vs. The AGREE Instrument Pradeep Navaratne Andrew J. Organek McMaster University Department of Family Medicine Evidence Based Medicine Session December 12, 2007

Primary Resources Brown, J & Fortier, M. Canadian Consensus Conference on Osteoporosis, 2006 update. JOGC, Feb 2006, 172:S95-S112 The AGREE Collaboration. Appraisal of Guidelines for Research & Evaluation (AGREE) Instrument.

Outline Introduction and Epidemiology Screening and Monitoring Osteoporosis Treating Osteoporosis The AGREE Instrument Applying AGREE to the Osteoporosis Guidelines Conclusions

Introduction and Epidemiology

Introduction Epidemiology Definitions Risk Factors Assessment General Recommendations

Introduction Osteoporosis is a systemic skeletal disorder characterized by a low BMD and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk Osteoporosis is a disease with its roots in childhood as bone size, strength and mineralization peak in one’s 20’s Peak bone mass, while largely genetically determined can be affected by: inadequate Ca and Vit D intake, poor nutrition, lack of physical exercise, smoking and other lifestyle factors

WHO Diagnostic Categories for BMD in Postmenopausal Caucasian Women Normal: BMD or BMC not more than 1 SD below the peak bone mass or young adult mean (T-score above -1) Osteopenic: BMD or BMC between 1 and 2.5 SD below the young adult mean (T-score between -1 and -2.5) Osteoporosis: BMD or BMC 2.5 SD or more below the young adult mean (T-score at or below -2.5) Severe osteoporosis (established osteoporosis): BMD or BMC 2.5 SD or more below the young adult mean (T-score at or below -2.5) and the presence of one or more fragility fractures WHO: World Health Organization; BMD: bone mineral density; BMC: bone mineral content; SD: standard deviation

Epidemiology Prevalence increases with age from approx. 6% at 50 years of age to over 50% above 80 years of age Because of its association with fractures, osteoporosis is a major public health hazard with high morbidity, mortality, and social costs Annual economic implications of hip fracture in Canada are $650 million and are expected to rise to $2.4 billion by 2041

Fragility Fracture - Definition Fracture caused by injury that would be insufficient to fracture normal bone The result of reduced compressive and/or torsional strength of bone (WHO) Fracture that occurs as a result of minimal trauma

Major Risk Factors Age > 65 years Vertebral compression fracture Fragility # > 40yo FHx of osteoporotic fracture Systemic glucocorticoid therapy 3 months Malabsorption syndrome Primary hyperparathyroidism Propensity to fall Osteopenia apparent on XR Hypogonadism Early menopause (< 45yo)

Minor Risk Factors Rheumatoid arthritis Past history of clinical hyperthyroidism Chronic anticonvulsant therapy Low dietary calcium intake Smoker Excessive alcohol intake Excessive caffeine intake Weight 57 kg Weight loss 10% of weight at age 25 Chronic heparin therapy

Assessment Only 5% to 25% of Canadian women with fragility fractures are subsequently investigated for osteoporosis, and only half of those receive treatment It is important to assess for the presence of one major or two minor risk factors for osteoporosis to identify who should have a BMD test Osteoporosis Canada (former Osteoporosis Society of Canada) recommends that all postmenopausal women older than 50 years be assessed for the presence of risks factors for osteoporosis

General Recommendations The goals of osteoporosis management should be fracture risk assessment and prevention of fracture (IB). Bone mineral density should not be viewed as the only indicator for management success because therapy may or may not be associated with significant increases in BMD (IA)

General Recommendations Physicians should be aware that a prevalent vertebral or non-vertebral fragility fracture markedly increases the risk of future fracture (IA)

General Recommendations Fragility fracture after the age of 40, over 65 years of age without fragility fracture, low BMD, and family history of osteoporotic fracture (especially maternal hip fracture) should be recognized as the key risk factors for fragility fractures. Systemic glucocorticoid use of more than 3 months duration should be considered as another major risk factor (IA)

