Osteoporosis

Training Course in Sexual and Reproductive Health Research

Geneva, February 17 2009

Prof René Rizzoli M.D.

Division of bone diseases

WHO collaborating center for osteoporosis prevention

Department of rehabilitation and geriatrics

Geneva university hospitals and Faculty of medicine

Geneva, Switzerland

A systemic skeletal disease characterized

by low bone mass and

microarchitectural deterioration, with a

consequent increase in bone fragility with

susceptibility to fracture.

Osteoporosis Definition

Consensus Development Conference: Am J Med 1991;90:107-110

Osteoporosis:

a 2-Stage Disease

•With

•Without Fracture

Osteoporosis:

Lecture Content

•Disease Definition

•Epidemiology

•Burden

•Diagnosis

•Pathophysiology

•Management

0

5

10

15

20

25

30

Women Men Women Men Women Men

Age Group (Years)

Minor Fractures

Other Major Fractures

Vertebral Fractures

Proximal Femur Fractures

60–69 70–79 > 80

Center J et al. Lancet. 1999;353:878–882.

Fractures by Age and GenderDubbo Osteoporosis Epidemiology Study, 1989–

1994

Lifetime risk of fragility fracture in the

Swedish population at the age of 50 years (%)

Women Men

• Proximal femur 23 11

• Distal forearm 21 5

•Vertebral (clinical) 15 8

•Proximal Humerus 13 5

• Any 46 % 22 %

From Kanis et al 2000

(Switzerland 51 % 20 %)

1 500 000 *

0

500

1000

1500

2000

Osteoporotic

Fractures

Riggs BL, Melton LJ. Bone. 1995.

Heart and Stroke Facts. 1996. American Heart Association.

Cancer Facts & Figures. 1996. American Cancer Society.

*annual incidence all ages

† annual estimate women 29+

‡annual estimate women 30+

§1996 new cases,all ages

513 000 †

228 000 ‡ 184 300 §750 000vertebral

250 000 other sites

250 000forearm

250 000hip

An

nu

al

incid

en

ce x

1000

Heart

AttackStroke Breast

Cancer

Osteoporotic Fractures in Women:

Comparison With Other Diseases

Projected burden of osteoporotic

hip fractures worldwide

0

200

400

600

800

North

America

Europe Latin

America

Asia

1950

2050

3250

Estimated n°of hip

Fractures (1000s)

Number of hip fractures: 1990: 1.66 million; 2050: 6.26 million

Adapted from Cooper C., Melton U, Osteoporosis Int 2:285-289, 1992

If the prevalence of hip fracture continues

to rise at current rates, it may well be that

in the next few decades, orthopaedists

will do little else but treat this problem.

W. C. Hayes, In: Bone Formation and Repair

(American Academy of Orthopaedic Surgeons) 1994

Burden

Degree of dependence

50 70 80 9060

normal

aging

Forearm

fracture

Vertebral

fracture

Hip fracture

Age (years)

Morbidity After Vertebral Fractures

• Back pain

• Loss of height

• Deformity (kyphosis, protuberant abdomen)

• Reduced pulmonary function

• Diminished quality of life: loss of self-esteem,

distorted body image, dependence on narcotic

analgesics, sleep disorder, depression, loss of

independence

A Fragility Fracture -> Fracture

A dangerous vicious circle

New fracture

First fracture

Inactivity

Social

isolation

DepressionPain

Loss of

autonomy

Low bone mass

Mortality after Major Types of

Osteoporotic Fracture

in Men and Women: an Observational StudyCenter et al, Lancet 1999

5 - Year Prospective Cohort Study

Age-Standardized Mortality Ratio

Fracture Women Men

Proximal Femur 2.2 3.2

Vertebral 1.7 2.4

Other Major 1.9 2.2

Other Minor 0.8 1.5

Time after hip fracture (years)

2 4 6 8 10

0.00

0.25

0.50

0.75

1.00

Hip fractured Women

Hip fractured Men

Women

Men

Su

rviv

al p

rob

ab

ilit

y

Expected survival in the the general population

Survival after Hip FractureTrombetti et al, Osteoporos Int 2002

0 1000 2000 3000 4000

Osteoporosis

Ischemic Heart Diseases

Chronic Obstructive Pulmonary Diseases

Osteoarthritis

Alzheimer’s

Cirrhosis

Asthma

Migraine

Hypertensive Heart Disease

Rheumatoid Arthritis

Peptic Ulcer

Parkinson’s

Multiple Sclerosis

Benign Prostatic Hyperplasia

Johnell & Kanis, Osteoporos Int 2006 Disability-Adjusted Life-Years (DALYs) Lost

Disability-Adjusted Life-Years Lost because of

Non-communicable Diseases in Europe

Osteoporosis Results in More Cost than

Many Other Diseases

Number of bed days (men and women)

