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OsteoporosisOsteoporosis
• The most common metabolic bone disorder The most common metabolic bone disorder • Systemic skeletal disease characterized by:Systemic skeletal disease characterized by:
– Low bone massLow bone mass
– Microarchitectural deterioration of bone tissueMicroarchitectural deterioration of bone tissue
– Increased bone fragility and susceptibility to fractureIncreased bone fragility and susceptibility to fracture
3-D Micro CT:Healthy vs Osteoporotic Bone
52 year old Female84 year old Female
(w/ vertebral fracture)
Borah et al Anat. Rec.(2001)
Pathophysiology of OsteoporosisPathophysiology of Osteoporosis
• Bone remodeling occurs throughout an individual’s Bone remodeling occurs throughout an individual’s lifetimelifetime
• In normal adults, the activity of osteoclasts (bone In normal adults, the activity of osteoclasts (bone resorption) is balanced by that of osteoblasts (bone resorption) is balanced by that of osteoblasts (bone formation) formation)
• With the onset of menopause (mid-forties or fifties), With the onset of menopause (mid-forties or fifties), diminishing estrogen levels lead to excessive bone diminishing estrogen levels lead to excessive bone resorption that is not fully compensated by an resorption that is not fully compensated by an increase in bone formationincrease in bone formation
Bone RemodelingBone Remodeling
Hormones
AcF
BMU Balance
Reversal
Formation
Bone
Osteoid Mineralization
BioMarkers
Bone
Bone
BioMarkers
Howship’s lacuna
BMU
Resting Activation
ResorptionBone
osteoclasts
osteoblasts
Contributors to Bone Strength
• Bone size, BMD, and mineralization play a role
• Bone turnover rates affect the quality of bone
• Preservation of bone architecture plays a major role in determining bone strength
Why Recognize & Treat Osteoporosis?Why Recognize & Treat Osteoporosis?
To Prevent FracturesTo Prevent Fractures
• 1.5 million fractures/yr1.5 million fractures/yr
• $10 billion direct costs$10 billion direct costs
• 300,000 hip fractures/yr300,000 hip fractures/yr– 20% die20% die– 25% confined to long-term care facilities25% confined to long-term care facilities– 50% long-term loss of mobility50% long-term loss of mobility
Why Recognize & Treat Osteoporosis?Why Recognize & Treat Osteoporosis?
• Less than 5% of hip fractures are evaluated for osteoporosis!
(NIH Health report, 2001)
To Prevent FracturesTo Prevent Fractures
Osteoporotic Fractures in Women Compared With Other Diseases
Osteoporotic Fractures in Women Compared With Other Diseases
1,200,0001
513,0002
228,0002184,3003
0
500,000
1,000,000
1,500,000
2,000,000
OsteoporoticFractures
Heart Attack
Stroke BreastCancer
An
nu
al I
nci
den
ce
1 National Osteoporosis Foundation, 2002. Available at: http://www.nof.org.2 American Heart Association. Heart & Stroke Facts: 1999 Statistical Supplement.3 American Cancer Society. Breast Cancer Facts & Figures 1999-2000.
*p<0.05, vs patients with no prevalent vertebral fractures (12-fold increased risk).Lindsay R, et al, JAMA. 2001;285:320-323.
• Overall, 20% fractured again within the year following a new fracture• Risk of fracture increased with the number of baseline fractures
% o
f P
atie
nts
05
1015
20
2530
Overall 0 1 2+
Number of Baseline Vertebral Fractures
**
Risk of Another Vertebral Fracture Is Higher Risk of Another Vertebral Fracture Is Higher
in the Year Following a New Fracturein the Year Following a New Fracture
National Osteoporosis Foundation Guidelines for Bone Density Testing
• All women aged 65 or olderAll women aged 65 or older
• All postmenopausal women under age 65 All postmenopausal women under age 65 who have one or more additional risk factorswho have one or more additional risk factors
• Postmenopausal women who present with Postmenopausal women who present with fracturesfractures
• USPSTF makes no recommendation for or USPSTF makes no recommendation for or against routine screening in women under against routine screening in women under age 60age 60
www.nof.org
ClassificationClassification
Normal
Osteopenia (low bone mass)
Osteoporosis
Severe or established osteoporosis
WHO Criteria for DiagnosisWHO Criteria for Diagnosis
**T score indicates the # of SDs below or above the average peak bone mass in young adultsT score indicates the # of SDs below or above the average peak bone mass in young adults
T score*T score*
< –1< –1
––1 to –2.5 1 to –2.5
––2.5 or greater2.5 or greater
––2.5 or greater + 2.5 or greater + fx(s) fx(s)
One-Minute Treatment Decision
Therapy Decision
Treat all patients with an existing fracture
High Risk-
Treat
Moderate Risk -
Treat if other risk factors
Low Risk-
Check again in 1-2 years
T-Score *
Below -2.0
-1.5 to -2.0
Above -1.5
National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ: Excerpta Medica, Inc.; 1998.
