Uno strumentoitaliano per la valutazione

del rischio di fratturadel rischio di frattura

Francesca De GiorgioU.O. Medicina Interna

Ospedale S. JacopoASL3 Pistoia

Valutazione clinica dell’OsteoporosiValutazione clinica dell’Osteoporosi

Identificazione dei soggetti a rischio

Valutazione del rischio di fratturaValutazione del rischio di frattura

Diagnosi di forme secondarie

Quando e come trattare

Valutazione del rischio di frattura

Identificare i pazienti a maggior rischioutilizzando strumenti in grado di fornire una stima del rischio

La gestione dell’OsteoporosiLa gestione dell’Osteoporosi

Avviare un trattamento di efficacia coerente con il rischio di frattura

Stili di vita

Farmaci

Migliorare la percezione del rischio da parte di medici e pazienti

Measurement site Fracture site (relative risk)

Wrist Hip Vertebrae

Relationship of bone mass and fractures as assessed by the relative risk of fracture of wrist, hip and vertebrae per 1 SD change in BMD

in different regions, adjusted for age

Relationship of bone mass and fractures as assessed by the relative risk of fracture of wrist, hip and vertebrae per 1 SD change in BMD

in different regions, adjusted for age

Forearm 1.8 1.6 1.6

Femoral neck 1.6 2.6 1.9

Lumbar spine 1.6 1.3 2.0

Eddy et al. Osteoporos Int, 1998

Yea

r fr

actu

re r

isk

(%)

15

20

- 3.5

T score

FEMORAL TFEMORAL T --SCORE AND FIVESCORE AND FIVE--YEAR RISK OF YEAR RISK OF HIP FRACTUREHIP FRACTURE IN WHITE WOMEN IN WHITE WOMEN

Relazione esponenziale tra diminuzione della BMD e aumento del rischio di frattura

Cummings SR et al. JAMA, 2002

5-Y

ear

frac

ture

ris

k (%

)

55 60 65 70 75 80 8550

0

5

10

Age (yrs)

- 1.0- 1.5- 2.0

- 2.5

- 3.0

Relazione esponenziale tra diminuzione della BMD e aumento del rischio di frattura

60

Inci

den

za d

i fra

ttu

re (

per

10

00

paz

ien

te-a

nn

i)

50

40

ColonnaRadio

Rischio di Rischio di frattura vertebrale, radialefrattura vertebrale, radiale e e BMDBMD

aumento del rischio di frattura

Miller PD et al. Calcif Tissue Int, 1996

Inci

den

za d

i fra

ttu

re (

per

10

00

paz

ien

te

Densità Minerale Ossea

30

20

10

02 SD 1 SD Mean -1 SD -2 SD

Definizioni OMS dell’esito Definizioni OMS dell’esito dell’esame densitometricodell’esame densitometrico

NORMALE: BMD entro 1 DS rispetto alla media del picco di massa ossea (T score ≥ -1)

OSTEOPENIA: BMD compreso tra -1 e -2,5 DS rispetto alla media del picco di massa ossea (T score < -1 e > rispetto alla media del picco di massa ossea (T score < -1 e > -2,5)

OSTEOPOROSI: BMD inferiore a -2,5 DS rispetto alla media del picco di massa ossea (T score < -2,5)

OSTEOPOROSI SEVERA: BMD inferiore a -2,5 DS rispetto alla media del picco di massa ossea in presenza di una o più fratture da fragilità

WHO Technical report series 843. Geneva, 1994

Osteopenia

Bone Bone MineralMineral DensityDensity, , osteoporoticosteoporoticfracturefracture rate, rate, and and numbernumber of of womenwomenwith with fracturesfractures in 149.524 in 149.524

postmenopausalpostmenopausal womenwomen

Siris ES et al. Arch Intern Med, 2004

Major Major riskrisk factorsfactors for for fracturefracturein in clinicalclinical practicepractice