• 701,000 for osteoporosis

• 891,000 for COPD

• 533,000 for stroke

• 328,000 for myocardial infarction

• 201,000 for breast cancer

Lippuner et al. Osteoporosis Int 1997; 7: 414-25

Osteoporosis

# 1 when

looking at

women only

Diagnosis

X-ray techniques

DXA

pQCT

pDXA

Io

I

DXA: Principle

• Two attenuation profiles:

Low energy X-ray attenuation

High energy X-ray attenuation

• Multiply high energy profile by ‘k’ factor (ratio of soft tissue attenuation at low- & high-energy)

• BMD along scan = Low-energy profile - k-corrected high energy profile

0

2

4

6

8

10

12

I II III IV

BMD & Hip fracture

BP & stroke

Cholesterol & MI

Gradients of risk

Relative risk

Quartile

Noninvasive Measurement

of Bone Mineral Mass

Technique Site Precision Cost Response

to Therapy

SXA Forearm ++ ± ±

Heel

DXA Spine ++ + ++

Hip + + +

Tot. Body ++ + ±

QCT Spine ± ++ +

Forearm ++ +(+) ±

US Heel ± - -

+ Fingers

Medicare Coverage for BMD Tests

Procedure Site Fee Schedule

Medicare *

DXA Axial $ 128

pDXA Appendicular $ 40

RX Absorptiometry Appendicular $ 38

QUS Appendicular $ 53

SXA Appendicular $ 40

QCT Axial $ 185

pQCT Appendicular $ 40

* Medicare Allowable Charge = 80% of the Costs

JAMA 288:1889-1897,2002

Example for T-score = - 2.0, 60 year old

and Z-Score = - 0.5

20 40 60 80 100

1.20

0.96

0.84

0.72

1.08

1.32

BM

D g

/cm

2

Spine: L1-L4

Age

Z

T-Score

0

-1

-2

-3

+1

-4

T

T-score

Normal -1

Osteopenia < -1 and > -2.5

Osteoporosis -2.5

SevereOsteoporosis

-2.5 with Fracture

Diagnosis of Osteoporosis Using Central DXA

WHO-Definition

Mainly for Spine and Hip in Women

Pathophysiology

Osteoporosis Pathogenesis and Management

Fracture

Fracture Treatment

Rehabilitation

-> To Restore Independence

-> To Reduce Disabilities

Prevention Subsequent Fracture

Osteoporosis Pathogenesis and Management

Fracture

Fracture Treatment

Mechanical Incompetence

Osteoporosis

Low Peak Bone Mass

Sex Hormone Deficiency

Age

Nutritional Insufficiency

Rehabilitation

-> To Restore Independence

-> To Reduce Disabilities

Prevention Subsequent Fracture

Osteoporosis Pathogenesis and Management

Fracture

Fracture Treatment

Mechanical Overload Mechanical Incompetence

Falls

Sway

Walking

Muscle Strength

Neuro-muscular Impairment

Osteoporosis

Low Peak Bone Mass

Sex Hormone Deficiency

Age

Nutritional Insufficiency

Rehabilitation

-> To Restore Independence

-> To Reduce Disabilities

Prevention Subsequent Fracture

Determinants of Fracture Risk

1.Age

2. Prevalent Fracture

3. Family history of Fracture

4. Glucocorticoid

5. Low BMI

6. Alkohol, Smoking

7. Baseline BMD

8. Baseline Turnover

Type I collagen epitopes and

Cathepsin K cleavage sites

N C

a2 (I) JYDGKGVG GPP-SAGFDFSFLPQPPQ EKAHDGGR a 1

NTX CTXICTP

CK CK CK CK

CK CK

Garnero et al., JBC, 1998

Sassi et al., Bone, 2000

Deoxypyridinoline

Pyridinolines

Age (years)

