2010 Guidelines 2010 Clinical Practice Guidelines for the

2010 Guidelines 2010 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

2010 Guidelines Fracture Risk Assessment Section Four

2010 Guidelines Indications for BMD Testing in Older Adults (Age > 50 Years) • • All women and men age > 65 Postmenopausal women, and men aged 50 – 64 with clinical risk factors for fracture: – – – – – Fragility fracture after age 40 Prolonged glucocorticoid use† Other high-risk medication use* Parental hip fracture Vertebral fracture or osteopenia identified on X-ray Current smoking High alcohol intake Low body weight (< 60 kg) or major weight loss (>10% of weight at age 25) Rheumatoid arthritis Other disorders strongly associated with osteoporosis † At least three months cumulative therapy in the previous year at a prednisone-equivalent dose ≥ 7. 5 mg daily; * e. g. aromatase inhibitors, androgen deprivation therapy.

2010 Guidelines Indications for BMD Testing for Individuals Under Age 50 Years • • Fragility fracture Prolonged use of glucocorticoids* Use of other high-risk medications† Hypogonadism or premature menopause • Malabsorption syndrome • Primary hyperparathyroidism • Other disorders strongly associated with rapid bone loss and/or fracture † At least three months cumulative therapy in the previous year at a prednisone-equivalent dose ≥ 7. 5 mg daily; * e. g. aromatase inhibitors, androgen deprivation therapy.

2010 Guidelines BMD Reporting Categories Age Category Criteria* Below expected range for age Z-score < -2. 0 Within expected range for age Z-score > -2. 0 Severe (established) osteoporosis T-score < -2. 5 with fragility fracture Osteoporosis T-score < -2. 5 Low bone mass T-score -1. 1 to -2. 4 Normal T-score > -1. 0 < 50 years > 50 years Click here for a list of considerations about BMD reporting.

2010 Guidelines Absolute 10 -year Fracture-Risk Tools • Tools validated in Canada (choice based on personal preference and convenience) – CAROC: Joint initiative of the Canadian Association of Radiologists and Osteoporosis Canada 1 – FRAX: Fracture Risk Assessment Tool developed by the World Health Organization 2 • There are large differences in fracture rates from country to country 3 -5 – Assessment tools need to be country specific 1. Leslie WD, Berger C, et al. Osteoporosi Int; In press. . 2. Leslie WD, Lix LM, et al. Osteoporosi Int; In press. 3. Kanis JA, et al. J Bone Miner Res 2002; 17(7): 1237 -1244. 4. Melton LJ, III. Endocrinol Metab Clin North Am 2003; 32(1): 1 -13. 5. Leslie WD, et al. J Bone Miner Res 2010; in press.

2010 Guidelines 10 -year Risk Assessment: CAROC • Semiquantitative method for estimating 10 -year absolute risk of a major osteoporotic fracture* in postmenopausal women and men over age 50 – Stratified into three zones (Low: < 10%, moderate, high: > 20%) • Basal risk category is obtained from age, sex, and T-score at the femoral neck * Combined risk for fractures of the proximal femur, vertebra [clinical], forearm, and proximal humerus. Other fractures attributable to osteoporosis are not reflected; total osteoporotic fracture burden is underestimated Siminoski K, et al. Can Assoc Radiol J 2005; 56(3): 178 -188.

2010 Guidelines 10 -year Risk Assessment for Women (CAROC Basal Risk) Click here for CAROC risk assessment in table format. Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

2010 Guidelines 10 -year Risk Assessment for Men (CAROC Basal Risk) Click here for CAROC risk assessment in table format. Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

2010 Guidelines Risk Assessment with CAROC: Important Additional Risk Factors • Factors that increase CAROC basal risk by one category (i. e. , from low to moderate or moderate to high) – Fragility fracture after age 40*1, 2 – Recent prolonged systemic glucocorticoid use**2 * Hip fracture, vertebral fracture, or multiple fracture events should be considered high risk ** >3 months use in the prior year at a prednisone-equivalent dose ≥ 7. 5 mg daily 1. Siminoski K, et al. Can Assoc Radiol J 2005; 56(3): 178 -188. 2. Kanis JA, et al. J Bone Miner Res 2004; 19(6): 893 -899.

