OsteoporosisOsteoporosis

Natasa Janicic M.D.Assistant Professor

Georgetown University Hospital

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

9

OsteoporosisOsteoporosis

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

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 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