Osteoporosis:Osteoporosis:Moving Beyond Bone Mineral DensityMoving Beyond Bone Mineral Density

Osteoporosis:Osteoporosis:Moving Beyond Bone Mineral DensityMoving Beyond Bone Mineral Density

Tuan V. NguyenBone and Mineral Research ProgramGarvan Institute of Medical Research

Sydney, Australia

Osteoporosis, Fracture and BMD

• Fracture is the ultimate outcome of osteoporosis

• Osteoporosis is defined by bone mineral density (BMD)

• BMD is a good predictor of fracture risk, but a poor discriminator of fracture

• There are BMD-independent predictors of fracture risk

• The current definition of osteoporosis is inadequate

• A probability-based definition is proposed

A Shift in ThinkingA Shift in Thinking

Low bone mass, microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk (Consensus Development Conference, 1991)

Osteoporosis: Risk factor

Fracture: Outcome

Incidence of All-limb FracturesIncidence of All-limb Fractures

0

100

200

300

400

500

0-4 5-14 15-24

25-34

35-44

45-54

55-64

65-74

75-84

85+

Rat

e p

er 1

00,0

00 p

op

ula

tio

n

Donaldson, et al., J Epidemiol Comm Health 1990

Utility loss associated with fxUtility loss associated with fx

0.000.050.100.150.200.250.300.350.400.450.50

Hip Tibia andfibula

Vertebra Ribs Pelvis Humerus Clavicle,sternum

Distalforearm

First yearSubs year

Risk of Death From Hip FractureRisk of Death From Hip Fracture

50-year old women: Lifetime risk of mortality 50-year old women: Lifetime risk of mortality from:from:

Hip Fracture: 2.8%Hip Fracture: 2.8%

Breast Cancer: 2.8%Breast Cancer: 2.8%

Endometrial Cancer: 0.7%Endometrial Cancer: 0.7%

Cummings et al. Arch Intern Med 1989; 149: 2445-8Cummings et al. Arch Intern Med 1989; 149: 2445-8

Burden of Hip FracturesBurden of Hip Fractures

0

500

1000

1500

2000

2500

3000

3500

4000

Hip fx Myocardialinfarction

DiabetesMellitus

Bronchitis& Asthma

Num

ber

of b

ed-d

ays

(100

0)

Cost of FracturesCost of Fractures

Disease Prevalence Annual Direct Cost (US$

Billion)

Osteoporosis 10 million 13.8

Asthma 15 million 7.5

Chronic Heart Failure

4.6 million 20.3

National Heart Lung and Blood Institute National Heart Lung and Blood Institute

National Osteoporosis FoundationNational Osteoporosis Foundation

American Heart AssociationAmerican Heart Association

Current StatusCurrent Status

• BMD is a golden standard for assessment of osteoporosis

• BMD is used as (a) selection criteria, and (b) an endpoint in clinical trials

• BMD is the major focus of basic, clinical and epidemiological research in osteoporosis

BMD in the Medical LiteratureBMD in the Medical Literature

0

400

800

1200

1600

2000

1/1964 -12/1980

1/1981 -12/1990

1/1991 -12/1995

1/1996 -12/2000

1/2001 -Now

N p

ubli

cati

ons/

year

Change in BMD with AgeChange in BMD with Age

Peak bone density

Puberty

Menopause

Osteopenia

Osteoporosis

Bone MineralDensity

Age

Bone Mineral Density and Definition of “Osteoporosis”

Bone Mineral Density and Definition of “Osteoporosis”

Gaussian distribution

Constant standard deviation

Decrease with advancing age

T-scorei = (BMDi – Peak BMD) / SD

The Use of T-scoresThe Use of T-scores

• Define “osteoporosis” and “osteopenia”

T-score < -2.5 = “osteoporosis”

-2.5 < T-scores < -1 = “osteopenia”

