Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too...
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![Page 1: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.](https://reader035.fdocuments.us/reader035/viewer/2022062716/56649dba5503460f94aaa54e/html5/thumbnails/1.jpg)
Osteoporosis
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Introduction
Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.”
- National Osteoporosis Foundation
Currently, there are 6 million people diagnosed with osteoporosis in the United States
Most of them are FEMALE
But MEN have worse outcomes
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Anatomy
Compared to men, women have:
Weaker bones:
• Smaller bone cross-sectional area1,4
• Less cortical bone thickness4
• Lower peak bone mass1,2
Higher risk for osteoporosis:
• Less bone mineral density2,4
• Bone density that decreases more with age1
Normal Bone Osteoporosis
Corticalthickness
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Physiology
Osteoclast
RANK LigandRANK ReceptorOsteoprotegerinCells of bone remodeling:
• Osteoblasts build bone
• Osteoclasts resorb bone
Proteins that regulate bone remodeling:
• RANK Ligand stimulates osteoclasts1
• Osteoprotegerin inhibits RANK Ligand2
OsteoblastsOsteoclasts
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Pathology
Higher Peak Bone Mass3,4
0 20 40 60 80 100
MenWomen
Age (in years)
Bone Mass Menopause
(rapid bone loss) 2
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Estrogen
Estrogen promotes bone formation1
RANK LigandOsteoprotegerin
• After menopause, estrogen levels drop
• Women experience rapid bone loss after menopause due to estrogen deficiency2
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Testosterone
Testosterone:• Stimulates osteoblasts3
• Inhibits osteoclasts3
• Increases bone size and BMD3
• Mediated by an androgen receptor3
Men with low testosterone are susceptible to osteoporosis3
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Epidemiology
80%20%
Will suffer an osteoporosis related fracture within their lifetimes2
Reported Cases of Osteoporosis1
- Total: about 6 million people
20% of Men
50% of Women
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Fracture Incidence
Estimated annual incidence2
• Total fractures: 9 million
• Hip fractures: 1.6 million
• Forearm fractures: 1.7 million
• Vertebral fractures: 1.4 million
Hip
Forearm
Spine
Humerus
Other Sites
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Fracture Comparison
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Treatment
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Bisphosphonates
• Promotes bone formation and decreases bone resorption
Mechanism of Action
• First line treatment for osteoporosis in both men and post-menopausal women1
Application• Approved in both
sexes for the prevention and treatment of osteoporosis
Aledronate2, Risedronate3 and Zoledronic Acid4
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Bisphosphonates
Ibandronate (Boniva)
Only FDA approved for treatment (not prevention) of osteoporosis in post-menopausal women
Not FDA approved for males
• Paucity of studies1 • Similar
pharmocokinetics in men and women2
• Similar efficacy in men and women probable3
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Bisphosphonates
Drug Vertebral Fracture RR
Hip Fracture RR
Non-vertebral RR
Route/ Frequency
Indicated for which gender
Alendronate PO/QDay, QWeek
WomenMen
Risedronate PO/QDay, QWeek, QMonth
WomenMen
Ibandronate NE NE PO/QMonthIV/Q3Month
Women
Zoledronic Acid
IV/QYear WomenMen
RR = Risk Reduction NE = No effect demonstrated
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Other Agents
Drug Vertebral Fracture RR
Hip Fracture RR
Non-vertebral RR
Route/ Frequency
Indicated for which gender
Raloxifene NE NE PO QDay Women
Calcitonin NE NE Nasal QDaySQ QDay
Women
Teriparatide SQ QDay WomenMen
Denosumab SQ Q6Months
WomenMen
RR = Risk Reduction NE = No effect demonstrated
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Estrogen & Bone Metabolism
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Estrogen in Females
Estrogen’s protective role in bone metabolism has long been appreciated1
Decline of estrogen in postmenopausal females provides a ready example of estrogen’s protective role in bone metabolism2
Estrogen HRT in postmenopausal women has been shown to: • prevent bone loss (Maintain BMD) • decrease bone remodeling and incidence of vertebral fracture3
HRT- Hormone Replacement Therapy
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Estrogen in Males
Testosterone & estrogen decline
with aging1
Estrogen has a greater role in
preventing bone resorption in both males & females2
Testosterone’s influence on bone
metabolsm is minimal in both
sexes2
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Raloxifene
• Mechanism of Action: selective estrogen-receptor modulator
– Benefits• Increases BMD of hip and spine in women1
• Females: approved for treatment and prevention of osteoporosis in women.
• Not approved in males2
– Narrow study contexts3,5
– Was not shown to significantly impact BMD in males4
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Tissue Selective Estrogen Complex
• Bazedoxifine/Conjugated Estrogen (Duavee)– Mechanism of Action: SERM that selectively stimulates
lipid metabolism and bone, however, has no effect on the uterus and breast.
– Benefits• FDA approved for – postmenopausal moderate/severe vasomotor
symptoms – prevention of postmenopausal osteoporosis.
• Increased hip and lumbar BMD
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Tissue Selective Estrogen Complex
• Bazedoxifene/Conjugated Estrogen (Cont’d)– Approved in Women for2 • prevention of osteoporosis• osteopenia • post menopausal vasomotor and sleep disturbances
– Men: None of the three major clinical trials included men, despite that estrogen has been demonstrated to play a significant role in bone formation3,4,5.