Female genderAge*Asian or Caucasian raceLow Bone Mineral Density

Premature menopauseAmenorrhoeaHypogonadism in menLow body weight*

High Bone turnover*Poor visual acuity*Neuromuscular disorders*Parental history of fractures*Previous fragility fractures*Comorbidities

Cigarette smoking*Alcohol consumption*Prolonged immobilisationLow dietary calcium intakeVitamin D deficiencyGlucocorticoid use*Fall propensity*

* oltre la BMDKanis JA et al. Osteoporos Int, 2005

World Health Organization

Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK

WHO: Assembly of cohortsWHO: Assembly of cohorts

Global literature reviewIndividual datasets EVOS/EPOS Sheffield

EPIDOS DOES Dubbo RotterdamCaMos Rochester Hiroshima KuopioHiroshima KuopioGothenburg

Incident fractures any 5,444osteoporotic 3,495hip 957

Kanis JA, WHO Study Group, 2005

Female 74% No. 59,232p-y 249,898

VARIABILI CONTINUE

VARIABILI DICOTOMICHE

Familiarità

VARIABILI VARIABILI FRAXFRAX®®

CONTINUEEtà

BMD (T-score)

BMI

Fumo

Cortisonici

Pregresse fratture

Secondarietà

Alcool

Artrite reumatoide

Hip Fracture

MultipleFractures

Hip Fracture

Multiple Fractures

Previous Fractures 1.55 1.50 2.1 2

Family History 2.12 1.64 2.1 1.7

Calculated FRAX®

Risk gradients (with BMD)

Calculated FRAX®

Risk gradients (without BMD)

Family History 2.12 1.64 2.1 1.7

Smoking 1.63 1.15 1.4 1.15

Glucocorticoid therapy 1.80 1.58 2.1 1.7

Rheumatoid arthritis 1.42 1.28 1.7 1.4

Secondary Osteoporosis 1 1 1.7 1.4

Alcohol > 3 units/day 1.50 1.25 1.4 1.2

1

1,5

TenTen--yearyear probabilityprobability of hip of hip fracturefractureaveragedaveragedfor for ageage and gender and and gender and adjustedadjusted to the to the

probabilitiesprobabilities of of SwedenSweden

0

0,5

Kanis JA et al. J Bone Miner Res, 2002

7349578354 80804

89796 90753 94471

80000

100000 Men Women Total

IncidenceIncidenceof hip of hip fracturesfractures in in ItalyItalybetweenbetween2000 and 20052000 and 2005

0

20000

40000

60000

2000 2001 2002 2003 2004 2005

Piscitelli P et al. Osteoporos Int, 2010

FRAXFRAX

assumere come affidabile il FRAX con le variabili FRAX con le variabili

continue (età, BMD, BMI)

LIMITI INTRINSECI DEL FRAX ®LIMITI INTRINSECI DEL FRAX ®

I fattori di rischio “dicotomici”necessitano di una rivalutazione perchè:

Per alcuni esiste gradiente di rischio (pregresse Per alcuni esiste gradiente di rischio (pregresse fratture, fumo, terapia cortisonica)

Non sono previsti fattori di rischio importanti solo perché rari (es. connettiviti )

Non sono previsti dati utili per la validazione(pregressa terapia, terapia in corso)

Il FRAX™ è protetto da brevetto

L’algoritmo del FRAX® non è stato reso noto

Non è possibile fare stime su coorti di soggetti

LIMITI “POLITICI” DEL FRAXLIMITI “POLITICI” DEL FRAX ®®LIMITI “POLITICI” DEL FRAXLIMITI “POLITICI” DEL FRAX ®®

Non è possibile fare stime su coorti di soggetti (prospettiche o retrospettive)

Non è possibile registrare in un data-base i risultati

Non è validabile

VARIABILI VARIABILI FRAXFRAX®®

VARIABILI VARIABILI CONTINUECONTINUE

VARIABILI DICOTOMICHE

FamiliaritàFumoCONTINUECONTINUE

EtàEtàBMD (TBMD (T--score)score)BMIBMI

FumoCortisoniciPregresse frattureSecondarietàAlcoolArtrite reumatoide

Fracture Risk by FRAX and DeFRA(Weight 65, Height 165, No risk factors)

