dashed arrows > Differentiation of cells Manolagas, SC et al., Nat Rev Endocrinol 2013 Dec;9(12):699 712. 8
Bone Health in Men Males with aromatase deficiency and a mutation in the estrogen receptor had unfused epiphyses and an increase in bone turnover (Smith et al. NEJM 1994; 331(16):1056 61.; Morishima et al. JCEM 1995; 80(12):3689 98.; Carani Et al. NEJM 1997; 37(2):91 5.) In males, estrogen is the main sex steroid that controls bone breakdown and formation (Falahati Nini et al. J Clin Invest 2000; 106(12):1553 60.) Orchiectomy in men causes a loss in testosterone leading to an increase in bone resorption and bone loss (Stepan et al. JCEM 1989;69(3):523 7.) Androgen deprivation for prostate cancer is associated with bone loss and fractures Osteoporosis and Secondary Osteoporosis Hypogonadism Glucocorticoid Excess Hyperthyroidism Anorexia Renal Insufficiency Gastrointestinal Disorders Hypercalciuria Hyperparathyroidism Chronic Respiratory Disorders Immobilization Osteogenesis imperfecta Systematic mastocytosis Neoplastic diseases Rheumatoid arthritis 9
Why is the Identification of Secondary Osteoporoses Important? Secondary osteoporoses can lead to: Skeletal changes that may be reversible Reduced acquisition of peak bone mass, a determinant of osteoporosis later in life Increased bone loss and elevated fracture risk Bone Health Across Lifespan Adolescents and Young Adults: Anorexia Female Athlete Triad * Women: Sex steroid deficiency; chemotherapy and adjuvant therapy for breast cancer * Gordon CM and LeBoff MS ed. The Female Athlete Triad A Clinical Guide, NY. Springer. 2015 10
Osteoporosis Associated with Amenorrhea Anorexia Anorexia leads to 25% lower spine bone mass, decreased peak bone mass and 7 fold increased fractures Anorectic women have subnormal DHEA, testosterone, IGF I, and estrogen and high cortisol levels Transdermal estrogen increases bone density and a low dose oral contraceptive and micronized DHEA prevents bone loss in anorexia Correction of nutritional deficits of paramount importance Misra, M, et al., J Bone Miner Res. 2011; 26:2430. Gordon, CM, et al., J of Bone and Miner Res. 1999; 14:136. Gordon, CM et al., J Clin EndoMetab. 2002; 87:4935. DiVasta, AD et al., J Bone Miner Res. 2014; 29:151. 11
Women and Breast Cancer Breast cancer is the most common cancer in women. Breast cancer patients have prolonged survival. Chemotherapy has been the standard of care in premenopausal women and most women lose normal menstrual function. Chemotherapy and cancer treatments lead to rapid bone loss Breast Cancer in Premenopausal Women: Chemotherapy Associated Bone Loss Change (%) in Bone Density 0.0 Spine Bone Density % Change -2.5-5.0-7.5 ++ Normal Loss of Ovarian Function ++ P=0.05 ** P<0.003 ** ** -10.0 6.0 12.0 24.0 Months Shapiro, C, Manola, J, LeBoff,M, J Clin Oncol 2001 Jul 15;19(14):3306 11. 12
Yearly Bone Loss Associated with Breast Cancer Therapies 1.0% Late menopausal women 2% (range 1 3%) Early menopausal women 2.6% Aromatase inhibitor (AI) therapy ~4 6.0% Gonadotropin releasing hormone agonist 7.7% Ovarian failure secondary to chemotherapy 10.7% Ovarian failure from Oophorectomy (premenopausal) Lumbar spine BMD loss at 1 year (%) Hashimoto 1995, Kanis 1997, Eastell 2006, Shapiro 2001 Menopausal Estrogen and Bone Oral Estrogen and Progesterone Transdermal Estrogen Discontinuation of Hormone Therapy Selective Estrogen Modulator 13
Women s Health Initiative :Hormone Study Design Conjugated equine estrogen (CEE) 0.625 mg/d Hysterectomy Percent Change in Total Hip and Spine Bone Density in the WHI (Mean ± SEM) Cauley, JA, et al., JAMA. 2003;290(13);1729 38. 14