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Calcitonin-Salmon
• Mechanism of Action– Analogous to endogenous calcitonin
• Indications– Approved for the treatment (not prevention)
of osteoporosis in women who are ≥5 years post-menopausal
– Not utilized in men
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Teriparatide (Forteo)
• Mechanism of Action: recombinant parathyroid hormone (PTH); stimulates bone formation.
• Approved for
– Treatment & prevention of osteoporosis in men and postmenopausal women1
– Especially those at high risk for vertebral fracture2
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Teriparatide Efficacy
Extent of lumbar BMD increase similar in both males1 and postmenopausal females2
Significantly increased lumbar BMD from baseline levels3
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Calcium & Vitamin D
NOF Recommended Daily Intake:
Calcium
Men: 1000 mg Women: 1200 mg
Vitamin D
Men & Women: 800 –
1000 units
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Calcium and Vitamin D
Total Fracture Incidence
• DIPART Group analysis of 7 major Vitamin D and Calcium trials in the US and Europe.
• Analysis included 68,500+ patients• Only 14% of subjects
were males
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Calcium and Vitamin D
Hip Fracture Incidence
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Calcium & Vitamin D
• Efficacy: combination Calcium (1200 mg) and Vitamin D (800 mg) reduces the risk of hip, vertebral and total fractures in both men and women1
• Study Demographics• Men were understudied• 2010 DIPART Group Meta-Analysis: only14% of
68,500 subjects studied were men1 • 2007 Tang et al2. Meta-Analysis included only 8% men3
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RANK-L Inhibitor (Denosumab)
• Mechanism of Action: monoclonal antibody; prevents osteoclast maturation.
“RANK-L”, RANK-Ligand
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Denosumab (Prolia)
• Approved to increase BMD in1,2
–Women: • With non-metastatic breast cancer • post-menopausal women with osteoporosis at high
risk for fracture.
–Men:2 • With non-metastatic prostate cancer who are
receiving Androgen Deprivation Therapy. • With osteoporosis who are at high risk for fracture.
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Denosumab
Increased: BMD at all skeletal sites (lumbar spine, femoral neck, trochanter, radius & total hip)
Decreased: serum bone turnover markers, incidence of vertebral fracture in those with non-metastatic prostate cancer.
Efficacy in Males
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Denosumab
Increased vertebral, hip and non-vertebral BMD1.
Decreased incidence of vertebral, hip and non-vertebral fractures1,3
Efficacy in Females
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Denosumab Research Disparities
• No data for fracture incidence in males without non-metastatic prostate cancer1.
• Few phase III clinical trials have thoroughly investigated the efficacy of Denosumab in males, though it has been shown to be a beneficial treatment option.
In Males,
• Major phase III clinical trials studied Denosumab efficacy in >2000 postmenopausal females2– no equivalent in males.
• Examples: FREEDOM, DEFEND, DECIDE & STAND studies3
In Females,
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Fracture Prognosis
Return
to In
depe
nden
t Liv
ing
Inde
pend
ent M
obili
ty
Mor
tality
with
in 1
Yr.
0%
20%
40%
60%
80%
MenWomen
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Fracture Morbidity
Compared to men, Women:
- Are almost twice as likely to survive
- Are more likely to return to home
- Are more likely to return to walking independently
Compared to women, Men:
- Have higher early post-operative mortality
-Are less likely to return to independent living or mobility.
WO
ME
NM
EN
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Fracture MortalityMen Women
42%
44%
46%
48%
50%
52%
54%
56%
58%
60%
Men197 out of 343 died
Women461 out of 952 died
The Dubbo Osteoporosis Epidemiology Study1
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Osteoporosis Treatment after Hip Fracture
0%
20%
40%
60%
80%
MenWomen
1 2
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Risk Factors
Cannot Change1 Potential for Change1
Menopause
History of fracture infirst-degree relative
Caucasian race
Advanced age
Female
Smoking
Estrogen deficiency, including menopause onset <age 45
Low calcium intake (lifelong)
Excessive Alcohol
Vitamin D Insufficiency
Specific MedicationsSpecific Diseases
Sedentary
Female Athlete Triad
Malnutrition
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Screening
Criterion1 Women MenAge-Based • 65 years and older 70 years and older
Based on Risk Factors
• Postmenopausal, < 65 with 1+ risk factor(s)
• Perimenopausal with specific high-risk factor associated with increased fracture risk
• Postmenopausal, discontinuing estrogen
50-70 years with 1+ risk factor(s)
Regardless of Gender
• Fragility fracture (after age 50)
• High-risk condition or exposure to high-risk medication associated with low bone mass or bone loss
• Anyone being considered for pharmacologic therapy
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DXA Scan
• The gold standard test for diagnosis1
• Measures1
– Spine– Hip– Forearm
• Less radiation than in the
environment1
• Provides the T Score1
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T-Score Definitions
Diagnosis1 T-Score1
Normal BMD BMD is within 1 SD of a healthy young adult: T-score > -1.0
Osteopenia BMD is between 1.0 and 2.5 SD below thatof a healthy young adult:T-score between -1.0 and -2.5
Osteoporosis BMD is 2.5 SD or more below that of a healthy young adult:T-score < -2.5
Established Osteoporosis BMD representing a T-score ≤ –2.5 and the presence of one or more fragility fractures
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Cost-Effectiveness
Screening is Cost-Effective in
Women >651
Screening is NOT Cost-Effective in
Men >701
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Gender Awareness
• Osteoporosis considered a “Woman’s Disease”1
• 20% of men will suffer from osteoporosis1
• Research is biased towards women2
• Men have worse outcomes3