General Recommendations Evaluation of osteoporosis in postmenopausal women should include the assessment of clinical risk factors for low BMD and BMD testing (IB)

Screening and Monitoring Osteoporosis

Central Dual Energy X-ray Absorptiometry (DXA) Radiographs Peripheral Bone Mineral Density Testing Bone Turnover Markers

Central Dual Energy X-ray Absorptiometry (DXA) Depending on the clinical situation, central DXA scans (lumbar spine and hip) may be repeated in 1 to 3 years, on the same instrument, using the same procedure Usually done to monitor the response to a pharmacologic therapy or to document the stability of bone density in untreated patients at risk for bone loss

DXA Recommendation Central (hip and spine) measurements by dual energy x-ray absorptiometry (DXA) should be used for both risk assessment (IA) and follow-up (IB), as they provide the most accurate and precise measurements of BMD

Radiographs AP and lateral projections of both the thoracic and lumbar spine radiographs remain the best method for assessing the presence of vertebral fractures

Radiographs Recommendation Postmenopausal women with historical height loss greater than 6 cm, prospective height loss greater than 2 cm, kyphosis, or acute incapacitating back pain syndrome should be sent for spine radiographs with a specific request to rule out vertebral fractures (IA)

Peripheral Bone Mineral Density Testing Peripheral BMD can be measured by DXA, ultrasound, or single X-ray absorptiometry at several skeletal sites (radius, phalanx, calcaneus, tibia, metatarsal) Predictive of hip # in women over the age of 65, but cannot be used at the present time for follow-up Peripheral testing may play an important role for women in underserviced areas and in raising awareness about osteoporosis These services may be provided by unregulated practitioners, raising concerns about quality control

Peripheral BMD Recommendation Further evidence should be collected to determine the role of peripheral BMD measurements (e.g., ultrasound or DXA measurements in the radius, phalanx, or heel) in clinical practice (II-2D)

Bone Turnover Markers Provide information that is different and complementary to BMD Because of the coupling between resorption and formation in the remodelling cycle, both markers of bone formation (within 3 to 6 months) and bone resorption (within 1 to 3 months) will decrease or increase in parallel, in response to drug therapies Bone formation markers include: serum osteocalcin, bone alkaline phosphatase (BAP), and the C- and N- terminal propeptides of type I collagen (PICP, PINP)

Bone Turnover Markers Bone resorption markers include urinary hydroxyproline, urinary pyridinoline (PYR), urinary deoxypyridinoline (D-PYR), as well as urinary collagen type I cross-linked N-telopeptide (uNTx), and urinary and serum collagen type I cross-linked C- telopeptide (uCTx and sCTx) To reduce the impact of circadian variability on clinical interpretation of bone turnover markers, it is important that the sample is early morning (serum before 9 AM, first or second morning urine with Cr correction) after an overnight fast

Bone Turnover Markers Recommendation Until more data becomes available on other clinical applications, bone turnover markers can be used to rapidly assess adherence and effectiveness of pharmacological interventions (IB)

Treating Osteoporosis

Calcium and Vitamin D Hormone Therapy Bisphosphonates SERMs Calcitonin PTH When To Initiate Therapy Length of Therapy Efficacy of Therapy

Calcium and Vitamin D Calcium –Adequate dietary Ca necessary for mineralization of skeleton and attainment of peak bone mass –Increasing dietary Ca associated with increasing BMD –Many options, Ca Carbonate least expensive

Calcium and Vitamin D Vitamin D –High prevalence of deficiency in Canada due to northern latitude (short summer, long winter) –Worse in house-bound and institutionalized –Vit D supplementation in those with deficiency probably reduces vertebral #s and may also impact non vertebral #s –Muscle strength is affected by Vit D, which may reduce risk of falling –Ca and Vit D supplementation is not effective in reducing the risk of #s in community-dwelling older women w/ ≥ 1 self- reported risk factor, or those with recent fragility #