• Criteria for clinical trial entry

• Intervention threshold

BMD and Fracture RiskBMD and Fracture Risk

0

2

4

6

8

10

12

14

16

18

Femoral neck BMD

Pre

vale

nce

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

10-y

ear

Ris

k o

f F

x

12-year Risk of Fracture by BMD and AgeWomen

12-year Risk of Fracture by BMD and AgeWomen

0.000.050.100.150.200.250.300.350.400.450.50

-3.0 -2.0 -1.0 0.0 1.0 2.0 3.0

Femoral neck BMD T-scores

Pro

babi

lity

of

fx

60 70 80Age

Data: n = 1287 women; No. of fractures: 328

12-year Risk of Fracture by BMD and AgeMen

12-year Risk of Fracture by BMD and AgeMen

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

-3.0 -2.0 -1.0 0.0 1.0 2.0 3.0

Femoral neck BMD T-scores

Pro

babi

lity

of

fx

60 70 80Age

Data: n = 821 men; No. of fractures: 118

12-year Risk of Hip Fracture by BMD and Age - Women

12-year Risk of Hip Fracture by BMD and Age - Women

0.00

0.05

0.10

0.15

0.20

0.25

-3.0 -2.0 -1.0 0.0 1.0 2.0 3.0

Femoral neck BMD T-scores

Prob

abil

ity

of f

x

60 70 80Age

Data: n = 1287 women; No. of hip fractures: 89

BMD and Prevalence of OsteoporosisBMD and Prevalence of Osteoporosis

Prevalence of Low BMDPrevalence of Low BMD

0

10

20

30

40

50

60

70

80

90

60-69 70-70 80+ All

Age group

Per

cent

T<-2.5 T<-2.0

0

10

20

30

40

50

60

70

80

90

60-69 70-70 80+ All

Age group

Per

cen

t

T<-2.5 T<-2.0

Women Men

U.S Preventive Services TaskforceU.S Preventive Services Taskforce

"… recommendation that women 65 and older be routinely screened for osteoporosis to reduce the risk of fracture and spinal abnormalities often associated with the disease.

… recommends that routine screening begin at 60 for those women identified as high risk because of their weight or estrogen use."

Annals of Internal Medicine, Sept 17, 2002

1287women

Low BMD 345 (27%)

Not Low BMD 942 (73%)

Fx = 137 (40%)

No Fx = 208 (60%)

No Fx = 751 (80%)

Fx = 191 (20%)

42%

Low BMD (T<-2.5) and Fractures in Women

1287 women

Low BMD 562 (44%)

Not Low BMD 725 (56%)

Fx = 199 (35%)

No Fx = 363 (65%)

No Fx = 596 (82%)

Fx = 129 (18%)

61%

Low BMD (T<-2.0) and Fractures in Women

821 men

Low BMD N = 90 (11%)

Not Low BMD 731 (89%)

Fx = 27 (30%)

No Fx = 63 (70%)

No Fx = 640 (88%)

Fx = 91 (12%)

23%

Low BMD (T<-2.5) and Fractures in Men

821 women

Low BMD N = 173 (21%)

Not Low BMD 648 (79%)

Fx = 40 (23%)

No Fx = 133 (77%)

No Fx = 570 (88%)

Fx = 78 (12%)

34%

Low BMD (T<-2.0) and Fractures in Men

T-scores Sensitivity Specificity PPV

T < -2.5

Women

Men

40

30

80

88

42

23

T < -2.0

Women

Men

35

23

82

88

61

34

Specificity, Specificity, and PPV

Specificity, Specificity, and PPV (T<-2.5)Specificity, Specificity, and PPV (T<-2.5)

Site Sensitivity Specificity PPV

Hip fx

Women

Men

19

16

97

97

72

41

Vertebral fx

Women

Men

20

24

93

96

51

42

Dist Rad & Hum

Women

Men

11

4

96

99

48

40

Specificity, Specificity, and PPV by age

Specificity, Specificity, and PPV by age

Age Sensitivity Specificity PPV

Less than 70 yr 23.2

23.0

89.0

89.6

17.0

28.3

70 or older 30.5

23.2

85.8

85.9

27.7

38.5

Low BMD: T<-2.5

Low BMD: T<-2.0

Can we identify "low-BMD women" by age, weight and prior fx?

Can we identify "low-BMD women" by age, weight and prior fx?

100 women

Low BMD N=27

Not Low BMD N=74

+ve (22, or 82%)

-ve (5, or 18%)

+ve (36, or 48%)

-ve (38, or 52%)

37%

Can we identify low-BMD and fx women? Can we identify low-BMD and fx women?