10 20

Tracking of Bone Mineral MassB

on

e M

inera

l M

ass

50 90

Fracture

Risk

A

B

10 20 40 70Age:

Rizzoli et al.,J Mol Endocrinol 2001

Peak Bone Mass

HeredityGender

Hormones

Nutrition

Risk Factors

Mechanical

Forces

• Resting

• Resorption

• Formation

• Reversal

•Coupled and balanced

•Uncoupled and imbalanced

•Coupled but imbalanced

•Uncoupled but balanced

MALNUTRITION IN ELDERLY

Calcium Deficiency

- > PTH - > Bone Resorption

Vitamin D Deficiency

OSTEOPOROSIS

- > IGF-1

Protein Deficiency - > Bone Formation

- > Sensitivity

to IGF-1

Management

•Indication to treatment

•Treatment possibilities

–4 –3 –2 –1 0 1 2 3

BMD (SD units)

Su

bje

cts

Nu

mb

er

Osteoporosis Preventive Strategies

Present Situation

Whole Population

Modification

Target very

High Risk

Higher Risk

Population

Modfication

0

10

20

30

40

50

60

70

0 -1 -2 -3

T-score

0 -1 -2 -3

None

Prior fracture

+Glucocorticoids

+Family history

Men Women

US Caucasian, no CRF, BMI=24 *Hip, spine, humerus, forearm

Probability of osteoporotic

fracture* at age 65

10-year probability (%)

06ca106 FRAX

Patient

65

65

165

-2.5

23.9

8.0

24

Age

10-Year Risk:

50%

40%

30%

20%

°

°

10%

2

1

General Management

•Treatment of any Disease Causing Bone Loss

•Ensure Dietary Calcium Intake ≥ 1000 mg /d

•Ensure Adequate Dietary Protein Intake

•Correct or Prevent Vitamin D Insufficiency (800 IU/d)

•Promote Weight-Bearing Physical Exercise

•Reduce Falling Risk

•Reduce Fall Consequences (Hip Protectors)

Risk Factors Associated with Falls

1. Impaired Mobility, Disability

2. Impaired Gait and Balance

3. Neuromuscular or Musculoskeletal Disorders

4. Age

5. Impaired Vision

6. Neurological, Heart Disorders

7. History of Falls

8. Medication

9. Cognitive Impairment

After Myers et al., Bone 1996

The Hip Protector

Hip Fracture Prevention

•RCT in Community: No

•RCT in Nursing Homes:

Cluster Random.: Yes

Individual Random.: No

Left vs Right: No

•Problems

Compliance

Persistence

Therapeutic Agents Used in Osteoporosis

Anticatabolic

Agents

Anabolic

Agents

•Estrogens ± Progestagens

•SERMs

•Bisphosphonates

•Calcitonin

•Calcium

•Denosumab

•(Fluoride)

•Parathyroid Hormone

Complex Action•Vitamin D and Derivatives

•Anabolic Steroids

•(Ipriflavone)

•Tibolone

Mixed Action•Strontium Ranelate

H. Bischoff-Ferrrari et al JAMA 2004

Vitamin D and Risk of Falling

WHI Study,

Cauley et al, 2003

Hormone Replacement Therapy and Fracture Risk

Hip

Vertebral

All Fractures

Placebo

HRT

Women’s Health Initiative - First randomized, controlled trial in women

(50-79 years) treated with HRT

6700 women with 5.2 years of follow-up

-37% -34% -34%

+29% +26%+41%

+112%

-80

-40

0

40

80

120

160

Inte

sti

nal can

cer

Dif

fere

nce %

vs. p

laceb

o

Vert

eb

ral fr

actu

re

Hip

fra

ctu

re

Card

iovascu

lar

dis

eases

Str

ok

e

Bre

ast

can

cer

AdvantagesTro

mb

. ven

ou

s

Disadvantages

Manson JE at al, N Engl J Med, 2003;349:523-534

* with prev vert fracture(s) ** without prev vert fractures *** with or without prev vert fractures

Vertebral Fx

0.6 1.00.2

RLX 60 (MORE)*

RLX 60 (MORE)**

CT 200 (PROOF)*

Teriparatide 20µg*

ALN 5/10 (FIT1)*

ALN 5/10 (FIT2)**

RIS 5 (VERT-NA)*

RIS 5 (VERT-MN)*

Strontium ranelate(SOTI)*

Strontium ranelate

(SOTI +TROPOS)**

Update from Delmas 2002

IBAN 2.5 ***IBAN inter

Anti -fracture efficacy (RR ± 95% CI)

