Transcript Prevalence ofLBM in Viet women

Osteoporosis:
Moving Beyond Bone Mineral Density
Tuan V. Nguyen
Bone and Mineral Research Program
Garvan 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 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 Fractures
Rate per 100,000 population
500
400
300
200
100
0
0-4
5-14
1524
2534
3544
4554
5564
6574
7584
85+
Donaldson, et al., J Epidemiol Comm Health 1990
Utility loss associated with fx
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
First year
Subs year
Hip
Tibia and Vertebra
fibula
Ribs
Pelvis
Humerus Clavicle,
sternum
Distal
forearm
Risk of Death From Hip Fracture
50-year old women: Lifetime risk of mortality
from:
Hip Fracture: 2.8%
Breast Cancer: 2.8%
Endometrial Cancer: 0.7%
Cummings et al. Arch Intern Med 1989; 149: 2445-8
Burden of Hip Fractures
Number of bed-days (1000)
4000
3500
3000
2500
2000
1500
1000
500
0
Hip fx
Myocardial Diabetes
infarction Mellitus
Bronchitis
& Asthma
Cost 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 Osteoporosis Foundation
American Heart Association
Current 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 Literature
N publications/year
2000
1600
1200
800
400
0
1/1964 - 1/1981 - 1/1991 - 1/1996 - 1/2001 12/1980 12/1990 12/1995 12/2000
Now
Change in BMD with Age
Peak bone density
Bone
Mineral
Density
Menopause
Osteopenia
Puberty
Osteoporosis
Age
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-scores
•
Define “osteoporosis” and “osteopenia”
T-score < -2.5 = “osteoporosis”
-2.5 < T-scores < -1 = “osteopenia”
•
Criteria for clinical trial entry
•
Intervention threshold
10
0.5
8
0.4
6
0.3
4
0.2
2
0.1
0
0
Femoral neck BMD
10-year Risk of Fx
0.6
1.
05
-
12
0.
95
-
0.7
0.
85
-
14
0.
75
-
0.8
0.
65
-
16
0.
55
-
0.9
0.
45
-
18
<0
.4
0
Prevalence
BMD and Fracture Risk
Probability of fx
12-year Risk of Fracture by BMD and Age
Women
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
Age
-3.0
-2.0
-1.0
60
0.0
70
1.0
80
2.0
Femoral neck BMD T-scores
Data: n = 1287 women; No. of fractures: 328
3.0
12-year Risk of Fracture by BMD and Age
Men
0.35
Age
60
70
80
Probability of fx
0.30
0.25
0.20
0.15
0.10
0.05
0.00
-3.0
-2.0
-1.0
0.0
1.0
2.0
Femoral neck BMD T-scores
Data: n = 821 men; No. of fractures: 118
3.0
12-year Risk of Hip Fracture
by BMD and Age - Women
0.25
Age
Probability of fx
0.20
60
70
80
0.15
0.10
0.05
0.00
-3.0
-2.0
-1.0
0.0
1.0
2.0
Femoral neck BMD T-scores
Data: n = 1287 women; No. of hip fractures: 89
3.0
BMD and Prevalence of Osteoporosis
Prevalence of Low BMD
Women
T<-2.5
90
T<-2.0
80
80
70
70
60
60
50
50
Percent
Percent
90
Men
40
30
20
20
10
10
0
0
70-70
80+
Age group
All
T<-2.0
40
30
60-69
T<-2.5
60-69
70-70
80+
Age group
All
U.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
Low BMD (T<-2.5) and Fractures in Women
1287women
Low BMD
345 (27%)
Fx = 137
(40%)
No Fx =
208 (60%)
42%
Not Low BMD
942 (73%)
Fx = 191
(20%)
No Fx = 751
(80%)
Low BMD (T<-2.0) and Fractures in Women
1287 women
Low BMD
562 (44%)
Fx = 199
(35%)
No Fx =
363 (65%)
61%
Not Low BMD
725 (56%)
Fx = 129
(18%)
No Fx = 596
(82%)
Low BMD (T<-2.5) and Fractures in Men
821 men
Low BMD
N = 90 (11%)
Fx = 27
(30%)
No Fx = 63
(70%)
23%
Not Low BMD
731 (89%)
Fx = 91
(12%)
No Fx = 640
(88%)
Low BMD (T<-2.0) and Fractures in Men
821 women
Low BMD
N = 173 (21%)
Fx = 40
(23%)
No Fx =
133 (77%)
34%
Not Low BMD
648 (79%)
Fx = 78
(12%)
No Fx = 570
(88%)
Specificity, Specificity, and PPV
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 (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
Age
Less than 70 yr
70 or older
Sensitivity
Specificity
PPV
23.2
89.0
17.0
23.0
89.6
28.3
30.5
85.8
27.7
23.2
85.9
38.5
Low BMD: T<-2.5
Low BMD: T<-2.0
Can we identify "low-BMD women" by
age, weight and prior fx?