AUC = 0.75 + 0.03 AUC = 0.72 + 0.03 AUC = 0.48 + 0.04

T < -2.5 T < -2.0 Incident Fracture

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.2 0.4 0.6 0.8 1.0

1-Specificity

Sens

itivi

ty

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.2 0.4 0.6 0.8 1.0

1-Specificity

Sens

itiv

ity

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.2 0.4 0.6 0.8 1.01-Specificity

Long-term Effect of Alendronate on BMD in Postmenopausal Women with Osteoporosis (PMO)

Lumbar spine Femoral neck Hip trochanter

0

1

2

3

4

5

6

0 12 24 36 48 60 72 84

% c

hang

e in

BM

D

0

2

4

6

8

10

0 12 24 36 48 60 72 84

% c

hang

e in

BM

D

20/5 mg/placebo 1–5 yrs.20/5 mg/placebo 6–7 yrs.

5 mg10 mg

0

2

4

6

8

10

12

0 12 24 36 48 60 72 84

% c

hang

e in

BM

D

Months Months Months

Tonino RP, et al. J Clin Endocrinol Metab. 2000;85:3109-3115.

Relationships between Change in BMD and Fracture Risk

• Each standard deviation lowering in BMD is associated with a 2.5 (or higher)-fold increase in the risk of hip fracture.

• An increase by 3% would be predicted to reduce fracture risk by 12%.

Alendronate and Hip FractureAlendronate and Hip Fracture

Fracture RR (95% CI)

Any non-vertebral fx 0.80 (0.63 – 1.01)

Hip fx 0.49 (0.23 – 0.99)

Wrist fx 0.52 (0.31 – 0.87)

Other fx 0.99 (0.75 – 1.31)

Black et al, Lancet 1996

Risedronate and Hip Fracture Risk in Women 70-79 yrs. with PMO

Risedronate and Hip Fracture Risk in Women 70-79 yrs. with PMO

*RR=0.6, 95% CI=0.4-0.9.

Placebo (n=1821)

Risedronate (n=3624)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Hip fractures

Rel

ativ

e ris

k

40% *

McClung MR, et al. N Engl J Med. 2001;344:333-340.

BMD and Fracture: SummaryBMD and Fracture: Summary

• BMD and fracture risk: Good predictor

• BMD and fracture event: Poor discrimination

• Moderate increase in BMD => larger-than-

expected decrease in fracture risk

• BMD has been a major focus in osteoporosis

research during the past 20 years

Osteoporotic FracturesOsteoporotic Fractures

Garvan Institute of Medical Research

Osteoporotic fractures ?Osteoporotic fractures ?

Bone Trauma

Falls

Padding

Muscle

Mass/density

Turnover

Geometry

Time

Beyond BMDBeyond BMD

Risk factor Relative risk

Anticonvulsants 2.0

History of maternal hip fx 1.8

History of hyperthyroid 1.7

On feet less than 4 hr/day 1.7

Inability to raise from a chair 1.7

Resting pulse >80 1.7

Benzodiazepines 1.6

Age (>5 yrs) 1.4

Height 1.3

Cummings SR, et al. N Engl J Med. 1995;332(12):767-73.

Revisit Risk FactorsRevisit Risk Factors

• Aetiologic risk factors– Genotypes– Lifestyle factors (eg smoking, alcohol, dietary habit,

physical activity, etc)– Mechanical factors– Falls and fall-related factors

• Clinical risk factors– BMD– Quantitative ultrasound measurements (QUS)– History of fx

Genetics of Bone Mineral DensityGenetics of Bone Mineral Density

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4

Twin 1

Tw

in 2

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4

Twin 1

Tw

in 2

MZ DZ

rMZ = 0.73 rMZ = 0.47

Nguyen et al., 1998

Candidate Genes for Bone Mineral DensityCandidate Genes for Bone Mineral DensityOsteocalcin BGLAP 1q25 Dohi et al 1998