ZOL

* with prev vert fracture(s) ** without prev vert fractures *** with or without prev vert fractures

0.6 1.00.2

Non-Vertebral Fx

RLX 60, 120

(MORE)***

CT 200 (PROOF)*

Teriparatide 20µg*

ALN 5/10 (FIT1)*

ALN 5/10 (FIT2)**

RIS 5 (VERT-NA)*

RIS 5 (VERT-MN)*

RIS 2.5/5 (Hip Study)***

Vertebral Fx

0.6 1.00.2

RLX 60 (MORE)*

RLX 60 (MORE)**

CT 200 (PROOF)*

Teriparatide 20µg*

ALN 5/10 (FIT1)*

ALN 5/10 (FIT2)**

RIS 5 (VERT-NA)*

RIS 5 (VERT-MN)*

Strontium ranelate(SOTI)*

Strontium ranelate

(SOTI +TROPOS)**

Strontium ranelate

(TROPOS)***

Strontium ranelate

(SOTI)*

Update from Delmas 2002

IBANIBAN 2.5 ***

IBAN inter

Anti -fracture efficacy (RR ± 95% CI)

ZOLZOL

* with prev vert *** with or without prev vert fractures

0.6 1.00.2

Hip Fx

RLX 60, 120

(MORE)***

CT 200 (PROOF)*

Teriparatide 20µg*

ALN 5/10 (FIT1)*

ALN 5/10 (FIT2)**

RIS 5 (VERT-NA)*

RIS 5 (VERT-MN)*

RIS 2.5/5 (Hip Study)***

Strontium ranelate

(TROPOS)***

Strontium ranelate

(SOTI)*

IBAN

Anti -fracture efficacy (RR ± 95% CI)

Significant hip fracture risk

Reduction: 3 studies

Only studies with

preplanned analysis:

RIS 2.5/5 (Hip Study)

ZOL 5 mg (Horizon Study)

ZOL

Bisphosphonate New Schedules of Administration

1. Weekly (Alendronate, Risedronate)

-> Monthly Oral Administration - Ibandronate

- Risedronate

2. Trimonthly Intravenous Administration - Ibandronate

3. Annual Intravenous Administration - Zoledronate *

4. Sequential Regimen (PTH -> ALN, RIS or ALN -> PTH)

*: Fracture Data

Mechanism of Action of Denosumab

Activated

Osteoclast

CFU-M

Pre-Fusion

Osteoclast

Multinucleated

Osteoclast

BONE

Growth Factors

Hormones

Cytokines

RANK

Denosumab

RANKL

OPG

ASBMR 2008 - D’après Cummings S.R. et al., San Francisco, États-Unis, abstract 1286,

Placebo

Denosumab

0

0,5

1

1,5

2

2,5

3

3,5

Year 10-1

Year 21-2

Year 32-3

2,2 %

0,9 %0,7 %

3,1 % 3,1 %

1,1 %

Inc

ide

nc

e (

%)

61 %p < 0,0001

78 %p < 0,0001

65 %p < 0,0001

Reduction in vertebral fracture risk

Phase III Trial on the Effects of Denosumab on

Vertebral Fracture Risk in Women with

Postmenopausal Osteoporosis

0 6 12 18 24 30 36

0

0,5

1,0

1,5

2,0

Cu

mu

lati

ve

In

cid

en

ce

(%

)

Months

Placebo

Denosumab

0,7 %

1,2 %

40 %

p = 0,036IC95 : 3-63

Hip Fractures

Hip Fracture : 69

Non-Vertebral Fractures

Placebo

Denosumab 8,0 %

6,5 %

0 6 12 18 24 30 36

Months

0

2

4

6

8

10

20 %

p = 0,011IC95 : 5-33

Cu

mu

lati

ve

In

cid

en

ce

(%

)

ASBMR 2008 - D’après Cummings S.R. et al., San Francisco, États-Unis, abstract 1286,