Calcium and Vitamin D Recommendation Although it might not be sufficient as a sole therapy for osteoporosis, routine supplementation with Ca (1000mg/d) and Vit D (800 IU/D) is still recommended as mandatory adjunct therapy to the main pharmacological interventions (1B)

Hormone Therapy SOGC recommends the use of HT in postmenopausal women for moderate to severe symptoms of menopause For symptomatic menopausal women choosing HT as a therapeutic option, osteoporosis prevention can still be considered as a secondary benefit due to the positive effect ovarian hormones have on BMD

Hormone Therapy Recommendation HT should be prescribed to symptomatic postmenopausal women as the most effective therapy for symptom relief (IA) and a reasonable choice for the prevention of bone loss and fracture (IA)

Bisphosphonates 3 oral bisphosphonates approved in Canada for the prevention and treatment of osteoporosis: etidronate, alendronate, and risedronate Alendronate (Fosamax) has been found to reduce #s both in high-risk women with vertebral fractures and those with osteopenia The most commonly prescribed alendronate doses are 70 mg once weekly or 10 mg daily

Bisphosphonates A significant reduction in new vertebral fractures in high-risk women with osteoporosis and vertebral fractures has been observed within the first year of therapy with risedronate (Actonel) Risedronate is prescribed either at 35 mg once weekly or 5 mg daily

Bisphosphonates Recommendations Treatment with alendronate or risedronate should be considered to decrease vertebral, non-vertebral, and hip fractures (IA) Treatment with etidronate can be considered to decrease vertebral fractures (IB)

Selective Estrogen Receptor Modulators (SERMs) Presently, raloxifene is the only SERM approved in Canada for the management of osteoporosis Because of its vertebral fracture efficacy data and its additional extraskeletal benefits, raloxifene (Evista)60 mg daily is recommended to prevent and treat osteoporosis in younger, asymptomatic postmenopausal women

SERMs Recommendation Treatment with raloxifene should be considered to decrease vertebral fractures (IA)

Calcitonin Effective in specifically inhibiting osteoclastic bone resorption Poor oral absorption necessitates either SC or intranasal administration Nasal spray calcitonin 200 IU is approved for the treatment of postmenopausal osteoporosis and has a possible analgesic effect that may be useful in managing the pain of acute vertebral compression fractures BMD stabilizes at the lumbar spine and at the hip, similar to the effect of calcium and vitamin D

Calcitonin Recommendation Treatment with calcitonin can be considered to decrease vertebral fractures and to reduce pain associated with acute vertebral fractures (IB)

Parathyroid Hormone Teriparatide (recombinant human PTH(1-34), the only approved drug is this class Teriparatide (Forteo) is administered as a daily subcutaneous injection of 20 mcg and is approved for therapy of up to 18 months Teriparatide is contraindicated patients with metabolic bone diseases other than osteoporosis in patients with cancer in children, adolescents, pregnancy and breastfeeding

Parathyroid Hormone Recommendation Treatment with teriparatide should be considered to decrease vertebral and non- vertebral fractures in postmenopausal women with severe osteoporosis (IA)

When To Initiate Therapy OSC now proposes that age, sex, fracture history, and glucocorticoid use be incorporated into the assessment of fracture risk Additional clinical variables may be included in the absolute fracture risk estimate in the future when the methods are more firmly established and validated. OSC recommends using the lowest BMD T-score to determine a person’s 10-year absolute fracture risk: combined risk for fractures of the hip, spine, forearm, and proximal humerus

When To Initiate Therapy There are 3 categories for absolute risk: –Low Risk (less than 10%), –Moderate Risk (10% to 20%) –High Risk (over 20%) Fragility fracture after age 40 or glucocorticoid use increase risk to the next level

Low Risk Therapeutic intervention could be limited to counseling about bone hygiene: –Nutrition (adequate calcium and vitamin D through diet and/or supplements), –Physical activity –Risk-factor modification (smoking, alcohol, weight)

Moderate Risk Pharmacological intervention could be considered on: –A woman’s perception of a serious threat arising from the disease (e.g., strong FHx of osteoporotic #) – Extra skeletal benefits associated with some therapeutic options such as raloxifene Either of these will lead to an improved persistence