Effects of Estrogen and Progesterone on Fractures in the WHI: Kaplan Meier Estimates Cauley, JA, et al., JAMA. 2003;290(13);1729 38. Hormone Replacement Therapy and Osteoporosis Studies Outcome by HRT Use Relative Risk or Type of Study Change From Baseline Non spine fractures Current 0.73 Meta analysis (22 trials) Hip fractures Current 0.64 Cohort Ever 0.76 Cohort Wrist fractures Current 0.39 Cohort Ever 0.44 Cohort Spine fractures Ever 0.60 Cohort Bone density change % Lumbar spine 6.98 (5.53 8.43) Meta analysis(18trials) Femoral neck 4.07 (3.30 4.84) Meta analysis (8 trials) Forearm 4.53 (3.68 5.36) Meta analysis(14trials) Nelson, H et al., JAMA 2002 Aug 21;288(7):872 81. 15
Women s Health Initiative: Estrogen and Progesterone for 5.2 Years(n=16,608) RISK Breast Cancer Stroke Heart Attack Benefit Osteoporosis Colon Cancer 26% Increased Risk 41% Increased Risk 29% increased risk 33% reduction spine and hip fracture 24% reduction in all fractures 37% reduction Effects of Estrogen Plus Progestin on WHI Global Index Assessment of Risk Benefit: Overall Results RH= 1.15 (95% CI=1.03 1.28) Number of Women with a First Global Index Event *Global index events include: coronary heart disease, stroke, pulmonary embolism, breast cancer, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. Writing Group for the Women s Health Initiative. JAMA. 2002; 288:321 333 16
Summary: WHI Bone Density and Fracture Study Estrogen plus Progestin increases BMD and reduces the risk of fracture in healthy pre dominantly nonosteoporotic women. Decreased risk of fracture in women at low, medium, and high risk for fracture The effect of Estrogen and Progestin on the Global Index did not differ across levels of fracture risk. There was no evidence of a net benefit in women at high risk of fracture Cauley, JA, et al., JAMA. 2003;290(13);1729 38 Manson, JE, et al., JAMA. 2013;310(13):1353 1368 Hormone Replacement Therapy Falls Out of Favor with Expert Committee JAMA, April 17, 2002 Vol. 287, No. 15 17
Effects of Stopping Oral Estrogen and Progesterone Therapy Postmenopausal Estrogen/ Progestin Interventions (PEPI RCT) Study 45 64 years old between 1 10 years post menopause n=847 4 treatment regimens: unopposed oral conjugated equine estrogen conjugated equine estrogen + 2.5mg of medroxyprogesterone acetate conjugated equine estrogen + 10mg of cyclical medroxyprogesterone acetate taken on days 1 12 each month Conjugated equine estrogen + 200mg of cyclical micronized progesterone taken on days 1 12 each month Greendale GA et al., Arch Intern Med. 2002;162(6):665 672. Risks of fractures in the WHI: Post intervention Post intervention in the Estrogen and Progesteronoe and Estrogen alone fracture reduction was attenuated A persistent hip fracture benefit was present with 13 years of follow up in the women assigned to E+P HR 0.81 (0.68 0.97) Heiss G et al., JAMA. 2008;299(9):1036 1045. Manson, JE, et al., JAMA. 2013;310(13):1353 1368 18
Low dose and Transdermal Estrogen Low dose oral combined hormone replacement therapy (.3 mg premarin) increased bone mass 2.7% over 2 years (Gambacciani et al., Am J Ob Gyn 2001) Transdermal estrogen increases bone density and has minimal effects on inflammation and the liver parameters (Shifren, J. et al., J Clin Endocrinol Metab. 2008) Data from randomized, controlled studies using transdermal estrogen on fracture risk needed Effects of Ultralow dose Transdermal Estradiol on BMD in Postmenopausal Women -------- placebo estradiol Ultra Low dose Transdermal estrogen Assessment (ULTRA) RCT -------- placebo estradiol 60 80 years old, 5 years post menopause n=417 Intervention: placebo vs. 0.25mg/d estradiol for 2 yrs Ettinger B, et al., Obstetrics and gynecology. 2004;104(3):443 51. 19