No-Vertebral Fractures : 531

Phase III Trial on the Effects of Denosumab on

Non-Vertebral Fracture Risk in Women with

Postmenopausal Osteoporosis

Osteoporosis Treatment in 2009

Summary

•HRT: spine fx; hip fx

• SERMS: spine fx; no effect on peripheral fx

•Calcitonin: possible spine fx; no hip data

• Alendronate: spine fx; hip fx

•Risedronate: spine fx; hip fx

• Ibandronate: spine fx; no effect on hip

• Zoledronate: spine fx; hip fx

• PTH: spine fx

• Strontium Ranelate: spine fx; hip fx

•Denosumab: spine fx; hip fx

BISPHOSPHONATES

CALCIUM

Vit D (if deficient)

•Advancing age

•Lower BMD

•Presence of Fracture

•Risk factors or disease

causing continued

bone loss

•Leanness

•Family history

Factors Influencing

Treatment

DecisionHRT

RALOXIFENE

50 55 60 65 70 75

No Normal

Treatment

Yes, if fx

OsteoporosisIncreasing

need to

treat

Older

Lower

BMD

80

Osteopenia- 2.5 SD

- 1.0 SD

BMD

T score

Yes

Adapted from

E. Seeman

(2004)

PTH

STRONTIUM RANELATE

≠ Treatment of

Osteoporosis

= Treatment of Patients

with Osteoporosis

1. Aim of Therapy

2. Never Too Late

Fractures are not Unavoidable Expenses to Pay

as a Consequence of Increased Life-Expectancy

Because of

•Better Identification of Risk Factors for Osteoporosis

•Early Diagnosis, before the First Fracture

•A Larger Use of Preventive and Therapeutical Strategies,

whose Efficacy has been Demonstrated in Randomized

Controled Trials, with Fracture Incidence as Primary End-

Point

Bazedoxifene significantly reduces the risk of new vertebral fracture in postmenopausal women with osteoporosis

ASBMR 2007 – From Silverman SL et al., Beverly Hills, USA, abstract 1206, updated

Incidence of new vertebral fracture (intent-to-treat population 0-36 months)

0 6 12 18 24 30 36 42

Months

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Kapla

n-M

eie

r (K

-M)

fra

ctu

re r

ate

(%

)

Bazedoxifene 20 mgBazedoxifene 40 mgRaloxifene 60 mgPlacebo

*

* p < 0.05 for any active group versus placebo

• Results

– the reduction in the incidence of new

vertebral fractures was (as compared to

placebo)

• - 42% in group I

• - 37% in group II

• - 42% in group III

– there was no treatment effect on NVF

– there was no difference between the

different groups with regard to adverse

effects

Effect of Bazedoxifene on Vertebral Fracture in Postmenopausal Women with Osteoporosis

Long-Term Vertebral and Non-vertebral FractureRisk Reduction with Strontium Ranelate

Favors Strontium ranelate

RELATIVE RISKS AND 95% CI

RR

Over 5 years

0 0.5 1 1.5

- 24% P<0.001Vertebral fractures

- 15%

P=0.025- 18%

Non vertebral fractures P=0.032

Major non vertebral fractures

P=0.010- 31% Vertebral fractures, 80 years

P=0.019- 26% Non-vertebral fractures, 80 years

Reginster et al 2007

Pathogenesis of Osteoporotic Fracture

LOW PEAK

BONE MASSAGE-RELATED

BONE LOSS

POSTMENOPAUSAL

BONE LOSS

LOW BONE

MASSOther risk

factors

Nonskeletal factors

(propensity to fall) FRACTUREPoor bone quality

(architecture)

Boonen, Lips et al., unpublished observations

Hip Fracture Risk – Vitamin D & CalciumVersus Placebo/No Treatment

Source

Pooled Estimate

Dawson-Hughes et al. 1997

Chapuy et al. 2002

Porthouse et al. 2005

0.36 (0.02-8.78)

0.62 (0.36-1.07)

1.14 (0.76-1.73)

0.71 (0.31-1.64)

0.82 (0.71-0.94)

FavorsTreatment

FavorsPlacebo

Weight(%)

Relative Risk

(95% CI)

0.1 0.5 1.0 1.5 2.0

0.2%

6.5%

2.8%

10.9%

100.0%

Relative Risk (95% CI) of Hip

Fracture

RECORD Trial Group 2005

0.88 (0.72-1.07)40.7%

Chapuy et al. 1994 0.74 (0.60-0.91)38.9%

WHI Trial Group, 2006

P=0.0005

Bo

ne M

inera

l M

ass

Age (years)

10 20

Tracking of Bone Mineral Mass Accrual