NICE SCOOP OF THE DAY FRAX with NOGG. Eugene McCloskey Professor of Adult Bone Diseases University of Sheffield

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1 NICE SCOOP OF THE DAY FRAX with NOGG Eugene McCloskey Professor of Adult Bone Diseases University of Sheffield

2 Disclosures Consultant/Advisor/Speaker for: o ActiveSignal, Amgen, AstraZeneca, Consilient Healthcare, GSK, Hologic, Internis, Lilly, Medtronic, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Servier, Synexus,Tethys, UCB, Warner Chilcott Research support: o Including above plus ARUK, I3 Innovus, MRC, IOF, Unilever Financial holdings: o None

3 12ca027 Rationale for the SCOOP Study Osteoporotic fractures in the EU 1 Number of fractures 18% 51% 16% Cost of fractures 15% Effective therapies 2 Vertebral fracture Non-vertebral fracture Hip fracture FRAX Hip Spine Wrist Other 1 Kanis et (2012) IOF-ESCEO12 Hernlund et al, Arch Osteoporos 2013; 2 Hopkins et al. BMC Musculoskeletal Disorders 2011

4 12ca027 Rationale for the SCOOP Study Osteoporotic fractures in the EU 1 Number of fractures 18% Can a community-based screening 0.4programme, based on hip 51% 15% 0.3 fracture probability assessed by the FRAX 0.2 risk algorithm, reduce Cost of fractures Effective therapies fractures in 16% older women 0 in the UK? Vertebral fracture Non-vertebral fracture Hip fracture FRAX Hip Spine Wrist Other 1 Kanis et (2012) IOF-ESCEO12 Hernlund et al, Arch Osteoporos 2013; 2 Hopkins et al. BMC Musculoskeletal Disorders 2011

5 Topics to cover Risk Assessment Tools o o Background Calibration Intervention thresholds o o o Do patients at high risk respond to osteoporosis therapy? Fixed vs. age-dependent approaches Implementation example from the UK The SCOOP study

6 The aims in managing osteoporosis TO REDUCE THE INCIDENCE OF FRACTURES To identify patients at increased risk of fracture To be able to assess that risk accurately To give advice to aid understanding of the disease, the aims of therapy and the choice of therapy Treatment Lifestyle advice Therapeutic agents

7 Fracture risk assessment models Garvan QFracture FRAX Externally validated Yes (limited) Yes (UK only) Yes Calibrated No No Yes Applicability? UK 63 countries Falls input Yes Yes No BMD input Yes No Yes Prior fracture input Yes Yes Yes Family history input No Yes Yes Output Incidence Incidence Probability Treatment response assessed No No Yes Thresholds/guidance No No Yes

8 NICE SCG Fracture Risk Assessment Consider assessment of fracture risk in in all women aged 65 years and over and all men aged 75 years and over. o Interpret with caution if aged over 80 years, because predicted 10-year fracture risk may underestimate short-term fracture risk. Consider fracture risk in women <65 years and men <75 years if they have any of the following risk factors: previous fragility fracture current or frequent use of oral glucocorticoids history of falls family history of hip fracture causes of secondary osteoporosis low BMI (<18.5 kg/m 2 ) smoking >10 cigarettes per day alcohol intake > recommend units Do not routinely assess fracture risk in people <50 years unless major risk factors (e.g. GC use, untreated premature menopause, previous fragility fracture). Osteoporosis: fragility fracture risk: NICE guideline August 2012

9 Further NICE Proposed Recommendations Use either FRAX (without a BMD value) or QFracture to calculate 10-year predicted absolute fracture risk when assessing risk of fracture in people of between 40 and 84 years. Do not routinely measure BMD to assess fracture risk without prior assessment using FRAX (without a BMD value) or QFracture. Osteoporosis: fragility fracture risk: NICE guideline August 2012

10 Absolute risk values are not the same 40 Woman with prior fracture, BMI 24, no other CRFs Qfracture-2012 (Major) Qfracture-2012 (Hip) FRAX (Major) FRAX (Hip)

