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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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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
Shapiro, C, Manola, J, LeBoff ,M, J Clin Oncol 2001 Jul 15;19(14):3306‐11.
6.0 12.0 24.0-10.0
-7.5
-5.0
-2.5
0.0
Normal
Loss of OvarianFunction++
**
++ P=0.05** P<0.003
**
Months
Sp
ine
Bo
ne
Den
sity
% C
han
ge
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7.7% Ovarian failure secondary to chemotherapy
~4‐6.0% Gonadotropin‐releasing hormone agonist
2.6%
1.0%
Yearly Bone Loss Associated with Breast Cancer Therapies
Lumbar spine BMD loss at 1 year (%)
Hashimoto 1995, Kanis 1997, Eastell 2006, Shapiro 2001
2% (range 1‐3%) Early menopausal women
Aromatase inhibitor (AI) therapy
Late menopausal women
10.7% Ovarian failure from Oophorectomy (premenopausal)
• Oral Estrogen and Progesterone
• Transdermal Estrogen
• Discontinuation of Hormone Therapy
• Selective Estrogen Modulator
Menopausal Estrogen and Bone
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Women’s Health Initiative :Hormone Study Design
Hysterectomy
Conjugated equine estrogen (CEE) 0.625 mg/d
Percent Change in Total Hip and Spine Bone Density in the WHI (Mean ± SEM)
Cauley, JA, et al., JAMA. 2003;290(13);1729‐38.
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Cauley, JA, et al., JAMA. 2003;290(13);1729‐38.
Effects of Estrogen and Progesterone on Fractures in the WHI: Kaplan‐Meier Estimates
Hormone Replacement Therapy and Osteoporosis Studies
Outcome by HRT Use Relative Risk or Type of StudyChange From Baseline
Non‐spine fracturesCurrent 0.73 Meta‐analysis (22 trials)Hip fracturesCurrent 0.64 CohortEver 0.76 CohortWrist fracturesCurrent 0.39 CohortEver 0.44 CohortSpine fracturesEver 0.60 CohortBone 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.
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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
• n=847
4 treatment regimens:• unopposed oral conjugated equine estrogen• conjugated equine estrogen + 2.5mg ofmedroxyprogesterone acetate
• 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
-------- placebo_____ estradiol
-------- placebo_____ estradiol
Ultra‐Low‐dose Transdermal estrogen Assessment (ULTRA) RCT
• 60‐80 years old, 5 years postmenopause
• n=417
• Intervention: placebo vs. 0.25mg/destradiol for 2 yrs
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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
Estrogen Raloxifene
HO
OH
OHHO S
O
ON
Structure of Estrogen and Raloxifene
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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 muscle‐strengthening exercises
• Reduce the risk of falls and fractures
• Avoid cigarette smoking or excessive alcohol intake
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Calcium Adults and Required Calcium
Dietary Reference Intakes, Institute of Medicine 2011
Who(years)
Men Women Pregnant/Lactating
Upper Calcium Limit
9‐18 years 1300mg 1300mg 1300mg 3000mg
19‐50 years
1000mg 1000mg 1000mg 2500mg
51‐70 years
1000mg 1200mg 2000mg
71+ years 1200mg 1200mg 2000mg
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)
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FDA‐Approved Drug Therapies: Fracture Reductions
ET/HT = estrogen therapy/hormonal therapy.
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
STRONG MINDS,
STRONG BODIES,
STRONG BONESMassachusetts Department of Public Health
Osteoporosis 2002
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Questions?
THANK YOU
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Assess risk factors and measure bone density in adults with risk factors
FRAX: 10‐year probability of major fractures 20% or higher or hip fracture 3% or higher
Fragility fracture at the hip, spine,
humerus, and some wrist fractures
Osteoporosis with T‐score −2.5 or lower
Treatment Initiation for Postmenopausal Women and Men ≥50 Years
Treatment Initiation for Postmenopausal Women and Men ≥50 Years
Osteopenia: T‐score between −1.0 and −2.5
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 and Men
Vertebral deformity osteoporotic fracture
Hyperparathyroidism
Glucocorticoid therapy (>7.5 mg/d)>3 months
Monitor response to therapy
Medical necessity
Women
Age 50 with >1 risk factor
Women: > 65 and older
Men: > 70 yrs and older*
Medicare mandated coverage, 1998; (* not mandated)
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Effective Low‐Dose Hormones for Treating Vasomotor Symptoms in Postmenopausal Women
Manufacturer’s EffectiveRecommended Lower Initial Dose, mg Dose, mg
EstrogensConjugated estrogens (Premarin) 2000‐present 0.625 0.3
Esterified estrogens (Estratab) 1.25 0.3‐0.625Oral estradiol (Estrace, generics) 1‐2 0.5Transdermal estradiol* (Estraderm) 0.05‐0.1 0.02‐0.025
CombinationPrempro 0.625 0.3 Conjugated estrogens with 2.5 1.5medroxyprogesterone
*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