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Osteoporosis
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
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
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
Pathology
Higher Peak Bone Mass3,4
0 20 40 60 80 100
MenWomen
Age (in years)
Bone Mass Menopause
(rapid bone loss) 2
Estrogen
Estrogen promotes bone formation1
RANK LigandOsteoprotegerin
• After menopause, estrogen levels drop
• Women experience rapid bone loss after menopause due to estrogen deficiency2
Testosterone
Testosterone:• Stimulates osteoblasts3
• Inhibits osteoclasts3
• Increases bone size and BMD3
• Mediated by an androgen receptor3
Men with low testosterone are susceptible to osteoporosis3
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
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
Fracture Comparison
Treatment
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
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
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
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
Estrogen & Bone Metabolism
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
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
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
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
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.
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
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
Teriparatide Efficacy
Extent of lumbar BMD increase similar in both males1 and postmenopausal females2
Significantly increased lumbar BMD from baseline levels3
Calcium & Vitamin D
NOF Recommended Daily Intake:
Calcium
Men: 1000 mg Women: 1200 mg
Vitamin D
Men & Women: 800 –
1000 units
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
Calcium and Vitamin D
Hip Fracture Incidence
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
RANK-L Inhibitor (Denosumab)
• Mechanism of Action: monoclonal antibody; prevents osteoclast maturation.
“RANK-L”, RANK-Ligand
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.
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
Denosumab
Increased vertebral, hip and non-vertebral BMD1.
Decreased incidence of vertebral, hip and non-vertebral fractures1,3
Efficacy in Females
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,
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
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
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
Osteoporosis Treatment after Hip Fracture
0%
20%
40%
60%
80%
MenWomen
1 2
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
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
DXA Scan
• The gold standard test for diagnosis1
• Measures1
– Spine– Hip– Forearm
• Less radiation than in the
environment1
• Provides the T Score1
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
Cost-Effectiveness
Screening is Cost-Effective in
Women >651
Screening is NOT Cost-Effective in
Men >701
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