High Risk Pharmacological intervention should be considered, particularly those known to have low BMD or prevalent fragility fracture Not all clinical risk factors for fracture are amenable to pharmacotherapy (e.g., in a non- osteoporotic individual with high risk of falling, a fall prevention program could be preferred to pharmacotherapy

Length of Therapy Teriparatide - 18 months in Canada. HT - 5 years Risedronate - 7 years Raloxifene - 8 years Alendronate - 10 years

Combination Therapy Recommendation Although combination of anti-resorptive therapies maybe synergistic in increasing BMD, the anti-fracture effectiveness has not been proven; therefore, it is not recommended (ID)

Efficacy of Therapy RCTs have proven the efficacy of drugs such as bisphosphonates, calcitonin, estrogen and progestin therapy, SERMs, and recombinant human PTH (1-34) to treat osteoporosis These studies also proved undoubtedly that drug therapies for osteoporosis can reduce risk of fractures and improve quality of life

Efficacy of Therapy The studies’ beneficial results are obtained under ideal conditions In real life, effectiveness (efficacy in real practice) matters more than efficacy Compliance with and adherence to a specific drug may influence effectiveness

Efficacy of Therapy Adequate calcium and vitamin D through diet and/or supplements are essential adjuncts to osteoporosis prevention and treatment

The Instrument

The AGREE Instrument Introduction Purpose Structure and Content Domains Applying the Instrument Calculating Scores

Introduction The AGREE Collaboration started in 1998 as a research project ‘Appraising clinical guidelines' funded by the European Union In November 2002 the AGREE Collaboration received additional funding from the Accompanying Measures EU until April 2004 to further disseminate and implement the AGREE Instrument

Purpose For assessing the quality of clinical practice guidelines: –confidence that potential biases have been addressed adequately –recommendations are both internally and externally valid, and feasible for practice –predicted validity of a guideline (i.e., the likelihood that it will achieve its intended outcome)

Purpose Takes into account benefits, harms and costs of the recommendations, as well as the practical issues attached to them Assessment includes –Judgements about methods used for developing the guidelines –Content of the final recommendations –Factors linked to their uptake

Structure and Content 23 key items organized in six domains Each domain is intended to capture a separate dimension of guideline quality

Domains Scope and purpose - overall aim of the guideline; specific clinical questions and the target patient population Stakeholder involvement - extent to which the guideline represents the views of its intended users Rigour of development - process used to gather and synthesize the evidence; methods to formulate and update recommendations Clarity and presentation - language and format of the guideline Applicability - likely organizational, behavioural and cost implications of applying the guideline Editorial independence - independence of the recommendations; acknowledgement of possible conflicts of interest

Applying the Instrument Recommended 2-4+ appraisers Each item is rated on a 4-point scale ranging from 4 (Strongly Agree) to 1 (Strongly Disagree), measuring the extent to which each item has been fulfilled If you are confident that the criterion has been fully met then you should answer ‘Strongly Agree’ If you are confident that the criterion has not been fulfilled at all or if there is no information available then you should answer ‘Strongly Disagree’

Calculating Scores

Applying to the Osteoporosis Guidelines

Scope and Purpose Clearly stated: “To provide guidelines for the health care provider on the diagnosis and clinical management of postmenopausal osteoporosis”

Scope and Purpose “Strategies for identifying and evaluating high-risk individuals, the use of bone mineral density (BMD) and bone turnover markers in assessing diagnosis and response to management, and recommendations regarding nutrition, physical activity, and the selection of pharmacologic therapy to prevent and manage osteoporosis.”

Scope and Purpose

“postmenopausal women” ? Does this apply to ALL postmenopausal women vs. N. American vs. Canadian

Scope and Purpose Domain Score obtained score (x) = = 11 x-3/12-3 = 8/9 Domain Score = 88.89%

Stakeholder Involvement Lists Authors, Guidelines Committee, and Coordinator with qualifications Qualifications include CFPC and FRCPC (likely OBs, given SOGC) No info listed about composition, discipline and relevant expertise of group

Stakeholder Involvement No evidence of this

Stakeholder Involvement “for the health care provider” Could be more specific...