Menopausal Symptoms For moderate to severe symptoms of menopause (and prevention of bone loss) Transdermal estrogen and oral micronized progesterone Other approaches: Soy, clonidine (patch or pill), black cohash, Antidepressant medications (SSRI/NSRIs), gabapentin, progesterone Structure of Estrogen and Raloxifene Estrogen Raloxifene OH O N O HO HO S OH 20
Raloxifene Reduces bone loss Reduces spine but not non spine (hip fractures) No increased cardiac risk (JAMA 2002) Decreases invasive breast cancer risk Side effects: Hot flashes, blood clots Indication: Prevention and treatment of osteoporosis Recommendations for All Adults Calcium intake of 1000 to 1200 mg/day, and vitamin D (600 to 1000 IU/day) Regular weight bearing and musclestrengthening exercises Reduce the risk of falls and fractures Avoid cigarette smoking or excessive alcohol intake 21
Calcium Adults and Required Calcium Who (years) Men Women Pregnant/ Lactating Upper Calcium Limit 9 18 years 1300mg 1300mg 1300mg 3000mg 19 50 1000mg 1000mg 1000mg 2500mg years 51 70 1000mg 1200mg 2000mg years 71+ years 1200mg 1200mg 2000mg Dietary Reference Intakes, Institute of Medicine 2011 FDA Approved Pharmacologic Osteoporosis Therapies Antiresorptives (reduce bone breakdown): Bisphosphonates Estrogen agonists/antagonists, also called SERMs Estrogen/Hormone Therapy (prevention) Estrogen and SERM: conjugated estrogens and bazedoxifene (prevention) (Med. Lett Drugs Ther. 2014 Apr 28;56(1441):33 4.) Human monoclonal antibody to RANK ligand Calcitonin Anabolic (increase bone formation): Teriparatide (PTH (1 34) 22
FDA Approved Drug Therapies: Fracture Reductions Spine Hip Nonspine Alendronate X X X Risedronate X X X Ibandronate X Zoledronic acid X X X ET/HT X X X Raloxifene X Denosumab X X X Teriparatide X X Calcitonin X ET/HT = estrogen therapy/hormonal therapy. Osteoporosis 2002 STRONG MINDS, STRONG BODIES, STRONG BONES Massachusetts Department of Public Health 23
THANK YOU Questions? 24
Treatment Initiation for Postmenopausal Women and Men 50 Years Assess risk factors and measure bone density in adults with risk factors Osteopenia: T score between 1.0 and 2.5 Fragility fracture at the hip, spine, humerus, and some wrist fractures Osteoporosis with T score 2.5 or lower FRAX: 10 year probability of major fractures 20% or higher or hip fracture 3% or higher Siris ES, Adler R, Bilezikian J, et al. Osteoporos Int: 2014 May; 25(5):1439 43; Cosman F, de Beur SJ, LeBoff MS, et al. Osteoporos Int: 2014 Oct;25(10):2359 81 Who Should Have A Bone Density Test Women Age 50 with >1 risk factor Women: > 65 and older Men: > 70 yrs and older* Women and Men Vertebral deformity osteoporotic fracture Hyperparathyroidism Medicare mandated coverage, 1998; (* not mandated) Glucocorticoid therapy (>7.5 mg/d)>3 months Monitor response to therapy Medical necessity 25
Effective Low Dose Hormones for Treating Vasomotor Symptoms in Postmenopausal Women Manufacturer s Recommended Initial Dose, mg Effective Lower Dose, mg Estrogens Conjugated estrogens (Premarin) 2000 present 0.625 0.3 Esterified estrogens (Estratab) 1.25 0.3 0.625 Oral estradiol (Estrace, generics) 1 2 0.5 Transdermal estradiol* (Estraderm) 0.05 0.1 0.02 0.025 Combination Prempro 0.625 0.3 Conjugated estrogens with 2.5 1.5 medroxyprogesterone *Transdermal estradiol is about 20 times more potent that oral estradiol; 0.05 mg of transdermal estradiol = 1 mg/day of oral estradiol Cohen J, JAMWA 2002 26