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
84 year old Female
52 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 Hormones
Resting Activation

AcF
Resorption
Bone Howship’s Bone
lacuna osteoclasts
BMU
Reversal
BioMarkers
Formation

osteoblasts BMU Balance

Bon Bone
e

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
2,000,000
Annual Incidence

1,500,000 1,200,0001

1,000,000
513,0002
500,000 228,0002 184,3003

0
Osteoporotic Heart Stroke Breast
Fractures Attack Cancer
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.
 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
• Risk of fracture increased with the number of baseline fractures

30
25 *
% of Patients

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
Normal
< –1
Osteopenia (low bone mass)
–1 to –2.5
Osteoporosis
–2.5 or greater
Severe or established osteoporosis
–2.5 or greater +
fx(s)

T score indicates the # of SDs below or above the average peak bone mass in young adults
 One-Minute Treatment Decision
Therapy Decision T-Score *
Treat all patients with
an existing fracture
High Risk- Below -2.0
Treat

Moderate Risk - -1.5 to -2.0

Treat if other risk factors

Above -1.5
Low Risk-
Check 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 20
27.3
Hip Fracture/
1000 15
Woman-Years 14.7
10 9.4
5
5
3-4 Number of
0 0-2 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 Women with fractures
Men controls Men with fractures
450
400
Mortality (deaths/1,000

350
person-years)

300
250
200
150
100
50
0
60-69 70-79 80 and older

Center et al. Lancet 1999.

 Diseases Associated with
Decreased Bone Mass
• Hypogonadism • Malabsorption
• Hypercortisolemia – Celiac Sprue
• – Surgical
Hyperthyroidism
• Hyperparathyroidism • Inflam. Bowel Dz
• Anorexia • Pregnancy
• Renal Failure • Type 1 Diabetes
• Chronic Liver Disease • HIV
 Medications associated with
Decreased Bone Mass
• Corticosteroids • Cyclosporine
• Heparin (high dose) • Prograf
• Aluminum • Aromatase inhibitors
• Anticonvulsants • Antiretroviral therapy
– phenobarbital, phenytoin • Retinoids
• Medroxyprogesterone
acetate
 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

Prevention Treatment
HRT Yes No
Raloxifene Yes Yes
Calcitonin No Yes*?
Alendronate Yes Yes
Risedronate Yes Yes
PTH No 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
36 month diff. = 5.3% *p < 0 .05 vs baseline 36 month diff. = 7.1%
5mg. vs. baseline
†
p < 0 .05 vs baseline & control 5mg. vs. baseline
% change from baseline

6
† †
† 8
†
5 † 7 †
† 6
4 †
5 †
† Placebo
3 4 †
Ris 5.0mg
2 3
* * * 2 *
1 * * *
1
0 0
0 6 12 18 24 30 36 -1 0 6 12 18 24 36
Months Months
North American Study Multi-National Study
Harris ST, et. al. JAMA. 1999;282(14):1344-52. 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 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 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