Chief Investigator: Dr Lee ShepstoneSchool of Medicine, Health Policy and Practice

Collaborating universities:-

Birmingham Bristol Manchester Sheffield Southampton York

Funders:-

• Screening Of Older women for Prevention 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 :

80 000 hips 50 000 wrists 120 000 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 :Normal Osteopenic Osteoporotic

70-74 : 18% 47% 35%75-79 : 15% 44% 41%80-84 : 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 60 000 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 RecommendedNo Treatment

BMD

Low Risk ‘Intermediate’ Risk High 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:

Norwich Sheffield

Considered 1200 1662

On medication 175 309

Other reasons 27 41

Invitations Sent out 998 (100 %) 1312 (100 %)

Declined 294 ( 29.5%) 560 ( 42.7%)

Non-responders 399 ( 40.0%) 445 ( 33.9%)

Ineligible (identified after mailing)

15 ( 1.5%) 10 ( 0.8%)

Consented 290 ( 29.1%) 297 ( 22.6%)

Baseline Mailing not returned after consent

3 ( 0.3%) 14 ( 1.1%)

Total Randomised 287 ( 28.8%) 283 ( 21.6%)

Feasibility Study (2)

• Characteristics of study subjects:

RandomisedN=570

Decliners1

N=881

Age at Entry Mean (SD) 75.7 (4.2) 77.1 (4.2)186

Height (cm) Mean (SD)

Missing

160.1 (6.8) 159.9 (7.5)196

Weight (Kg) Mean (SD)

Missing

68.7 (13.0) 65.6 (12.6)208

Body Mass Index Mean (SD)

Missing

26.8 (5.0) 25.5 (5.4)208

1: Includes 25 excluded post consent

Feasibility Study (3)

• Characteristics of study subjects:

RandomisedN=570

Decliners1

N=881

Continued Education after minimum leaving age

YesNoMissing

191 (33.6%)378 (66.4%) 1

141 (20.8%)536 (79.2%)204

Has a degree YesNoMissing

127 (22.4%)439 (77.6%) 4

58 ( 8.6%)619 (91.4%)204

Ethnic Group WhiteBlackOtherMissing

568 (100%) 0 0 2

687 (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 50 144 (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 :

Norwich Sheffield Total

InitialRisk ScoreMean (SD)

Intervention Group 145 138 283 9.0% (7.5%)

Initial Risk Allocation :

Low risk 31 34 65 (23.0%) 2.7% (9.0%)

Intermediate risk 57 47 104 (36.7%) 7.5% (3.7%)

High risk 57 57 114 (40.3%) 13.8% (0.8%)

Recommended for DXA 67 63 130 (45.9%) 8.1% (4.8%)

Feasibility Study (6)

• DXA Results (N=127):

Norwich Sheffield Total

InitialRisk ScoreMean (SD)

Mean t-score (SD) -1.05 (0.85) -0.81 (1.07) -0.93 (0.96)

BMD Category :

Normal 31 33 64 (50%) 7.3% (4.7%)

Osteopaenic 29 26 55 (43%) 8.5% (4.8%)

Osteoporotic 5 3 8 ( 7%) 11.9% (4.1%)

DNA 2 1 3

Feasibility Study (7)

• Medication :

91 (32%) recommended treatment in intervention group;

66 prescribed medication : Alendronate 34Risedronate 32

4 (1.4%) prescribed medication in control group.

Feasibility Study (8)

• 6-Month Follow-Up :

• 9 (1.6%) fractures objectively verified.

Norwich Sheffield Total

Mailings sent out 287 283 570

Mailings returned 284 255539 (94.6%)

Declines returned 2 6 8 ( 1.4%)

Non-response 1 22 23 ( 4.0%)

Feasibility Study (9)

• Second DXA Results (Norwich only, N=21):

N(%)

Mean t-score (SD) -1.65 (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) BirminghamBristol ManchesterSheffield SouthamptonYork

• 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:Female70 – 85 yearsExclusion:Known to be on prescription treatment for osteoporosisAny 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 questionnaireEQ-5DSF-12State-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 FracturesMortalityPsychological AnxietyQuality 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:-