04/21/2017 1 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
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04/21/2017
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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
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Normal Bone Woman with Osteoporosis
Loss of bone mass and horizontal trabeculaeBorah, B et al., Anat Rec. 2001;265(2):101‐10.
Osteoporotic Changes in the Trabecular Architecture of Vertebrae
2,000,000
0
500,000
1,000,000
1,500,000
2,000,000
OsteoporoticFractures
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
Osteoporotic Fractures are Common
790,000
Heart Attack
795,000
Stroke
252,710
Breast Cancer (new cases)
550,000vertebral
675,000 other sites
400,000wrist
300,000hip
Annual in
ciden
ce of common diseases
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
135,000pelvic
185,000recurrent
610,000new580,000
new
210,000recurrent
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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
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Spine (PA) Bone Density by DXA
Instant Vertebral Assessment (IVA)
Fracture
• 75% of spine fractures are not clinically evident
• 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
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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.
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Biomechanical Factors: In Men Bones Bigger, Greater Cross‐sectional Area and Periosteoum
MALE
FEMALE
YOUNG OLD
Yilmaz, D et al., J Bone Miner Metab. 2005;23(6):476‐82.
Serum Estradiol and Testosterone in Pubertal Girls and Boys
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Apter, D et al. Acta Paediatr Scand. 1979 Jul;68(4): 599–604.
Serum DHEA, ACTH, and cortisol in pubertal girls and boys
Interconversion to Androgens and Estrogen
Modified from: Buster and Casson, 1999
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Significant Relationships between Circulating Levels of Hormone and Bone Density
Women Men
Total estrogen + +a
Bioavailable estrogen + +
DHEA +a ‐
Bioavailable testosterone +b +
aExcept UD radiusbUD 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.
Estrogen is important for the female AND male skeleton:
Effects of Estrogens and Androgens on Bone Remodeling
Manolagas, SC et al., Nat Rev Endocrinol 2013 Dec;9(12):699‐712.
•Black → Posi ve effects•Red Ⱶ Negative effects•Black dashed arrows ‐‐‐> Differentiation of cells
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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
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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
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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.
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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
Women’s Health Initiative: Estrogen and Progesterone for 5.2 Years(n=16,608)
RISK
Breast Cancer 26% Increased Risk
Stroke 41% Increased Risk
Heart Attack 29% increased risk
Benefit
Osteoporosis 33% reduction spine and hip fracture
24% reduction in all fractures
Colon Cancer 37% reduction
Effects of Estrogen Plus Progestin on WHI Global Index Assessment of Risk‐Benefit: Overall Results
Number of Women with a
First Global In
dex 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
RH= 1.15 (95% CI=1.03 ‐ 1.28)
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Summary: WHI Bone Density and Fracture Study
• Estrogen plus Progestin increases BMD and reduces the risk of fracture in healthy pre‐dominantly non‐osteoporotic 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);1729‐38Manson, 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
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Greendale GA et al., Arch Intern Med. 2002;162(6):665‐672.
Effects of Stopping Oral Estrogen and Progesterone Therapy
Postmenopausal Estrogen/ Progestin Interventions (PEPI‐RCT) Study
• 45‐64 years old between 1‐10 years postmenopause
• conjugated equine estrogen + 10mg of cyclicalmedroxyprogesterone acetate taken on days 1‐12each month
• Conjugated equine estrogen + 200mg of cyclicalmicronized progesterone taken on days 1‐12 eachmonth
Risks of fractures in the WHI: Post‐intervention
Heiss G et al., JAMA. 2008;299(9):1036‐1045.
• Post‐intervention in the Estrogen and Progesteronoeand 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)
Manson, JE, et al., JAMA. 2013;310(13):1353‐1368
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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
Ettinger B, et al., Obstetrics and gynecology. 2004;104(3):443‐51.
Effects of Ultralow‐dose Transdermal Estradiol on BMD in Postmenopausal Women