garvan institute of medical research osteoporosis treatment: why, who, what & when ? john a...

Garvan Institute of Medical Research

Osteoporosis Treatment:Why, Who, What & When ?

John A Eisman AOMB BS PhD FRACP

Director, Bone and Mineral Research Program,Garvan Institute of Medical Research;Endocrinologist, St Vincent's Hospital;

Professor (Conjoint), University of New South Wales

Consulting and Research Support fromAmgen, deCode, Eli Lilly, GE-LUNAR, Interleukin Genetics, Merck Sharp and Dohme,

Novartis, Organon, Roche-GSK, sanofi-aventis, Servier, WHOHo Chi Minh City, July 2008


OsteoporosisA major health care problem

OsteoporosisA major health care problem

In Australia >1 in 2 older women and 1 in 3 older menwill have an osteoporotic fracture during their lifetime 1-3

Mortality increased 2-3 fold in men and women

after all types of Osteoporotic fractures 4,5

Major & increasing impact on well-being, mortality 3,6

& health care costs 1,7 1 Randell 1995, 2 Nguyen 2005, 3 Sanders 1999, 4 Center 1999, 5 Bliuc 2007,

6 Australian Consensus Statement 1997, 7 Access Economics 2000


Osteoporosis CostsOsteoporosis Costs

Affects 8 million Women and 2.5 million Men in USA Expected to increase by about 40% by 2020 1

Direct costs in US in 2001 = $ 12 - 17 billion annually estimated 1 $32 - $47 million every single day

Direct + Indirect costs in Australia of $7 billion annually estimated 2

AUD 19 million every single day

AUD $1/day for every person in Australiaevery single day

1 US Surgeon-Generals Report2 Access Economics

Hip Fracture Worldwide Projections Hip Fracture Worldwide Projections

Gullberg, Johnell & Kanis 1997

Osteoporosis Int 7:407-13

0

200

400

800

1990 2025 2050

All Europe

Asia

Africa

N America

Latin America

Oceania

Hip fractures

1000/yr

in 80+ yr olds

2008


Osteoporosis prevalence & therapyin primary care

Osteoporosis prevalence & therapyin primary care

52,780 of 88,040 postmenopausal women from 927 Australian GPs

29% at least 1 fracture post-menopause 1

< 20% on any osteoporosis-specific treatment

1829 women & men with low trauma fractures

from 16 Public hospitals around Australia 2

< 10% investigated & < 10% initiated on specific Rx

Of 37,957 GP patients (71 yrs), 12.6% had prior fracture & 30% prior spine # 3

Specific therapy in 29.7% with any # & 12.6% with prior spine #

1 Eisman et al, 2004 JBMR 19:1969-752 Teede et al, 2007 Int Med J 37:674-9

3 Sambrook et al, OI 2008 (Epub)


Osteoporosis: Scope of the ProblemOsteoporosis: Scope of the Problem

• Common in men as well as women

• Onset relatively early in older years

•Any fracture signals major increase in risk

• Major impact on morbidity, costs and mortality

• Majority at high risk,even after an osteoporotic fractures,

are not treated to reduce risk of future fractures


Osteoporotic fractures by site in Dubbo: 1989-2000

Womenn = 809809

Menn = 306306

13 Clavicle/Sternum

58 Proximal Humerus

52 Rib

13 Distal Humerus

201 Spine156 Forearm/Wrist

22 Hand

175 Hip

41 Distal Femur, KneeProximal Tibia

40 Ankle

33 Foot

716

52

1

7825

25

54

11

20

10

25 Pelvis

7

Chang et al, 2004JBMR 19:532-536


0

20

40

60

80

100

Women

60-69

Men Women

70-79

Men Women

80+

MenFirst Fracture

Re-Fracture

Age

Ris

k p

er 1

000

P-y

rs

Center et al (2007) JAMA 297:387-394

Absolute Risk of Subsequent Fracture Absolute Risk of Subsequent Fracture


0

5

10

15

20

25

30

35

Any Hip Major Minor

First Fracture Type

% o

f T

ota

l F

rac

ture

s

0

5

10

15

20

25

30

35

Any Hip Major Minor

First Fracture Type

Subsequent Fracture according to Initial Fracture

Women Men

HipMajorMinor

SubsequentFracture

Center et al (2007) JAMA 297:387-394


Osteoporosis-associated MortalityOsteoporosis-associated Mortality

Age-standardised mortality riskincreased 2-3 fold

after all types of osteoporotic fracture

Women Men

Proximal femur 2.2 3.2Vertebral 1.7 2.4Other major 1.9 2.2

Center et al, Lancet 1999


Standardized Mortality Ratio ofFirst and Subsequent Fractures Over Time


SMR2.5

3.1

1.2

0.6

0

1

2

3

4

Women Men

First fracture (0-5yr)