Interleukin 1 Receptor Antagonist CASR 2q13 Keen et al 1998

Calcium Sensing Receptor CASR 3q21-24 Cole et al 1998

2HS Glycoprotein AHSG 3q27 Zmuda et al 1998

Vitamin D binding protein DBP/GCv 4q11-13 Papiha et 1996

Osteopontin SPP1 4q21 Willing et al 1998

Osteonectin SPOCK 5q31 Kobayashi et al 1996

Estrogen receptor ESR6q25.1 Qi et al 1995; Willing et al

Interleukin-6 IL-6 7p21 Murray et al 1997

Calcitonin receptor CALCR 7q21.3 Taboulet et al, Masi et al

Collagen type I2 COLIA2 7q22 Willing et al

Parathyroid hormone PTH 11p15 Gong et al

Vitamin D receptor VDR 12q13 Morrison et al

Collagen Type I1 COLIA1 17q22 Grant et al

Transforming growth factor 1 TGF-1 19q13 Langdahl et al, Yamada et al

Apolipoprotein E ApoE 19q13 Kohlmeier et al

Potential Genes for Bone Mineral DensityPotential Genes for Bone Mineral Density

Genetic Predictors of Hip FractureGenetic Predictors of Hip Fracture

Variable Unit RR (95% CI)

Age +5 yr 1.4 (1.1 – 1.8)

Femoral neck BMD -0.12 g/cm2 3.4 (2.3 - 5.0)

VDR Taq-1 genotype tt vs TT & Tt 2.6 (1.2 - 5.3)

COLIA1 Sp-1 genotype

ss vs SS & Ss 3.8 (1.4 - 10.8)

Nguyen et al., 2003

Quantitative Ultrasound as a Predictor of Fracture Risk

Quantitative Ultrasound as a Predictor of Fracture Risk

Variable Unit RR (95% CI)

Age +5 yr 1.2 (1.0 – 1.5)

Femoral neck BMD -0.12 g/cm2 1.9 (1.4 - 2.4)

Speed of Sound – distal radius

150 m/s 1.8 (1.3 - 2.4)

Nguyen et al., 2003

Effects of a History of FxEffects of a History of Fx

Athor and study design Relative risk Relative risk after adj for

BMD

Lindsay et al., 4 placebo-controlled trials

5.2 5.1

Klotzbuecher et al, review 4.4 ?

Melton et al, observational study 12.6 No BMD

Black et al., SOF cohort 5.4 4.1

Ross et al., cohort 4.1 3.6

Nevitt et al, Placebo-controlled trial ? 3.0

Research DirectionsResearch Directions

• Improvement of models for long-term prediction of fractures– Etiologic risk factors

• Identification of high-risk individuals – Clinical risk factors

Long-term Prediction of FracturesLong-term Prediction of Fractures

• “Remaining Lifetime Fracture Probability (RLFP): the sum of rates of fracture over an estimated remaining lifetime.

• Make use of etiological risk factors to construct models of prediction –> Risk Index.

Risk Profile and Remaining Lifetime Fracture Probability (RLFP)

Risk Profile and Remaining Lifetime Fracture Probability (RLFP)

Risk Index Age RFLP Rx RFLP

-1.0 60

80

0.46

0.07

0.38

0.03

-2.0 60

80

2.5

0.50

1.98

0.19

-3.0 60

60

5.00

1.11

3.75

0.39

Individualisation of Fracture RiskIndividualisation of Fracture Risk

-4

-3

-2

-1

0

1

2

3

4

50 55 60 65 70 75 80 85 90

Risk Rx

0.5%

2.7

0.3

0.3

Age

Risk Index

High-risk Individuals and The Definition of “Osteoporosis”

High-risk Individuals and The Definition of “Osteoporosis”

• Make use of clinical risk factors and long-term predictive models for diagnostic purpose.

• Toward a probability-based definition of osteoporosis.

• Toward a probabilisty-based entry criteria for clinical trials.

The Future: A risk score calculatorThe Future: A risk score calculatorwww.RISKFx.com

Welcome to the Garvan Institute's Risk Score Calculator for Osteoporotic Fracture. Please enter your information in the following boxes and press CALCULATE to obtain your risk score. To recalculate, please press RESET and repeat the above procedure. Thank you.

Age:

Sex:

Your femoral neck BMD T-score:

Your QUS T-score:

Your genotype:

Do you have a history of fracture (Y/N)?

Are you a current smoker (Y/N):

Have you had a fall during the past 12 months (Y/N)?

Can you raise from a chair easily (Y/N)?

CALCULATE

RESET

Thank youThank you

• Garvan team:– John Eisman

– Jacqueline Center

– Natasha Ivanovic

– Jim McBride and "IT people"

• Dubbo team: – Janet Watters

– Donna Reeves

– Volunteers, participants