11 Identification of reversible risk Risk factor amenable to intervention (direct evidence) Demonstrated for low BMD, previous fracture and use of glucocorticoids Risk factor amenable to intervention (indirect evidence) Demonstrated for age, BMI, family history, smoking and alcohol

12 Cumulative Incidence of Fractures* (%) MRC Hip Fracture Study HR 0.77, 95%CI Placebo Randomized, double-blind, placebo controlled trial over 3 years Women aged at least 75 years unselected for osteoporosis or low BMD 6 4 Clodronate Clodronate (Bonefos ) 800mg/day or Placebo Time on study (years) * Excludes fractures of the hands, feet, ankle and skull 3 Fractures ascertained at 6- monthly visits and confirmed against source documents or radiographs McCloskey et al, JBMR 2007

13 McCloskey et al, OI 2008 Does treatment efficacy interact with baseline risk? Hazard ratio Clodronate vs. Placebo Interaction (without BMD) P= year MOF probability (%)

14 Efficacy and FRAX Percentile of FRAX major OP fracture probability Clinical fracture

15 Interaction of treatment effect and FRAX Intervention Interaction Reference Raloxifene no Kanis et al, Bone 2010 Strontium ranelate no Kanis et al, OI 2011 Teriparatide no Harvey et al, Bone 2015 Clodronate yes McCloskey et al, OI 2009 Denosumab yes McCloskey et al, OI 2012 Bazedoxifene yes Kanis et al, Bone 2009

16 Intervention thresholds - Guidance is essential!

17 Intervention Thresholds e.g. hip fracture probability Probability (%) 25 women Age (years)

18 Impact 10ca012 of single MOF threshold in the UK Identified for treatment (%) 100 >5% >10% >15% >20% >25% >30% Age (years) 0 >5% >10% >15% >20% >25% >30% FRAX threshold Threshold based on Major OP Probability Kanis et al, Osteoporos Int (2013) 24:23 57

19 15ca191 Age-dependent thresholds already in use Prior fracture T-score = -2.5 SD No risk factors, no BMD Age (years) Kanis JA et al (2015) J Bone Miner Res 30:

20 Implementing age-dependent thresholds

21 Linking guidance to the tool

22 Recalculation after BMD (FN T-score -2.5)

23 Incidence (%) Previous NOGG Assessment Thresholds 10 year incidence of hip fracture in women eligible for treatment Prior fracture No prior fracture Age (years) Johansson et al, Osteopor Int 2012

24 Impact on proportion treated by age Proportion of population within each age category (%) Age group (y) Current Alternative

25 FRAX and NOGG Usage within the UK 75% of NOGG access is for FRAX calculations without BMD in line with suggested use by NICE

26 Screening of older community-dwelling women using FRAX reduces hip fracture risk Findings from the SCOOP Trial E McCloskey, E. Lenaghan, S. Clarke, R. Fordham, N. Gittoes, I. Harvey, R. Holland, A. Howe, T. Marshall, T. Peters, J. A. Kanis, T. W. O'Neill, D. Torgerson, C. Cooper, L. Shepstone and the SCOOP Trial Group

27 Letter of invitation CONTROL High Risk Agree to take part Baseline Information Randomisation Intermediate/ High DXA FRAX Unknown Including FRAX questionnaire SCREENING FRAX Low Risk Low Risk Women aged years, not on osteoporosis medication identified from GP lists 7 geographical regions of the UK Randomly allocated to control (usual management) or intervention (screening). In those subjects deemed at high risk of hip fracture, family doctor advised to intervene. Follow-up for 5 years. Osteoporotic fracture as primary endpoint; hip fracture and mortality as secondary endpoints.