First fracture (>5yr)

Bliuc et al (2006) ANZBMS/IOF




SMR2.5

3.1

1.2

0.6

2.7

3.5

1.4

1.8

0

1

2

3

4

Women Men

First fracture (0-5yr)

First fracture (>5yr)

Subsequent fracture (0-5yr)

Subsequent fracture (>5yr)

Bliuc et al (2006) ANZBMS/IOF


Management of OsteoporosisManagement of Osteoporosis

• Public Health Approaches– Regular physical activity– Adequate calcium & protein intake– Avoid smoking, excessive alcohol intake– Minimise falls risk

• Low bone density– Personal aspects eg age and low weight– Family history– Corticosteroid use

• Prior low trauma fractures– Increased future fracture risk

clear cost-benefit for treatment


Management of OsteoporosisManagement of Osteoporosis

• Public Health Approaches– Regular physical activity– Adequate calcium & protein intake– Avoid smoking, excessive alcohol intake– Minimise falls risk

• Low bone density– Personal aspects eg age and low weight– Family history– Corticosteroid use

• Prior low trauma fractures– Increased future fracture risk

clear cost-benefit for treatment

Largely ignored

Limited access

Most untreated


Osteoporosis: Options for TherapyOsteoporosis: Options for Therapy

Age

Hormone therapy

Bisphosphonates Strontium ranelate

SERMs/tibolone

20 40 60 80

Vitamin DPTH

CalciumLife Style

Treatmentchoices

Bonedensity

Fracture risk


Calcium and Vitamin DCalcium and Vitamin D

Adequate calcium intake - dairy ± supplementsfor “optimal” peak bone health

Vitamin D deficiency commonin institutionalized-housebound

Current treatments validated ± calcium & vitamin D

Vitamin D and calcium insufficient alone


1 Rossouw & WHI, 2002 JAMA 288:321-332 Banks et al, 2004 JAMA 291:2212-20

Women’s Health Initiative 1

Hip fracture RR 0.66 (1/1,000 w.yr)

All fracture RR 0.76 (4/1,000 w.yr)

Million Women's Study and Fractures 2

All fracture RR 0.62 (0.58 - 0.66)(5/1,000 w.yr) irrespective of HRT type

Current users, rapid (≤ 1 year) onset and offset of benefit

Sex Hormone Therapy & FracturesSex Hormone Therapy & Fractures

MORE Trial - 4 YearsEastell et al 2000 JBMR 15:S229

% o

f W

om

en W

i th

I n

cid

ent

Ver

teb

ral

Fra

ctu

re

0

10

20

30

WITH Prevalent Vertebral Fractures

WITHOUT Prevalent Vertebral Fractures

RR 0.51(95% CI = 0.35, 0.73)

RR 0.66(95% CI = 0.55, 0.81)

Raloxifene 60 mg/d

Placebo

49%

34%

SERM Raloxifene & spine fractures SERM Raloxifene & spine fracturesSpine but not non-spine fracture risk reduction

Incidence of Invasive Breast CancerIncidence of Invasive Breast Cancer

Years in Study

0 1 2 3 4 5 6 7 80.0

1.0

2.0

3.0

4.0

HR 0.34 (95% CI = 0.22-0.50)

Placebo4.2 per 1000 Women-Yrs

Raloxifene1.4 per 1000 Women-Yrs

p <0.001

Cu

mu

lati

ve In

cid

enc

e (%

)

