Osteoporosis: Moving Beyond Bone Mineral Density

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OsteoporosisMoving Beyond Bone Mineral Density
Tuan V. NguyenBone and Mineral Research
ProgramGarvan Institute of Medical
ResearchSydney, Australia
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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

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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
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Incidence of All-limb Fractures
Donaldson, et al., J Epidemiol Comm Health 1990
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Utility loss associated with fx
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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
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Burden of Hip Fractures
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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
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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

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BMD in the Medical Literature
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Change in BMD with Age
Peak bone density
Bone Mineral Density
Menopause
Osteopenia
Puberty
Osteoporosis
Age
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Bone Mineral Density and Definition of
Osteoporosis
Gaussian distribution Constant standard
deviation Decrease with advancing age
T-scorei (BMDi Peak BMD) / SD
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The Use of T-scores

• Define osteoporosis and osteopenia
• T-score lt -2.5 osteoporosis
• -2.5 lt T-scores lt -1 osteopenia
• Criteria for clinical trial entry
• Intervention threshold

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BMD and Fracture Risk
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12-year Risk of Fracture by BMD and AgeWomen
Age
Data n 1287 women No. of fractures 328
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12-year Risk of Fracture by BMD and AgeMen
Age
Data n 821 men No. of fractures 118
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12-year Risk of Hip Fracture by BMD and Age -
Women
Age
Data n 1287 women No. of hip fractures 89
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BMD and Prevalence of Osteoporosis
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Prevalence of Low BMD
Women
Men
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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

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Low BMD (Tlt-2.5) and Fractures in Women
1287women
Low BMD 345 (27)
Not Low BMD 942 (73)
Fx 137 (40)
No Fx 208 (60)
No Fx 751 (80)
Fx 191 (20)
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Low BMD (Tlt-2.0) 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
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Low BMD (Tlt-2.5) and Fractures in Men
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)
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Low BMD (Tlt-2.0) 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)
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Specificity, Specificity, and PPV
T-scores Sensitivity Specificity PPV
T lt -2.5 Women Men 40 30 80 88 42 23
T lt -2.0 Women Men 35 23 82 88 61 34
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Specificity, Specificity, and PPV (Tlt-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
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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 Tlt-2.5
Low BMD Tlt-2.0
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Can we identify "low-BMD women" by age, weight
and prior fx?
100 women
Low BMD N27
Not Low BMD N74
ve (22, or 82)
-ve (5, or 18)
ve (36, or 48)
-ve (38, or 52)
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Can we identify low-BMD and fx women?
T lt -2.5
Incident Fracture
T lt -2.0
AUC 0.48 0.04
AUC 0.75 0.03
AUC 0.72 0.03
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Long-term Effect of Alendronate on BMD in
Postmenopausal Women with Osteoporosis (PMO)
Tonino RP, et al. J Clin Endocrinol Metab.
2000853109-3115.
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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.

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Alendronate 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
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Risedronate and Hip Fracture Risk in Women 70-79
yrs. with PMO
McClung MR, et al. N Engl J Med. 2001344333-340.
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BMD and Fracture Summary

• BMD and fracture risk Good predictor
• BMD and fracture event Poor discrimination
• Moderate increase in BMD gt larger-than-expected
  decrease in fracture risk
• BMD has been a major focus in osteoporosis
  research during the past 20 years

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Osteoporotic Fractures
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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 gt80 1.7
Benzodiazepines 1.6
Age (gt5 yrs) 1.4
Height 1.3
Cummings SR, et al. N Engl J Med.
1995332(12)767-73.
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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

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Genetics of Bone Mineral Density
MZ
DZ
rMZ 0.73
rMZ 0.47
Nguyen et al., 1998
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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 3
q27 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 Murra
y et al 1997 Calcitonin receptor CALCR 7q21.3 Tab
oulet 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
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Potential Genes for Bone Mineral Density
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Genetic 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
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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
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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
Nevitt et al, Placebo-controlled trial ? 3.0
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Research Directions

• Improvement of models for long-term prediction of
  fractures
• Etiologic risk factors
• Identification of high-risk individuals
• Clinical risk factors

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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 gt Risk Index.

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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
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Individualisation of Fracture Risk
Risk Index
Risk
Rx
0.3
0.5
0.3
2.7
50 55 60 65 70
75 80 85 90
Age
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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.

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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)? 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
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Thank you

• Garvan team
• John Eisman
• Jacqueline Center
• Natasha Ivanovic
• Jim McBride and "IT people"
• Dubbo team
• Janet Watters
• Donna Reeves
• Volunteers, participants