Transcript Metabolic Bone Disease and Osteoporosis

Osteoporosis
Natasa Janicic M.D.
Assistant Professor
Georgetown University Hospital
Osteoporosis
• The most common metabolic bone disorder
• Systemic skeletal disease characterized by:
– Low bone mass
– Microarchitectural deterioration of bone tissue
– Increased bone fragility and susceptibility to fracture
3-D Micro CT:
Healthy vs Osteoporotic Bone
52 year old Female
84 year old Female
(w/ vertebral fracture)
Borah et al Anat. Rec.(2001)
Pathophysiology of Osteoporosis
• Bone remodeling occurs throughout an individual’s
lifetime
• In normal adults, the activity of osteoclasts (bone
resorption) is balanced by that of osteoblasts (bone
formation)
• With the onset of menopause (mid-forties or fifties),
diminishing estrogen levels lead to excessive bone
resorption that is not fully compensated by an
increase in bone formation
Bone Remodeling
BioMarkers
Resting
Bone
Hormones
Activation
Howship’s
lacuna
BMU
Resorption
AcF
Bone
osteoclasts
Reversal
BioMarkers
Formation
osteoblasts
Bon
e
BMU Balance
Bone
Osteoid
Mineralization
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?
To Prevent Fractures
• 1.5 million fractures/yr
• $10 billion direct costs
• 300,000 hip fractures/yr
– 20% die
– 25% confined to long-term care facilities
– 50% long-term loss of mobility
Why Recognize & Treat Osteoporosis?
To Prevent Fractures
• Less than 5% of hip fractures
are evaluated for
osteoporosis!
(NIH Health report, 2001)
Osteoporosis
9
Osteoporotic Fractures in Women
Compared With Other Diseases
Annual Incidence
2,000,000
1,500,000
1,200,0001
1,000,000
513,0002
500,000
228,0002
184,3003
Stroke
Breast
Cancer
0
Osteoporotic
Fractures
1
Heart
Attack
National Osteoporosis Foundation, 2002. Available at: http://www.nof.org.
Heart Association. Heart & Stroke Facts: 1999 Statistical Supplement.
3 American Cancer Society. Breast Cancer Facts & Figures 1999-2000.
2 American
Risk of Another Vertebral Fracture Is Higher
in the Year Following a New Fracture
• Overall, 20% fractured again within the year following a new fracture
% of Patients
• Risk of fracture increased with the number of baseline fractures
30
25
20
15
10
5
0
*
Overall
0
1
2+
Number of Baseline Vertebral Fractures
*p<0.05, vs patients with no prevalent vertebral fractures (12-fold increased risk).
Lindsay R, et al, JAMA. 2001;285:320-323.
Postmenopausal Osteoporosis
• Who to Treat
• When to Treat
• What Therapy
• For How Long
National Osteoporosis Foundation
Guidelines for Bone Density Testing
• All women aged 65 or older
• All postmenopausal women under age 65
who have one or more additional risk factors
• Postmenopausal women who present with
fractures
• USPSTF makes no recommendation for or
against routine screening in women under
age 60
www.nof.org
WHO Criteria for Diagnosis
T score*
Classification
< –1
–1 to –2.5
Normal
–2.5 or greater
Osteopenia (low bone mass)
–2.5 or greater +
fx(s)
Osteoporosis
Severe or established
osteoporosis
*T score indicates the # of SDs below or above the average peak bone mass in young adults
One-Minute Treatment Decision
Therapy Decision
Treat all patients with
an existing fracture
High RiskTreat
Moderate Risk Treat if other risk factors
T-Score *
Below -2.0
-1.5 to -2.0
Above -1.5
Low RiskCheck again in 1-2 years
National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis.
Belle Mead, NJ: Excerpta Medica, Inc.; 1998.