66%

8 Years of MORE plus COREMartino et al. J Natl Cancer Inst 2004;96:1751-61

7705 womenover 8 years


Bisphosphonate & Fracture ReductionBisphosphonate & Fracture ReductionSpine #

0

20

40

60

80

100

Wrist #

48%

Hip #

51%

Any #

28%

Symptomatic

55%

Multiple

90%

FractureReduction

%

Black et al, 1996 Alendronate Lancet 348:1535–1541

47%

Any

Non-spine #

Fracture reduction 50 30%

ALENDRONATEOnset of fracture risk reduction

Clinical Vertebral Fractures

0

5

10

15

0 6 12 18 24 30 36

MonthsP

erce

nt

of

Pat

ien

ts PLBALN

**

27%*

Black DM et al. J Clin Endocrinol Metab 2000;85:4118-24

Nonvertebral Fractures

0

1

2

3

4

0 6 12 18 24 30 36

Months

Pe

rce

nt

of

Pa

tie

nts

PLBALN

* * * *

45%*

RISEDRONATE Onset of Fracture Risk reduction

Clinical Vertebral Fractures

**

59%*

Nonvertebral Fractures

0

1

2

3

4

0 6 12

Months

Pe

rce

nt

of

Pa

tie

nts

PLBRIS

**

69%*

*** ** * **

Roux et al. Curr Med Res Opin 2004; 4:433 Harrington et al. CTI 2004; 74:129

0

5

10

15

0 18 36Months

Per

cen

t o

f P

atie

nts PLB

RIS

0 6 12 18 24 30 36


BMD with alendronate up to 10 YearsBMD with alendronate up to 10 Years

Year

% change

from Bone et al 2004 NEJM;350:1189–99

ALN 5 mg (n=78)

ALN 10 mg (n=86)ALN 20/5 mg/placebo (n=83)

Year

0 1 2 3 4 5 6 7 8 9 100

2

4

6

8

10

12

14 Lumbar Spine

0 1 2 3 4 5 6 7 8 9 100

2

4

6

8Total Hip


Persistence of bisphosphonate effectsPersistence of bisphosphonate effects

Gradual loss of BMD & turnover effects over further 5 yrs

following 5 years of alendronate 1

Effect on BMD, turnover & fracture risk after cessation

duration of use up to 7 yrs of alendronate 2

Shorter for Risedronate 3 ?

1 Bone et al, 2004 NEJM 350:1189-992 Bagger et al, 2003, Bone 33:301-7

3 Watts et al, ISCD 2004, 2005

Efficacy after stopping AlendronateFLEX (FIT Long-term Extension Study)

Efficacy after stopping AlendronateFLEX (FIT Long-term Extension Study)

Relative loss of BMD & bone turnover suppressionbut remains ‘better’ than base-line

NO in overall fracture rate(morphometric spine & non-spine)

over 4-5 years off Alendronate

BUT in clinical spine fractures5.3% vs 2.4% RR = 0.45 (0.24-0.85)

AND mild osteoporosis (T-score -1.3 to -2.2)Black et al, JAMA 2006, 296:2927-38

Urinary NTx /Cr

* p<0.05 from baseline# p<0.05 from placebo

Risedronate Offset After 3-Yr ExposureReversal of Antiresorptive Effect

Risedronate Offset After 3-Yr ExposureReversal of Antiresorptive Effect

3 6 36 48-60

-50

-40

-30

-20

-10

0PlaceboRIS 5mg

Month

% c

ha

ng

e f

rom

ba

se

lin

e

*

***#

# #

Serum BSAP

1 3 6 12 36 48-40

-30

-20

-10

0

10 Placeb

oRIS 5mg

Month

*#

*#

*#

*#

RIS removed RIS removed

Watts et al ISCD 2004


Zoledronic AcidYearly IV infusions

Zoledronic AcidYearly IV infusions

• Fracture Site

• Vertebral– Morphometric

deformities– Multiple morphometric– Clinical

• Hip fracture• Non-vertebral fractures• Any clinical fracture

Black et al, 2007 NEJM 356:1809-22

Placebo

3106684

88388456

Zoled

927

19

52292308

Hazard ratio

0.30 (0.24-0.38)0.11 (0.05-0.23)0.23 (0.14-0.37)

0.59 (0.42-0.83)0.75 (0.64-0.87)0.67 (0.58-0.77)

SAE Atrial fibrillation

RELATIVE RISKS AND 95% CI

* humerus, pelvis-sacrumribs-sternum, hip, clavicle, wrist

Relative risk reduction

0 0.5 1 1.5

Over 3 years

Non-spine- 16% P=0.04

Hip- 36% P=0.046

Major non-spine *- 19% P=0.031

RR

Reginster et al. JCEM 2005;90:2816-22.

