www.shef.ac.uk/aubm “known knowns, known unknowns, unknown unknowns….. ronald dumsfeld senior...
TRANSCRIPT
www.shef.ac.uk/aubm
“Known knowns, known unknowns, unknown unknowns…..
Ronald Dumsfeld
Senior Lecturer in Metabolic Bone Diseases
www.shef.ac.uk/aubm
Aims
• Known knowns?– We can do better
• But what is the incremental benefit?
• And at what cost?
• Known unknowns?– The risk is reversible
• But doesn’t everyone need a BMD?
• Unknown unknowns and unknown knowns?– Suggestions on the back of a postcard to Liz by next
Thursday morning!
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Risk Factors Previous fragility fracture
Investigations
Measure BMD
Normal Osteopenia Osteoporosis
ReassureLifestyle advice
Lifestyle adviceTreat if previous
fracture
Lifestyle adviceTreatment
IOF Case-finding Strategy
RCP Guidelines 1999
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Combining risk factors for prediction of fracture
0
1
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3
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8
9
10
-4 -3 -2 -1 0 1 2 3 4
Risk ratio versus the
general population
GR=2.6
GR=1.6
Z-score
% 50.0100.0 97.799.9 84.1 15.9 2.3 0.1 0.0
Study Aim: To compare a case-finding strategy that combined the information from validated risk factors (WHO
Strategy) with the current IOF strategy.
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Methods
• Baseline and follow-up data from nine prospective population-based cohorts– Rotterdam, EVOS/EPOS, CaMos, Rochester, Sheffield, Dubbo
(DOES), Gothenburg, Japan (Adult Health Study )
• All cohorts had BMD estimates undertaken at baseline and a risk factor assessment.
• Both IOF and WHO strategies used same risk factors comprising– a prior history of a fragility fracture– BMI <19kg/m2
– parental history of hip fracture– long-term use of oral glucocorticoids– rheumatoid arthritis– current smoking– alcohol ≥3 units daily.
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Methods of Comparison
• IOF - selects candidates for BMD tests on the basis of prevalent clinical risk factors. We estimated:– The number of BMD tests that would be required in cohorts of
women aged 50 years or more.– The hip fracture risk in women so identified.– Treatment offered when T-score ≤ -2.5.
• WHO – Used the WHO algorithm (combined BMD and risk factors):– Maintained approximately the same number of BMD tests at
each age as the IOF strategy.– Treatment offered when the computed 10-year probability of
hip fracture exceeded an intervention threshold derived for the UK.
• Simulation samples of 1000 women using the different identification strategies
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Probability of Fracture
10-year Probability of Fracture- Targeting of BMD -
0%
Frequency
0%
100%
35%
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Strategy Costs
Risk Assessment£5.76
BMD Scan£35
No BMD Scan
TreatmentDiscussion
£19.20
No TreatmentDiscussion
£5.76
TreatmentDiscussion
£19.20
Primary outcome – Costs of the IOF and WHO identification strategies based on a UK setting.
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Risk factors in the cohorts
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10
20
30
40
50
60
Low B
MI
Ora
l GC u
se RA
Alcoho
l
Paren
tal h
ip fr
actu
re
Smoki
ngPrio
r fra
cture
Any >1
% Prevalence of risk factors (%)
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Hip fractures identified and costs of identification
Age DXA tests /1000
High risk women
identified /1000
Hip fractures expected*
Cost/identified hip fracture (£)
IOF WHO IOF WHO IOF WHO
50 450 26 41 <1 1 60,823 21,940
60 450 52 65 2 4 12,930 7,566
70 500 120 355 16 30 1,731 1,069
80 550 235 606 51 91 608 424
*in women at high risk
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Conclusions
• Compared to the IOF strategy, the WHO approach– identifies more patients at high risk of hip fracture– makes more effective use of BMD tests.
• At each age, the cost of the identification strategy per detected hip fracture is lower with the WHO approach.
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a. Risk amenable to intervention
Low BMD
Previous fracture
Use of glucocorticoids
b. Presence of risk factor does not adversely affect therapeutic
response
Age
Body mass index
Family history of fracture
Smoking and alcohol
Markers of bone turnover
c. Uncertain effects
Neuromuscular incompetence
Liability to falling
Identification of reversible risk
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Targeting and Treatment EfficacyIs the treatment appropriate for the risk regardless of the underlying risk factors?