28 SCOOP assessment and treatment thresholds - based on FRAX hip fracture probabilities* Age Group (y) BMD Threshold Treatment Threshold % 5.24% % 6.87% % 8.52% % 8.99% Fracture self-report or noted in HES data Contact GP and/or hospital to request confirmation of:- Fracture site Fracture date Radiological evidence Incident fracture ascertainment Confirmed non-fracture or remains unverified Verified fracture *Kanis et al, Bone 2005

29 The SCOOP Study Baseline characteristics Randomised versus Responding Non-Consenters Randomised (N = ) Responding Non-Consenters Has a degree? Yes 2536 (20.3%) 1080 ( 9.9%) Social Class I II IIIN IIIM IV V 1256 (10.2%) 3698 (30.1%) 2109 (17.2%) 3249 (26.5%) 1471 (12.0%) 494 ( 4.0%) 570 ( 5.8%) 2206 (22.4%) 1651 (16.8%) 3196 (32.5%) 1476 (15.0%) 739 ( 7.5%) Fallen in past year? Yes 3445 (27.6%) 2186 (19.9%) Broken bone since 50? Yes 2863 (22.9%) 1859 (17.0%) Parents broken hip? Yes 1162 ( 9.3%) 536 ( 5.3%) Smoker? Yes 581 ( 4.7%) 826 ( 7.4%) Moderate Drinker? Yes 444 ( 3.6%) 383 ( 3.4%) Age Mean (SD) 75.4 (4.15) 76.8 (5.84) BMI Mean (SD) 26.6 (4.73) 26.1 (4.90)

30 The SCOOP Study Baseline characteristics Controls versus Screening (and High Risk) Characteristic Question completion (%) Control Screening High risk subgroup Number Age (y) ± ± ± 4.4 BMI (kg/m 2 ) ± ± ± 4.1 Broken bone since 50 (%) Parental history of hip fracture (%) Glucocorticoid use (%) Rheumatoid arthritis (%) Smoking (%) Alcohol (%) Secondary osteoporosis (%) History of falls (%) FRAX 10 year MOF probability (%) ± ± ± 10.1 FRAX 10 year Hip probability (%) ± ± ± 10.9 Femoral neck BMD T-score ± ± 0.68

31 Baseline FRAX hip probability and incidence of fracture in SCOOP Control group only Incidence (per 100,000 years) Osteoporotic fracture Hip fracture Quintiles of FRAX Hip Fracture probability (without BMD)

32 SCOOP study Post-baseline exposure to osteoporosis medication Control Intervention - all High Low 80 % < 6m post-rand <12m post-rand <24m post-rand <36m post-rand <48m post-rand Time interval since randomisation

33 SCOOP Study - Fracture outcomes Controls Screening Hazard Ratio* Outcome No. (%) No. (%) (95% CI) P Value Primary outcome Osteoporotic fracture 846 (14.2) 800 (13.5) 0.94 (0.85, 1.03) 0.18 Secondary outcome Hip fracture 218 (3.7) 164 (2.8) 0.72 (0.59, 0.89) Any clinical fracture 1002 (16.0) 951 (15.3) 0.94 (0.86, 1.03) 0.18 Mortality 525 (8.4) 550(8.8) 1.05 (0.93, 1.19) 0.44 * Adjusted for centre, falls and baseline FRAX risk

34 SCOOP Study - Any osteoporotic fracture outcome HR 0.94 (0.85, 1.03) P=0.18

35 Number needed to screen to prevent one hip fracture = 111 SCOOP Study - Hip fracture outcome HR 0.72 (0.59, 0.89) P=0.002

36 SCOOP Study - Hip fracture reduction by baseline hip fracture probability Whole study population Interaction p=0.021 High risk population 10 th Centile 50 h Centile 90 h Centile

37 Summary A community-based screening strategy based on FRAX fracture risk assessment is feasible and achievable o Deliverable through primary care Women identified at high fracture risk based on hip fracture probability are responsive to appropriate osteoporosis management. The strategy is highly effective in reducing hip fracture risk in older women o A 28% reduction over 5 years o NNS 111

38 Thanks to: All of the women participating in the study Our many colleagues in primary care Research staff at the 7 centres The Trial Management Committee (especially Liz Lenaghan) and Trial Steering Committee The funders