Stakeholder Involvement No evidence of this

Stakeholder Involvement Domain Score obtained score (x) = = 7 x-4/16-4 = 3/12 Domain Score = 25%

Rigour of Development “MEDLINE and the Cochrane database were searched for articles in English on subjects related to osteoporosis diagnosis, prevention, and management from March 2001 to April The authors critically reviewed the evidence and developed the recommendations according to the Journal of Obstetrics and Gynaecology Canada’s methodology and consensus development process.” No further details of strategy published

Rigour of Development “articles” “in English” “March 2001 to April 2005” - no reason listed

Rigour of Development “ The Authors critically reviewed the evidence and developed the recommendations according to the Journal of Obstetrics and Gynaecology Canada’s methodology and consensus development process.” No details listed No further information found on SOGC website

Rigour of Development Good summaries/tables of common side effects, contraindications and precautions Recognition of appropriate populations for specific treatments (eg. HRT)

Rigour of Development All recommendations linked with list of references on which they are based

Rigour of Development Lists only of Authors and Guidelines Committee No evidence of external review

Rigour of Development No clear procedure or timescale has been given for updating the guideline Note: This guideline is an update!

Rigour of Development Domain Score obtained score (x) = = 17 x-7/28-7 = 10/21 Domain Score = 47.62%

Clarity and Presentation Appropriate use of specific information and uncertainty in recommendations Levels of evidence given according to the Canadian Taskforce on the Periodic Health Examination

Clarity and Presentation This is done quite well!

Clarity and Presentation Recommendations listed up front, and reviewed in context within the guideline

Clarity and Presentation None known/noted Available online???

Clarity and Presentation Domain Score obtained score (x) = = 13 x-4/16-4 = 9/12 Domain Score = 75%

Applicability No formal discussion of barriers No major organizational changes necessary for given recommendations

Applicability This is not addressed in the guidelines

Applicability No clearly defined review criteria presented

Applicability Domain Score obtained score (x) = = 4 x-3/12-3 = 1/9 Domain Score = 11.11%

Editorial Independence “The development of this consensus guideline was supported by unrestricted educational grants from Berlex Canada” No explicit statement that funding body has not influenced recommendations

Editorial Independence No explicit statement regarding conflicts of interest

Editorial Independence Domain Score obtained score (x) = = 3 x-2/8-2 = 1/6 Domain Score = 16.67%

Further Comments

Domain Scores Scope and Purpose Overall aim of the guideline Specific clinical questions and the target patient population 88.89% Stakeholder Involvement Extent to which the guideline represents the views of its intended users 25% Rigour of Development Process used to gather and synthesize the evidence Methods to formulate and update recommendations 47.62% Clarity and Presentation Language and format of the guideline 75% Applicability Likely organizational, behavioural and cost implications of applying the guideline 11.11% Editorial Independence Independence of the recommendations Acknowledgement of possible conflicts of interest 16.67%

Overall Assessment Guidelines provide useful review of currently available screening/monitoring techniques and available treatments, with current evidence for their use Ensure stakeholder involvement in clinical decisions, as not incorporated into guidelines Little to no consideration/recognition of cost or impact of following guidelines yes

Conclusions

AGREE Instrument is an easy-to-use tool to evaluate guidelines Multiple evaluators recommended SOGC Osteoporosis Guidelines are pretty and well-defined, but are lacking in several areas (as discussed)

REFERENCES Brown, J & Fortier, M. Canadian Consensus Conference on Osteoporosis, 2006 update. JOGC, Feb 2006, 172:S95-S112. The AGREE Collaboration. Appraisal of Guidelines for Research & Evaluation (AGREE) Instrument. Chocosho+Picks asp

THANK YOU Questions?