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2
3
4
5
6
Inci
den
ce (
%)
<80y with OP >79 with at least 1 riskfactor
Placebo Risedronate
RR 0.6 (0.4-0.9)
RR 0.8
2.5mg, 5mg daily for 3 years McClung et al NEJM 2001
N=5445 N=3886
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Fracture Prediction by Non-BMD Risk Factors
Fracture Probability (% in 10y)
Mean Hip BMD
T-score Mean age
0-5 5-10
10-15 0.93 -0.13 77.8 15-20 0.85 -0.75 78.5 20-25 0.76 -1.50 80.3 25-30 0.78 -1.33 79.5 30-35 0.74 -1.67 79.6
35-40 0.66 -2.33 82.1 40-45 0.69 -2.08 80.6 45-50 0.67 -2.25 80.6 50-55 0.57 -3.08 82.1
Johansson et al JBMR 2004
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Background
• Treatments for osteoporosis are commonly targeted to patients with low bone mineral density– Low BMD is associated with increased fracture risk– An entry criterion for phase III studies in
development of most osteoporosis therapies– DXA measured low BMD a pre-requisite to ensure
the efficacy of osteoporosis therapies?
• The WHO tool for fracture prediction estimates an individual’s probability of fracture in the next 10 years from clinical risk factors, with or without BMD measurement
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Methods (1)Aims and Study Population
• Aim– To determine if patients identified at high risk by the
algorithm are responsive to anti-resorptive treatment
* Excludes fractures of the hands, feet, ankle and skull
3210
12
10
8
6
4
2
0
Time on study (years)
Cu
mu
lati
ve I
nci
de
nce
of
Fra
ctu
res*
(%
)
HR 0.77, 95%CI 0.64-0.93
Placebo
Clodronate
• Randomized, double-blind, placebo controlled trial over 3 years
• Women aged at least 75 years unselected for osteoporosis or low BMD
• Clodronate (Bonefos®) 800mg/day orPlacebo
• Fractures ascertained at 6-monthly visits and confirmed against source documents or radiographs
McCloskey et al, JBMR 2007
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Methods (2)WHO Fracture Probability Model
• Age
• Sex
• Femoral neck BMD
• Previous fragility fracture after age 50
• Body mass index
• Ever use of glucocorticoids
• Secondary osteoporosis (e.g., rheumatoid arthritis)
• Parental history of hip fracture (Paternal)
• Current cigarette smoking
• Alcohol intake 3 or more units/day
Data not captured at entry
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Methods (3)Treatment Interaction
• Complete baseline data available in 3974 women (76.2% of cohort)– Efficacy of clodronate HR 0.76 (0.63-0.93)
• 10-year probability of osteoporotic fracture computed by WHO model– Without femoral neck BMD (expressed as the T-score)– With femoral neck BMD
• Fracture rates examined by quintile of fracture probability
• Interaction between treatment efficacy and fracture probability explored by Poisson regression
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Baseline Characteristics Clodronate
(N=2016) Placebo
(N=1958)
Age (years) 79.83.7 79.73.7
BMI (kg/m2) 26.84.4 27.04.7
Femoral Neck BMD (g/cm2) 0.650.12 0.650.12
Femoral neck BMD T-score -1.740.98 -1.720.99
Previous fracture (%) 22 24
Family history (%) 5 6
Current smoking (%) 6 6
Corticosteroids (%) 9 10
RA (%) 2 2
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Incidence of osteoporotic fracture and estimated 10-year probability
Without BMD
0
2
4
6
8
I II III IV V
Placebo
Clodronate
Fractures /100 patient-years
Quintiles of probability
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Incidence of osteoporotic fracture and estimated 10-year probability
0
2
4
6
8
I II III IV V
With BMDPlacebo
Clodronate
Fractures /100 patient-years
Quintiles of probability
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Interaction between treatment and fracture probability (without BMD)
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
0 10 20 30 40 50 60 70 80
10 year probability
HR
tre
atm
en
t v
ers
us
pla
ce
bo
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Interaction between treatment and fracture probability
Prcenti
0
0.5
1.0
1.5
13 15 18 24 30
Without BMD
Probability (%)
Percentile 10 25 50 75 90
HR
P = 0.043
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Interaction between treatment and fracture probability
10 12 16 22 30
0
0.5
1.0
1.5
HR
Probability (%)
With BMD
Percentile 10 25 50 75 90
P = 0.10
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Study Limitations
• Not all of WHO risk variables collected at baseline
• Community-dwelling women in the UK unselected for osteoporosis– Applicable to other populations?
• Clodronate not licensed for treatment of osteoporosis– Applicable to other agents?
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Conclusions
• Women identified to be at high risk of future fracture, as predicted by the WHO fracture risk algorithm:
• Are responsive to treatment with clodronate
• This response occurs in the presence or absence of BMD assessment in the risk model