2010 Guidelines Example of Adjusting Basal Risk: Based on Additional Risk Factors • 0. 0 Femoral neck T-score • 60 -year-old woman • Femoral neck T-score = -2. 8 • Based on age and T-score alone = moderate risk History of fragility fracture or prolonged systemic glucocorticoid use would shift her to high risk -0. 5 -1. 0 LOW RISK (<10%) -1. 5 -2. 0 MODERATE RISK -2. 5 -3. 0 HIGH RISK (> 20%) -3. 5 -4. 0 50 55 60 65 70 75 80 85 Age (years) Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

2010 Guidelines Risk Assessment Using FRAX • Uses age, sex, BMD, and clinical risk factors to calculate 10 -year fracture risk* – BMD must be femoral neck – FRAX also computes 10 -year probability of hip fracture alone • This system has been validated for use in Canada 1 • There is an online FRAX calculator with detailed instructions at: www. shef. ac. uk/FRAX * composite of hip, vertebra, forearm, and humerus 1. Leslie WD, et al. Osteoporos Int; In press.

2010 Guidelines FRAX Tool: On-line Calculator www. shef. ac. uk/FRAX.

2010 Guidelines FRAX Clinical Risk Factors • • • Parental hip fracture Prior fracture Glucocorticoid use Current smoking High alcohol intake Rheumatoid arthritis

2010 Guidelines Absolute Fracture Risk Tools • Calculate risk for treatment-naïve patients only • Cannot be used to monitor response to therapy • Using CAROC or FRAX in a patient on therapy only reflects theoretical risk of a hypothetical patient who is treatment naïve and does not reflect the risk reduction associated with therapy

2010 Guidelines Laboratory assessment: Bone Turnover Markers (BTMs) • The value of bone turnover markers (BTMs) in estimating future risk of fracture in individual patients needs further research • As a result, BTMs have not yet been integrated in current fracture-risk assessment systems Brown JP, et al. Clin Biochem 2009; 42(10 -11): 929 -42.

2010 Guidelines VFA Recognition and Reporting • VFA is a scanning and software option on bone densitometers • A fracture detected by vertebral fracture assessment (VFA) or radiograph should be considered a prior fracture under the FRAX or CAROC system

VFA JB 6/23/04; WW 5/11/04 IVA/VFA 2010 Guidelines • On the left we see a normal lateral VFA (vertebral fracture assessment) showing no vertebral fracture as high as we can see (T 6). • On the right, we see a lateral VFA with a wedge fracture of T 12

2010 Guidelines Impact of Prior Vertebral Fracture on Risk Assessment • Unequivocal vertebral fractures unrelated to trauma are associated with a five-fold increased risk for recurrent vertebral fractures • A fracture detected from VFA or radiograph alone should be considered a prior fracture under the FRAX or CAROC system

2010 Guidelines Fracture Risk Assessment after Age 50: Summary Statements Statement Strength Clinical risk factors (especially age, prior fragility fracture and prolonged glucocorticoid exposure) enhance fracture prediction independent of BMD alone Level 1 The Canadian FRAX tool and CAROC are well calibrated for prediction of major osteoporotic fracture risk Level 1 The CAROC model shows a high overall degree of concordance in risk categorization with the Canadian FRAX system Level 1 Click here for a summary of the grading system for levels of evidence.

2010 Guidelines Recommendations for Fracture Risk Assessment Recommendation Grade Absolute fracture risk assessment should be based on established factors including age, BMD, prior fragility fracture, and glucocorticoid use A The 2010 CAROC and Canadian FRAX should be used in Canada since they have been validated in the Canadian population A Multiple fractures confer greater risk than a single fracture. In addition, prior fractures of the hip and vertebra carry greater risk than other fracture sites B Click here for a summary of the grading system for levels of evidence.

