Chief Investigator: Dr Lee Shepstone School of Medicine, Health Policy and Practice Collaborating universities:- Birmingham Bristol Manchester Sheffield Southampton York Funders:-

S creening O f O lder women for P revention of fracture A pragmatic randomised controlled trial of the effectiveness and cost effectiveness of screening for osteoporosis in older women for the prevention of fractures Will a community based screening program for osteoporosis reduce the incidence of fractures, and is it cost-effective, in older women?

Around 3 million people have osteoporosis in the UK. Each year the number of fragility fractures includes : hips wrists vertebrae Average stay in hospitals after a hip fracture is about 20 days; hip fractures account for 20% of orthopaedic bed occupancy. A hip fracture costs the NHS around £12 000; the total cost of osteoporosis is about £1.7 billion per annum. What are the consequences of osteoporosis ?

Screening for osteoporosis How should those at risk be identified? Is there an effective treatment? Treatment : Includes Vitamin D, Calcium, HRT, Strontium Ranelate, SERMs and Bisphosphonates Bisphosphonates : - taken orally, typically one weekly or once monthly; - reduce vertebral fracture risk by around 50%; - reduce global fracture risk by around 35%; - recommended by NICE for secondary prevention.

Screening for osteoporosis Identification : Diagnosis based of bone mineral density (BMD) with dual x- ray absorptiometry (DXA) is ‘gold standard’ for measurement. WHO-based ‘T-scores’ provide diagnostic thresholds: > -1.0 : Normal -1.0 to -2.5 : Osteopenic < -2.5 : Osteoporotic In a population of white women : NormalOsteopenicOsteoporotic :18%47%35% :15%44%41% :15%42%43% *based upon femoral neck T-scores

Screening for osteoporosis Not recommended that DXA be used for mass screening (from RCP guidelines, 1999) : - discrimination between those that will fracture and those that will not is poor - sensitivity is around 50%; +Rotterdam study of non-vertebral fractures (7 years FU) -> 44% Osteoporotic +US study hip fracture (5 years FU) -> 46% Osteoporotic The risk of fracture is dependent on more than BMD.

Screening for risk of fracture Use a combination of BMD with clinical risk factors: Whilst some factors are risks via BMD (e.g. BMI), some are risks both via and independent of BMD (e.g. AGE). BMDClinical Risk Factors Risk of Fracture ?

WHO Risk Algorithm A set of flexible models commissioned by the WHO to be used in primary care, including where BMD not available. Based upon 12 international cohorts, totalling people and one million person years observation. Calculates a 10 year risk of fracture*, incorporating the risk of death. (*Hip, vertebral, non-vertebral or global) Country specific. Treatment thresholds have been published.

WHO Risk Algorithm Treatment Recommended No Treatment BMD Low Risk ‘Intermediate’ RiskHigh Risk Clinical Risk Factors 10 Year Risk BMD

Feasibility Study (1) First suggested in 2002 with initial funding from the ARC to investigate the feasibility of a large scale definitive study. Recruitment, GP participation and feedback, adherence, follow-up, mechanics of data collection etc. Two centres, Norwich and Sheffield. Planned to recruit 800 women aged 70 to 85 through primary care. Baseline data to include risk factors, QoL & demographics 6 Month follow-up for fractures and QoL.

Recruitment commenced in Norwich in October 2005, in Sheffield in February 2006: NorwichSheffield Considered On medication Other reasons Invitations Sent out998 (100 %)1312 (100 %) Declined294 ( 29.5%) 560 ( 42.7%) Non-responders399 ( 40.0%) 445 ( 33.9%) Ineligible (identified after mailing) 15 ( 1.5%) 10 ( 0.8%) Consented290 ( 29.1%) 297 ( 22.6%) Baseline Mailing not returned after consent 3 ( 0.3%) 14 ( 1.1%) Total Randomised287 ( 28.8%) 283 ( 21.6%) Feasibility Study (2)

Characteristics of study subjects: Randomised N=570 Decliners 1 N=881 Age at EntryMean (SD)75.7 (4.2)77.1 (4.2) 186 Height (cm)Mean (SD) Missing (6.8)159.9 (7.5) 196 Weight (Kg)Mean (SD) Missing 68.7 (13.0)65.6 (12.6) 208 Body Mass IndexMean (SD) Missing 26.8 (5.0)25.5 (5.4) 208 1: Includes 25 excluded post consent Feasibility Study (3)

Characteristics of study subjects: Randomised N=570 Decliners 1 N=881 Continued Education after minimum leaving age Yes No Missing 191 (33.6%) 378 (66.4%) (20.8%) 536 (79.2%) 204 Has a degreeYes No Missing 127 (22.4%) 439 (77.6%) 4 58 ( 8.6%) 619 (91.4%) 204 Ethnic GroupWhite Black Other Missing 568 (100%) (99.6%) 1 ( 0.1%) 2 ( 0.3%) 191 1: Includes 25 excluded post consent Feasibility Study (4)