Fracture Risk by FRAX and DeFRA(Weight 65, Height 165, No risk factors)

T Score = -3,5

20

25

30

10 y

ears

frac

ture

ris

k %

DeFRA FRAX

0

5

10

15

60 70 80

Age

10 y

ears

frac

ture

ris

k %

T Score = -3,0

T Score = -2,0

DeFRA algorithm for the estimation of Ln (natural logarithm) of the 10 year risk (10YR) of either hip or

multiple major fractures (as defined by FRAX®) as worked out from the tables published in the WHO technical report.

ln 10YR hip fracture = 0.121 age -0.000455 age2-1.512 Tscore --0.162 Tscore2 -0.0045 Tscore3 -7.538

ln 10 YR of multiple major fractures =(-0.001 age3/1000) +0.050 age-0.246 Tscore+0.032 Tscore2 +0.003

Tscore3 +0.012 BMI -1.75

T-score= BMD T score at either the femoral neck or the total hip as assessed by Dual X ray absortiometry (DXA)

Linee Guida Osteoporosi, SIOMMMS 2009

FratturaFrattura di di femorefemore: : RischioRischio a 10 a 10 annianni

FR

AX

Hip

BM

D0C

RF

20,00

15,00

FR

AX

TM

DeFRA Defra2Hip0BMD

20,0015,0010,005,000,00

FR

AX

Hip

BM

D0C

RF

10,00

5,00

0,00

FR

AX

FrattureFratture ClinicheCliniche: : RischioRischio a 10 a 10 annianni

FR

AX

Ost

BM

D0C

RF

40,00

30,00

FR

AX

TM

DEFRA2Ost0BMD40,0030,0020,0010,000,00

FR

AX

Ost

BM

D0C

RF

20,00

10,00

0,00

DeFRA

FR

AX

Relative Relative risksrisks of of fracturefracture by sex per by sex per decreasedecreaseof 1 SD in QUS of 1 SD in QUS measuresmeasures

((33 33 eventsevents in 6471 men and 88 in 6471 men and 88 eventsevents in 8328 in 8328 womenwomen))

Men Women

BUA

1.7 (1.2-2.8)

1.9 (1.3-2.6)

Khaw K et al. Lancet, 2004

SOS

Relative Risk

1.9 (1.3-2.6)

1.6 (1.1-2.3)

1.6 (1.2-2.0)

1 2 3 40

SerumCTX above the premenopausal rangepredicts hip fracture risk in elderly women

SerumCTX above the premenopausal rangepredicts hip fracture risk in elderly women

2.07 (1.49-2.9)

1.67 (1.19-1.32)1.86 (1.01-3.76)

Re

lativ

e h

aza

rd fo

r hi

p fr

act

ure

Re

lativ

e h

aza

rd fo

r hi

p fr

act

ure

Chapurlat RD et al. Bone, 2000

VARIABILI VARIABILI FRAXFRAX®®

VARIABILI

VARIABILI DICOTOMICHE

FamiliaritàVARIABILICONTINUE

EtàBMD (T-score)BMI

FamiliaritàFumoCortisoniciPregresse frattureSecondarietàAlcoolArtrite reumatoide

Hip fracture

Clinical fractures

Family history of hip fracture 1.6 1.2

Corticosteroid use: >5 mg Prednisone equivalents 2.5 2.5

Corticosteroid use: < 5mg >2.5 mg Prednisone equivalents

1.8 1.6

One previous vertebral o hip fracture 2.2 2.2

More than 1 previous hip or vertebral fracture 4.0 4.0

DeFRADeFRARisk gradientsRisk gradients

More than 1 previous hip or vertebral fracture 4.0 4.0

Previous non traumatic non-hip non-vertebral fracture

1.4 1.4

Alcool (>3 units/day) 1.5 1.2

Smoking <10 cigarettes /day 1.2 1.0

Smoking >10 cigarettes /day 1.9 1.5

Rheumatoid and psoriatic arthritis, Ankylosing spondylitis, LES, other CTDs

1.3 1.2

Smoking history and the risk of hip fracture in postmenopausal women assessed in 1328 cases

and 3312 controls

Smoking history and the risk of hip fracture in postmenopausal women assessed in 1328 cases

and 3312 controls

Baron JA et al. Arch Intern Med, 2001

Fracture Risk by FRAX and DeFRAaccording with smoking habits

(T score =-3.0; weight 65; height 165)

