1. www.shef.ac.uk/aubm “Known knowns, known unknowns, unknown unknowns….. Ronald Dumsfeld Senior Lecturer in Metabolic Bone Diseases

2. 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!

3. www.shef.ac.uk/aubm Risk FactorsPrevious fragility fracture Investigations Measure BMD Normal Osteopenia Osteoporosis Reassure Lifestyle advice Treat if previous fracture Lifestyle advice Treatment IOF Case-finding Strategy RCP Guidelines 1999

4. www.shef.ac.uk/aubm Combining risk factors for prediction of fracture 0 1 2 3 4 5 6 7 8 9 10 -4-3-201234 Risk ratio versus the general population GR=2.6 GR=1.6 Z-score %50.0100.097.799.984.115.92.30.10.0 Study Aim: To compare a case-finding strategy that combined the information from validated risk factors (WHO Strategy) with the current IOF strategy.

5. www.shef.ac.uk/aubm 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/m 2 –parental history of hip fracture –long-term use of oral glucocorticoids –rheumatoid arthritis –current smoking –alcohol ≥3 units daily.

6. www.shef.ac.uk/aubm 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

7. www.shef.ac.uk/aubm Probability of Fracture 10-year Probability of Fracture - Targeting of BMD - 0% Frequency 0% 100% 35%

8. www.shef.ac.uk/aubm Strategy Costs Risk Assessment £5.76 BMD Scan £35 No BMD Scan Treatment Discussion £19.20 No Treatment Discussion £5.76 Treatment Discussion £19.20 Primary outcome – Costs of the IOF and WHO identification strategies based on a UK setting.

9. www.shef.ac.uk/aubm Risk factors in the cohorts % Prevalence of risk factors (%)

10. www.shef.ac.uk/aubm Hip fractures identified and costs of identification *in women at high risk

11. www.shef.ac.uk/aubm 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.

12. www.shef.ac.uk/aubm 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

13. www.shef.ac.uk/aubm Targeting and Treatment Efficacy Is the treatment appropriate for the risk regardless of the underlying risk factors? 2.5mg, 5mg daily for 3 years McClung et al NEJM 2001 N=5445N=3886

14. www.shef.ac.uk/aubm Fracture Prediction by Non-BMD Risk Factors Johansson et al JBMR 2004

15. www.shef.ac.uk/aubm 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

16. www.shef.ac.uk/aubm 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 Time on study (years) Cumulative Incidence of Fractures* (%) 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 or Placebo Fractures ascertained at 6- monthly visits and confirmed against source documents or radiographs McCloskey et al, JBMR 2007

17. www.shef.ac.uk/aubm 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

18. www.shef.ac.uk/aubm 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

19. www.shef.ac.uk/aubm Baseline Characteristics

20. www.shef.ac.uk/aubm Incidence of osteoporotic fracture and estimated 10-year probability Without BMD 0 2 4 6 8 IIIIIIIVV Placebo Clodronate Fractures /100 patient-years Quintiles of probability

21. www.shef.ac.uk/aubm Incidence of osteoporotic fracture and estimated 10-year probability 0 2 4 6 8 IIIIIIIVV With BMD Placebo Clodronate Fractures /100 patient-years Quintiles of probability

22. www.shef.ac.uk/aubm Interaction between treatment and fracture probability (without BMD)

23. www.shef.ac.uk/aubm Interaction between treatment and fracture probability PrcentiPrcenti 0 0.5 1.0 1.5 1315182430 Without BMD Probability (%) Percentile 1025507590 HR P = 0.043

24. www.shef.ac.uk/aubm Interaction between treatment and fracture probability 1012162230 0 0.5 1.0 1.5 HR Probability (%) With BMD Percentile 1025507590 P = 0.10

25. www.shef.ac.uk/aubm 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?

26. www.shef.ac.uk/aubm 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