100 women
Low BMD
N=27
+ve (22,
or 82%)
-ve (5, or
18%)
37%
Not Low BMD
N=74
-ve (38, or
52%)
+ve (36, or
48%)
Can we identify low-BMD and fx women?
T < -2.5
1.0
1.0
1.0
0.8
0.8
0.8
Sensitivity
Sensitivity
Incident Fracture
T < -2.0
0.6
0.6
0.4
0.4
0.2
0.2
0.2
0.0
0.0
0.0
0.6
0.4
0.0 0.2 0.4 0.6 0.8 1.0
1-Specificity
AUC = 0.75 + 0.03
0.0
0.2
0.4
0.6
0.8
1-Specificity
AUC = 0.72 + 0.03
1.0
0.0 0.2 0.4 0.6 0.8 1.0
1-Specificity
AUC = 0.48 + 0.04
Long-term Effect of Alendronate on BMD in
Postmenopausal Women with Osteoporosis (PMO)
Lumbar spine
Femoral neck
6
10
8
6
4
2
10
5
% change in BMD
% change in BMD
12
% change in BMD
Hip trochanter
4
3
2
1
0
12
24
36 48
Months
60
72
84
6
4
2
0
0
0
8
0
12
5 mg
10 mg
24
36 48
Months
60
72
84
20/5 mg/placebo 1–5 yrs.
20/5 mg/placebo 6–7 yrs.
Tonino RP, et al. J Clin Endocrinol Metab. 2000;85:3109-3115.
0
12
24
36 48
Months
60
72
84
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 Fracture
Fracture
Any non-vertebral fx
Hip fx
Wrist fx
Other fx
RR (95% CI)
0.80
0.49
0.52
0.99
Black et al, Lancet 1996
(0.63 – 1.01)
(0.23 – 0.99)
(0.31 – 0.87)
(0.75 – 1.31)
Risedronate and Hip Fracture Risk in
Women 70-79 yrs. with PMO
40%*
1.0
Placebo (n=1821)
0.9
Risedronate (n=3624)
Relative risk
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Hip fractures
*RR=0.6, 95% CI=0.4-0.9.
McClung MR, et al. N Engl J Med. 2001;344:333-340.
BMD and Fracture: Summary
• BMD and fracture risk: Good predictor
• BMD and fracture event: Poor discrimination
• Moderate increase in BMD => larger-thanexpected decrease in fracture risk
• BMD has been a major focus in osteoporosis
research during the past 20 years
Osteoporotic Fractures
Osteoporotic
fractures ??
Osteoporotic fractures
Falls
Mass/density
Geometry
Trauma
Bone
Turnover
Padding
Time
Garvan Institute of Medical Research
Muscle
Beyond 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 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 Density
MZ
1.4
1.4
rMZ = 0.73
rMZ = 0.47
1.3
1.2
1.2
1.1
1.1
1
1
Twin 2
Twin 2
1.3
DZ
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
0.5
0.5
0.5 0.6 0.7 0.8 0.9 1
1.1 1.2 1.3 1.4
Twin 1
0.5 0.6 0.7 0.8 0.9
1
Twin 1
Nguyen et al., 1998
1.1 1.2 1.3 1.4
Candidate Genes for Bone Mineral Density
Osteocalcin
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
a2HS 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 a
ESRa
6q25.1
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 Ia2
COLIA2
7q22
Willing et al
Parathyroid hormone
PTH
11p15
Gong et al
Vitamin D receptor
VDR
12q13
Morrison et al
Collagen Type Ia1
COLIA1
17q22
Grant et al
Transforming growth factor b1
TGF-b1
19q13
Langdahl et al, Yamada et al
Apolipoprotein E
ApoE
19q13
Kohlmeier et al
Potential Genes for Bone Mineral Density
Genetic Predictors of Hip Fracture
Variable
Unit
RR (95% CI)
+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)
Age
Nguyen et al., 2003
Quantitative Ultrasound as a Predictor of
Fracture Risk
Variable
Age
Femoral neck BMD
Speed of Sound –
distal radius
Unit
RR (95% CI)
+5 yr
1.2 (1.0 – 1.5)
-0.12 g/cm2
1.9 (1.4 - 2.4)
150 m/s
1.8 (1.3 - 2.4)
Nguyen et al., 2003
Effects 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
?
3.0
Nevitt et al, Placebo-controlled trial
Research 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 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 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 Risk
Risk Index
Risk
Rx
4
3
2
1
0
0.3
-1
0.5%
-2
0.3
2.7
-3
-4
50
55
60
65
70
75
Age
80
85
90
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 calculator
www.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)?
CALCULATE
RESET
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)?
Thank you
• Garvan team:
–
–
–
–
John Eisman
Jacqueline Center
Natasha Ivanovic
Jim McBride and "IT people"
• Dubbo team:
– Janet Watters
– Donna Reeves
– Volunteers, participants