Fracture Risk by FRAX and DeFRAaccording with smoking habits

(T score =-3.0; weight 65; height 165)

20

25

0

5

10

15

FRAX-DeFRA no

Sm

FRAX-SmDeFRA Sm <10DeFRA Sm >10

10

yrs

Fx

risk

Incidenceof vertebral fractures in patientsreceivingGlucocorticoids comparedto non

users accordingto baseline BMD

Incidenceof vertebral fractures in patientsreceivingGlucocorticoids comparedto non

users accordingto baseline BMD

GCs GCsGCs

GCs GCs

Van Staa TP et al. Arthritis Rheum, 2003

Dose dependency of fracture risk in Dose dependency of fracture risk in 244,235 oral corticosteroid users244,235 oral corticosteroid users

5,186

<2.5 mg predn. 2.5-7.5 mg predn. >7.5 mg predn.

van Staa et al. JBMR, 2000

1,55

0,99

1,772,27

2,59

0

2

4

Vertebral Fx Hip Fx

Rel

ativ

e ris

k

Fracture Risk by FRAX and DeFRAaccording with Glucocorticoid therapy

(T score =-3.0; weight 65; height 165)

Fracture Risk by FRAX and DeFRAaccording with Glucocorticoid therapy

(T score =-3.0; weight 65; height 165)

30

40

0

10

20

FRAX-DeFRA no

GLC

FRAX-GLCDeFRA GLC <5

mg

DeFRA GLC >5

mg

10

yrs

Fx

risk

Second Hip FractureSecond Hip Fracturein older men and womenin older men and womenThe Framingham Study (481 patients with an initial hip fracture)The Framingham Study (481 patients with an initial hip fracture)

Second Hip FractureSecond Hip Fracturein older men and womenin older men and womenThe Framingham Study (481 patients with an initial hip fracture)The Framingham Study (481 patients with an initial hip fracture)

24,1

Berry SD et al. Arch Intern Med, 2007

% o

f pat

ien

ts

% o

f pat

ien

ts

First Second

10

15

inci

den

tfrac

ture

sin

cid

entfr

actu

res

Relative risk of incident Relative risk of incident vertebral fracturesvertebral fracturesaccording to prevalent fracturesaccording to prevalent fractures

0

5

0 1 2 3Black et al. J Bone Miner Res, 1999

Number of prevalent fracturesNumber of prevalent fractures

Rel

ativ

e ri

sko

f inci

den

tR

elat

ive

risk

of in

cid

ent

≥3210

Hip

Vertebral

RiskRisk of of subsequentsubsequentfracturesfractures in in peri/peri/postmenopausalpostmenopausal womenwomenwith with prevalentprevalent

vertebralvertebral fracturesfractures

Klotzbuecher et al. J Bone Min Res, 2000

All (nonspine)

0 2 4 6 8

Pooled

Wrist

Relative Risk

Risk of subsequent hip fracture in per Risk of subsequent hip fracture in per i/postmenopausal women with prior fracturesi/postmenopausal women with prior fractures

Hip

Vertebral 2.3 (2.0-2-8)

2.3 (1.5-3.7)

KlotzbuecherKlotzbuecher et al. et al. JJ Bone Bone MinMin Res, 2000Res, 2000

0 2 4

Pooled

Other

Wrist

Relative Risk

1.9 (1.6-2.2)

1.9 (1.3-2.7)