Frequency of clinical risk factors (N=570): Low level trauma fracture since age (25%) Maternal history of hip fracture 45 ( 8%) Current smoker 25 ( 4%) Long term use of corticosteroids 26 ( 5%) Diagnosed with rheumatoid arthritis 46 ( 8%) Current drinker (>2 units/day) 30 ( 5%) Body Mass Index – Mean (SD) 26.8 (5.0) Secondary risk factors : Menopause before 45 years 78 (14%) Longstanding poor mobility 30 ( 5%) Chron’s disease or ulcerative colitis 12 ( 2%) Insulin-dependent diabetes 6 ( 1%) Overactive thyroid gland 29 ( 5%) Major organ transplant 3 (<1%) Feasibility Study (5)

Group & Risk allocation : NorwichSheffield Total Initial Risk Score Mean (SD) Intervention Group % (7.5%) Initial Risk Allocation : Low risk (23.0%) 2.7% (9.0%) Intermediate risk (36.7%) 7.5% (3.7%) High risk (40.3%)13.8% (0.8%) Recommended for DXA (45.9%) 8.1% (4.8%) Feasibility Study (6)

DXA Results (N=127): NorwichSheffield Total Initial Risk Score Mean (SD) Mean t-score (SD)-1.05 (0.85)-0.81 (1.07) (0.96) BMD Category : Normal (50%) 7.3% (4.7%) Osteopaenic (43%) 8.5% (4.8%) Osteoporotic ( 7%)11.9% (4.1%) DNA Feasibility Study (7)

Medication : 91 (32%) recommended treatment in intervention group; 66 prescribed medication : Alendronate 34 Risedronate 32 4 (1.4%) prescribed medication in control group. Feasibility Study (8)

6-Month Follow-Up : 9 (1.6%) fractures objectively verified. NorwichSheffieldTotal Mailings sent out Mailings returned (94.6%) Declines returned ( 1.4%) Non-response ( 4.0%) Feasibility Study (9)

Second DXA Results (Norwich only, N=21): N(%) Mean t-score (SD) (0.90) BMD Category : Normal 6 (29%) Osteopenic 11 (52%) Osteoporotic 4 (19%) Feasibility Study (10)

Issues from feasibility study Treatment without BMD : - DXA’d all those on treatment and recalculate risks; - provided DXA for all ‘upper’ risk subjects for full study. Recruitment of subjects : - selection bias; - better educated, higher SES, higher BMD; - how do we get the higher risk subjects involved? Where next?

Full Scale Trial (1) Full scale trial funded by MRC and arc: circa £4 million 7 UK centres : Norwich (UEA) Birmingham BristolManchester SheffieldSouthampton York Sample size :11,580 women aged 70 – 85 Duration : 7 years total, including 5 years follow-up Incorporate qualitative studies on acceptability of screening and adherence with osteoporosis medication

Full Scale Trial (2) Recruitment through primary care, invitation letters coming from subject’s GP. Potential subjects identified through GP lists: Inclusion: Female 70 – 85 years Exclusion: Known to be on prescription treatment for osteoporosis Any known co-morbidity or factor (e.g. bereavement) which would make invitation to the study inappropriate

Full Scale Trial (3) Three recruitment phases each of 8 months duration staggered by 4 months Consent forms sent directly to recruiting centre (not back to GP) with demographic details. Followed by baseline mailing : Fracture risk assessment questionnaire EQ-5D SF-12 State-Treat Anxiety Index Randomisation into control or screening arm on receipt.

Full Scale Trial (4) Those screened, from questionnaire risk assessment:  Low risk  Higher risk and to DXA (circa 60%) Post DXA, risk assessment updated :  Below treatment threshold  Above threshold, treatment recommended GPs and study subjects will be informed by post of group and the need to make an appointment to discuss treatment.

Full Scale Trial (5) Primary Endpoint : All fractures Secondary Endpoints :Hip Fractures Mortality Psychological Anxiety Quality of Life Fracture data to be collected at 6 month and annual follow- up time points using, self-report, HES data and hospital radiology data. Self-report Quality of Life, Anxiety & Medication data collected. Medication data collected from GPs at follow-up time point.

Full Scale Trial (6) Expenses for GPs: i) Time for identifying eligible subjects and sending invitation packs ii) time for additional appointments to discuss treatment iii) time for providing follow-up data Also: (i) cost of DXAs paid to secondary care (ii) excess treatment costs paid to PCTs

Full Scale Trial (7) Timing: Sept / Oct 2007 Expression of interest from GPs Oct 2007 Ethical approval expected Nov 2007 First phase Sign-up of GPs Dec 2007 onwards Eligibility checks by GPs Jan 2008 onwards First phase invites to women March 2008 onwards First phase randomisations May – July 2008 onwards First phase DEXA

Local PI: [Name] [Department, Study Centre Name] [Contact details etc] [Insert Study Centre Logo] Funders:-