Strontium ranelate & non-spine fractures Strontium ranelate & non-spine fractures


0 0.5 1 1.5

Relative risk reduction

Over 3 yearsOver 3 years

- 32% P=0.013Spine

- 31% Non-spine P=0.011

- 32 % Hip fracture P=0.112

RR

Seeman et al. 2004JBMR;19:S57;Abs 1219.

Strontium ranelate and fracture risk reductionStrontium ranelate and fracture risk reduction

RELATIVE RISKS AND 95% CI

Elderly women


Teriparatide (hPTH 1-34) & fracture outcomesTeriparatide (hPTH 1-34) & fracture outcomes

BMD loss upon cessation of intermittent rhPTH1-34but reduction of vertebral fracture risk persisted

New vertebral fractures over further 18 months

Women1 Men2

Prior placebo 19.0% 11.7%

Prior 20 mg PTH 11.3% 5.4%

Prior 40 mg PTH 10.4% 6.0%

1 Lindsay et al 2004, Arch Int Med 164:2024-302 Kaufman et al 2005 Osteopor Int 16:510-6


Effect of Teriparatide on the Risk ofNonvertebral Fragility Fractures

Effect of Teriparatide on the Risk ofNonvertebral Fragility Fractures

Adapted from Neer et al. N Engl J Med 2001

* P = 0.02 vs. placebo † P = 0.01 vs. placebo

RR = relative risk vs. placebo

% o

f w

om

en w

ith

>

1 fr

agili

ty f

ract

ure

RR 53%* RR 54%†


Potential adverse treatment effectsPotential adverse treatment effects

Suppressed turnover ? microcracksOsteopetrosis ? unusual fractures

Osteonecrosis of jaw (ONJ)

OsteomalaciaOsteosarcomaBreast cancer

Cardiovascular eventsCerebrovascular events

DVT & pulmonary embolismSkin rash & Stevens-Johnson syndrome


Absolute Fracture Risk & NNTAbsolute Fracture Risk & NNT

10

100

1000

10000

1 10 100 200502052

NumberNeeded

to beTreatedper yr

Fractures per 1000 person.yr

0.20.40.6

1.0

FractureRelative

RiskReduction

60-69 yr Man No prior fracture

80+ yr Man Prior fracture

500

20


Absolute fracture risk in a womanAbsolute fracture risk in a woman

Points 0 10 20 30 40 50 60 70 80 90 100

Age (years)55 60 65 70 7580 85 90 95100

FNBMD T-scores4 3 2 1 0 -1 -2 -3 -4 -5 -6

Prior fracture (>50 yrs)0 2

1 ≥3

Number of falls (past 12 mo)0 2

1 ≥3

Total Points 0 20 40 60 80 100 120 140 160 180

5-year risk0.01 0.05 0.1 0.2 0.4 0.6 0.8

10-year risk0.05 0.1 0.2 0.4 0.6 0.8 0.99

78

11 %

22 %

4 659 28

106

30 %

52%

Nguyen et al, Osteoporosis Intentional 2007 & 2008 www. FractureRiskCalculator.com


,

Osteoporosis therapyOsteoporosis therapy

BMDT score

A

B

C

Age60 80

- 1.0

- 2.5

Calcium, Protein intake Vitamin D, ExerciseModerate alcohol & not smoking


Osteoporosis & Fracture Rational InterventionOsteoporosis & Fracture Rational Intervention

Why ?Large impact on health, mortality and costsTherapy effective (30-50%) and well tolerated

Whom ?Prior fracture ( ), low BMD + older age ()

When ?Reasonable life expectancy

What ? Nutrition & lifestyle, specific-osteoporosis treatmentsDisease severity, rapidity and persistence of action

How long ?Balance of benefits & risksTherapy interruption must be monitored

garvan institute of medical research osteoporosis treatment: why, who, what & when ? john a...

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