1.9 (1.6-2.2)

Fracture Risk by FRAX and Fracture Risk by FRAX and DeFRADeFRAaccording with prevalent fracturesaccording with prevalent fractures

(T score =(T score =--3.0; weight 65; height 165) 3.0; weight 65; height 165)

30

40

50

0

10

20

30

FRAX-DeFRA no Fx

FRAX-Fx DeFRA other Fx DeFRA Vert/Hip Fx

10

yrs

Fx

risk

Relative Relative riskrisk of of fracturefracture in 30,262in 30,262patientspatients with RAwith RA

MedianMedian followfollow up : 7,6 up : 7,6 yearsyears; N. 2,460 ; N. 2,460 fracturesfractures

Pelvis

Clinical Vertebral

Rib

Van Staa TP et al. Arthritis Rheum, 2006

Humerus

Tibia/Fibula

Femur/hip

Radius/Ulna

Clinical/Osteoporotic

0 1 2 3

FemmineFemmine30

25

20

MaschiMaschi

Studio EVOS: prevalenza delle deformità Studio EVOS: prevalenza delle deformità vertebrali in rapporto all’età ed al sessovertebrali in rapporto all’età ed al sesso

O’Neill et al. JBMR, 1996

41 ± 13

SLE patients Età (anni)

50-54 55-59 60-64 65-69 70-74 75-79

20

15

10

5

0

3836

35

40

45

50

Prevalence of fractures in 159 Prevalence of fractures in 159 SSCSSCand 235 and 235 ARAR patientspatients

% o

f F

frac

ture

s

0

5

10

15

20

25

30

SSc RA

Yuen SY et al. J Rheumatol, 2008

% o

f F

frac

ture

s

Major Major riskrisk factorsfactors for for fracturefracturein in clinicalclinical practicepractice

Female genderAge*Asian or Caucasian raceLow Bone Mineral Density

Premature menopauseAmenorrhoeaHypogonadism in menLow body weight*Low Bone Mineral Density

High Bone turnover*Poor visual acuity*Neuromuscular disorders*Parental history of fractures*Previous fragility fractures*Comorbidities

Low body weight*Cigarette smoking*Alcohol consumption*Prolonged immobilisationLow dietary calcium intakeVitamin D deficiencyGlucocorticoid use*Fall propensity*

* Over and above BMD

Kanis JA et al. Osteoporos Int, 2005

FallFall--relatedrelated factorsfactors and and riskrisk of hip of hip fracturefracture EPIDOS EPIDOS prospectiveprospectivestudystudy

((7575 7575 womenwomen agedaged 75 or 75 or olderolder))

Femoral neck BMD

Fall-risk status

Lower quartiles Highest quartile

Dargent-Molina P et al. Lancet, 1996

Femoral neck BMD

Lower quartiles of risk

Highest quartile of risk

(Hip fracture rate per 1000 person-year)

5.4

11.3

11.3

28.5

Probability of hip fracture in 47,868 Probability of hip fracture in 47,868 nanaïve women treated with alendronate ïve women treated with alendronate

(daily, weekly and switch)(daily, weekly and switch)

Rabenda V al. Osteoporos Int, 2008

1% MPR decrease vs Hip Fx risk = 0.996 CI 95% 0.994-0.998

%

National Osteoporosis Guideline GroupRoyal College of Physicians and Bone and Tooth Society of Great Britain

DeFRA, 2010

Consenso e Linee GuidaConsenso e Linee Guida

Il trattamento farmacologico è cost-effective in:

Pregresse fratture osteoporotiche Pregresse fratture osteoporotiche

Trattamento cortisonico cronico

Rischio di frattura a 10 anni > 20%

Kanis JA et al. Osteoporos Int, 2004

“It is cost-effective to treat subjects who have a 10-year hip fracture risk exceeding 3% or more”

Grazie

Uno strumentoitaliano per la valutazione

del rischio di fratturadel rischio di frattura

Francesca De Giorgio

U.O. Medicina 2ASL3 Pistoia