Combined Effect of Bone Density Combined Effect of Bone Density and Risk Factorsand Risk Factors
Rate ofHip Fracture/
1000Woman-Years
Bone Density
Cummings SR et al. N Engl J Med. 1995;332:767-773.
Number ofRisk Factors
27.3
14.79.4
0
5
10
15
20
25
30
Lowest Third Middle Third Highest Third
53-4
0-2
Center et al. Lancet 1999.
Mortality Associated with Mortality Associated with FractureFracture
0
50
100
150
200
250
300
350
400
450
60-69 70-79 80 and older
Women controls Women with fractures
Men controls Men with fractures
Mor
tali
ty (
deat
hs/1
,000
pers
on-y
ears
)
Diseases Associated with Diseases Associated with Decreased Bone MassDecreased Bone Mass
• Hypogonadism • Hypercortisolemia• Hyperthyroidism• Hyperparathyroidism• Anorexia• Renal Failure• Chronic Liver Disease
• Malabsorption– Celiac Sprue
– Surgical
• Inflam. Bowel Dz • Pregnancy• Type 1 Diabetes• HIV
Medications associated withMedications associated with Decreased Bone MassDecreased Bone Mass
• Corticosteroids• Heparin (high dose)• Aluminum• Anticonvulsants
– phenobarbital, phenytoin
• Medroxyprogesterone acetate
• Cyclosporine• Prograf• Aromatase inhibitors• Antiretroviral therapy• Retinoids
Glucocorticoid-Induced Bone LossGlucocorticoid-Induced Bone Loss
• Glucocorticoid tx at 7.5 mg/day for 3 months often results in rapid loss of trabecular bone
• Up to 50% of patients taking >7.5 mg/d of prednisone or equivalent will fracture
Management of Osteoporosis: Management of Osteoporosis: Goals of TherapyGoals of Therapy
• Prevent first fragility fracture or future Prevent first fragility fracture or future fractures if one has already occurredfractures if one has already occurred
• Stabilize/increase bone massStabilize/increase bone mass• Relieve symptoms of fractures and/or Relieve symptoms of fractures and/or
skeletal deformitiesskeletal deformities• Improve mobility and functional statusImprove mobility and functional status• Initiate lifestyle changes to enhance Initiate lifestyle changes to enhance
prevention of fracturesprevention of fractures
NOF GuidelinesNOF Guidelines
Public Health Recommendations
• 1-1.5 g of daily calcium
• 400-800 of vitamin D daily
• Weight-bearing exercise
• Discourage smoking
Drug therapy for osteoporosisDrug therapy for osteoporosisDrug therapy for osteoporosisDrug therapy for osteoporosis
PreventionPrevention TreatmentTreatment
HRTHRT Yes Yes NoNo
RaloxifeneRaloxifene Yes Yes YesYes
CalcitoninCalcitonin No No Yes*?Yes*?
AlendronateAlendronate Yes Yes Yes Yes
Risedronate YesRisedronate Yes YesYes
PTHPTH No No YesYes
Bisphosphonates for Osteoporosis
• Benefit: reduction of fracture risk (alendronate, risedronate, ibandronate)
• Problem: poor adherence to therapy• Cause: multifactorial, including issues of
convenience (complexity of dosing) and tolerability (GI irritation in clinical experience)
• Possible solutions: larger doses given less frequently, parenteral administration
Bisphosphonates: Molecular Mechanisms of Action
• Interfere with the action of osteoclasts– Recruitment, differentiation, and action
– Two mechanisms:• Incorporated into cytotoxic ATP analogs (etidronate)
– Affect cellular activity
• Interfere with the mevalonate pathway (nitrogen-containing BPs)– Cause apoptosis
Russell R, et al. Osteoporos Int. 1999;(suppl 2):S68-S80.
* Significant difference vs placebo.
VERT MN = Vertebral Efficacy With Risedronate Therapy Multinational study.
VERT NA = Vertebral Efficacy With Risedronate Therapy North America study.
Actonel® (risedronate sodium) Tablets Prescribing Information. Procter & Gamble Pharmaceuticals; July 2004.