Combined Effect of Bone Density
and Risk Factors
30
25
Rate of
Hip Fracture/
1000
Woman-Years
20
27.3
15
14.7
10
9.4
5
3-4
0-2
5
0
Number of
Risk Factors
Lowest Third Middle Third Highest Third
Bone Density
Cummings SR et al. N Engl J Med. 1995;332:767-773.
Mortality Associated with Fracture
Women controls
Men controls
Women with fractures
Men with fractures
Mortality (deaths/1,000
person-years)
450
400
350
300
250
200
150
100
50
0
60-69
Center et al. Lancet 1999.
70-79
80 and older
Diseases Associated with
Decreased 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 with
Decreased Bone Mass
•
•
•
•
Corticosteroids
Heparin (high dose)
Aluminum
Anticonvulsants
– phenobarbital, phenytoin
• Medroxyprogesterone
acetate
•
•
•
•
•
Cyclosporine
Prograf
Aromatase inhibitors
Antiretroviral therapy
Retinoids
Glucocorticoid-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:
Goals of Therapy
• Prevent first fragility fracture or future
fractures if one has already occurred
• Stabilize/increase bone mass
• Relieve symptoms of fractures and/or
skeletal deformities
• Improve mobility and functional status
• Initiate lifestyle changes to enhance
prevention of fractures
NOF 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 osteoporosis
HRT
Raloxifene
Calcitonin
Alendronate
Risedronate
PTH
Prevention
Yes
Yes
No
Yes
Yes
No
Treatment
No
Yes
Yes*?
Yes
Yes
Yes
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.
Relative Risk Reduction of Vertebral
Fractures in 3-Year Studies:
Risedronate 5 mg/d vs Placebo
VERT 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*
* 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.
VERT-NA: Placebo Patient
Trabecular
thinning
Baseline
3 Years
Increased perforation
Borah, et al, JBMR 16 (Suppl 1),
VERT-NA: Risedronate Patient
Baseline
3 Years
Similar thickness of trabeculae and number of perforations
Borah, et al, JBMR 16 (Suppl 1), 2001
Lumbar Spine BMD
% change from baseline
36 month diff. = 5.3%
5mg. vs. baseline
6
†
5
†
*p < 0 .05 vs baseline
† p < 0 .05 vs baseline & control
†
†
†
4
†
3
2
*
1
* *
*
*
0
0
6 12 18 24 30 36
Months
North American Study
Harris ST, et. al. JAMA. 1999;282(14):1344-52.
8
7
6
5
Placebo
4
Ris 5.0mg
3
2
1
0
-1 0
36 month diff. = 7.1%
5mg. vs. baseline
†
†
†
†
†
*
6
12
18
24
*
36
Months
Multi-National Study
Reginster JY, et al. Osteoporos Int. 2000;11:83-91.
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 Drugs
Fosamax 70mg qweek
Actonel 35mg qweek
Evista 60mg qd
Miacalcin 200IU nasal spray qd
Forteo 20 mcg SC injection qd
Premarin 0.3 qd
Prempro 0.3/1.5 qd
Prempro 0.45/1.5 qd
Menostar 14mcg daily patch
(Data from www.drugstore.com)
65.99
63.99
77.99
81.59
539.99
29.99
35.99
36.99
45.99
Women’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 Therapy
• Bisphosphonate + HRT
– Combination increases BMD > either agent alone
• Harris ST, et.al. J Clin Endocrin Metab. 2001;86:1888-1889
• Lindsay R, et al. J Clin Endocrin Metab. 1999;84:3076-3081
• Emkey R et al. Abstract from 63rd Annual ACR Scientific
Meeting Nov 1999
• Bisphosphonate + Raloxifene
– Combination increases BMD > either agent alone
• Stock, Johnell, Scheele, et al. Presented at 63rd annual
Scientific Meeting of ACR
• No 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
Summary
• All postmenopausal women
should be evaluated for
osteoporosis risk factors
• Bone density testing is the
best predictor of fracture risk
• Treatment should be initiated
to prevent osteoporotic
fractures and their subsequent
morbidity