Relative Risk Reduction of Vertebral Fractures in 3-Year Studies:
Risedronate 5 mg/d vs PlaceboVERT NA Study
Type of Fracture Relative Risk Reduction, %
New vertebral fracture 41*
VERT MN Study
Type of Fracture Relative Risk Reduction, %
New vertebral fracture 49*
Baseline 3 Years
VERT-NA: Placebo Patient
Increased perforation
Trabecular thinning
Borah, et al, JBMR 16 (Suppl 1), 2001
Similar thickness of trabeculae and number of perforations
Baseline 3 Years
Borah, et al, JBMR 16 (Suppl 1), 2001
VERT-NA: Risedronate PatientVERT-NA: Risedronate Patient
0
1
2
3
4
5
6
0 6 12 18 24 30 36
Months
% change from baseline
Placebo
Ris 5.0mg
-1
0
1
2
3
4
5
6
7
8
0 6 12 18 24 36
Months
**pp < 0 .05 vs baseline < 0 .05 vs baseline †† pp < 0 .05 vs baseline & control < 0 .05 vs baseline & control
North American StudyNorth American Study
Lumbar Spine BMDLumbar Spine BMD
Multi-National StudyMulti-National Study
††
** * **
**
†† ††
††
††††
††
††††
††
††
36 month diff. = 7.1%36 month diff. = 7.1%
5mg. vs. baseline5mg. vs. baseline
36 month diff. = 5.3%36 month diff. = 5.3%
5mg. vs. baseline5mg. vs. baseline
Harris ST, et. al. JAMA. 1999;282(14):1344-52. Reginster JY, et al. Osteoporos Int. 2000;11:83-91.
Bisphosphonates: Contraindications and Warnings
Bisphosphonates: Contraindications and Warnings
• Contraindications– Hypocalcemia
– Known hypersensitivity to any component of this product
– Inability to stand or sit upright for at least 30 minutes
• Warnings– Bisphosphonates may cause upper gastrointestinal disorders such
as dysphagia, esophagitis, and esophageal or gastric ulcer
.
Monthly Cost of Osteoporosis DrugsMonthly Cost of Osteoporosis Drugs
Fosamax 70mg qweek 65.99 Actonel 35mg qweek 63.99 Evista 60mg qd 77.99 Miacalcin 200IU nasal spray qd 81.59 Forteo 20 mcg SC injection qd 539.99 Premarin 0. 3 qd 29.99 Prempro 0.3/1.5 qd 35.99 Prempro 0.45/1.5 qd 36.99 Menostar 14mcg daily patch 45.99
(Data from www.drugstore.com)
Women’s Health InitiativeWomen’s Health Initiative
• Estrogen + Progestin arm – stopped 5/31/02– Follow-up mean 5.2 years– Absolute excess risks per 10000 person years
• 7 more CHD
• 8 more CVA
• 8 more Pulmonary embolism
• 8 more invasive breast cancers
– Absolute risk reduction per 10000 person years• 6 fewer colorectal cancers
• 5 fewer hip fractures
HRT
• When prescribing solely for the prevention of postmenopausal osteoporosis HRT should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered
• Patients should be treated with the lowest effective dose. Generally women should be started at 0.3 mg/1.5 mg PREMPRO daily
• Dosage may be adjusted depending on individual clinical and bone mineral density responses
Combination TherapyCombination Therapy
• Bisphosphonate + HRTBisphosphonate + HRT– Combination increases BMD > either agent alone Combination increases BMD > either agent alone
• Harris ST, et.al. Harris ST, et.al. J Clin Endocrin Metab.J Clin Endocrin Metab. 2001;86:1888-1889 2001;86:1888-1889 • Lindsay R, et al. Lindsay R, et al. J Clin Endocrin Metab.J Clin Endocrin Metab. 1999;84:3076-3081 1999;84:3076-3081• Emkey R et al. Abstract from 63rd Annual ACR Scientific Emkey R et al. Abstract from 63rd Annual ACR Scientific
Meeting Nov 1999Meeting Nov 1999
• Bisphosphonate + RaloxifeneBisphosphonate + Raloxifene– Combination increases BMD > either agent aloneCombination increases BMD > either agent alone
• Stock, Johnell, Scheele, et al. Presented at 63rd annual Stock, Johnell, Scheele, et al. Presented at 63rd annual Scientific Meeting of ACRScientific Meeting of ACR
• No fracture dataNo fracture data
Recently Approved
• Boniva – 150 mg monthly– 2.5 mg daily approved May, 2003– Vertebral fracture efficacy shown with daily– Based on 1 year BMD data, 150 mg monthly is
superior to the 2.5 mg daily – 60 minute post dose fast, not 30 minute
• Fosamax PLUS D – 70 mg/2800 IU weekly
SummarySummary
• All postmenopausal women All postmenopausal women should be evaluated for should be evaluated for osteoporosis risk factorsosteoporosis risk factors
• Bone density testing is the Bone density testing is the best predictor of fracture riskbest predictor of fracture risk
• Treatment should be initiated Treatment should be initiated to prevent osteoporotic to prevent osteoporotic fractures and their subsequent fractures and their subsequent morbiditymorbidity