2010 Guidelines Recommendations for Fracture Risk Assessment (Cont'd) Recommendation Grade Initiation of pharmacologic treatment for osteoporosis should be predicated on an assessment of absolute fracture risk using a validated fracture prediction tool D In both men and women age 50 or older, only the femoral neck Tscore (derived from the NHANES III reference range for Caucasian women) should be used for the calculation of future osteoporotic fracture risk under the Canadian FRAX and CAROC systems D For purposes of BMD reporting, 2010 CAROC is the preferred national risk assessment system at the present time D All individuals with a T-score of the spine or hip ≤ -2. 5 should be considered as having at least moderate risk of osteoporotic fractures D

2010 Guidelines Back-up Material Additional slides that can be accessed from hyperlinks on core slides Section Four – Fracture Risk Assessment

2010 Guidelines Disorders Associated with Osteoporosis and Increased Fracture Risk • • • Primary hyperparathyroidism Type I diabetes Osteogenesis imperfecta Untreated long-standing hyperthyroidism, hypogonadism, or premature menopause (< 45 years) Cushing’s disease Chronic malnutrition or malabsorption Chronic liver disease Chronic obstructive pulmonary disease (COPD) Chronic inflammatory conditions (e. g. , rheumatoid arthritis [RA], inflammatory bowel disease) Return to main presentation

2010 Guidelines Considerations for BMD Reporting • T-score is the number of standard deviations that BMD is above or below the mean normal peak BMD for young white women (NHANES III for hip measurements) • Z-score is the number of standard deviations that BMD is above or below the mean normal BMD for sex, age, and (if references are available) race/ethnicity

2010 Guidelines Considerations for BMD Reporting (Cont'd) • Osteoporosis cannot be diagnosed by BMD alone below age 50 • BMD reporting is based upon lowest value for lumbar spine (minimum two vertebral levels), total hip, and femoral neck – If either the lumbar spine or hip is invalid, then the forearm should be scanned and the distal one-third region reported • Fracture risk assessment under the FRAX / CAROC system is based upon the femoral neck T-score only Return to main presentation

2010 Guidelines Variations in Estimated FRAX 10 -Year Fracture Probabilities According to Country Canada Return to main presentation Version 3. 1 FRAX website (www. sheffield. ac. uk/FRAX).

2010 Guidelines Bone Turnover Markers and Fracture Risk in Postmenopausal Women Relative risk 4. 0 3. 5 Serum BAP 3. 0 Urinary CTX 3. 2 (1. 4 -7. 4) 2. 5 2. 1 (1. 1 -4. 4) 1. 8 (0. 8 -4. 6) 2. 0 1. 5 0. 7 (0. 3 -1. 8) 1. 0 1. 3 1. 2 (0. 5 -3. 1) (0. 5 -2. 8) 0. 5 0. 0 Q 1 Q 2 Q 3 Bone marker levels in quartiles Q 4 Garnero P, et al. J Bone Miner Res 2000; 15(8): 1526 -1536.

2010 Guidelines Hip Fracture Risk: BMD and BTM Risk factor(s) 10 -year Prevalence Odds Relative probability (%) ratio Risk (%) Average 100 1. 0 18. 0 Low BMD 56 2. 8 1. 4 23. 6 Prior fracture 39 3. 5 1. 77 28. 8 High CTX 23 2. 4 1. 82 29. 5 Low BMD + prior fracture 23 4. 1 2. 39 36. 3 Low BMD + high CTX 16 4. 1 2. 74 40. 1 Prior fracture + high CTX 12 5. 3 3. 50 47. 3 All of the above 7 5. 8 4. 43 54. 5 Return to main presentation Johnell O, et al. Osteoporos Int 2002; 13(7): 523 -526.

2010 Guidelines Criteria Used to Assign Levels of Evidence: Studies of Diagnosis Level 1 Criteria i Independent interpretation of test results ii Independent interpretation of the diagnostic standard iii Selection of people suspected, but not known to have the disorder iv Reproducible description of the test and diagnostic standard v At least 50 people with and 50 people without the disorder 2 Meets four of the Level 1 criteria 3 Meets two of the Level 1 criteria 4 Meets one or two of the Level 1 criteria

2010 Guidelines Criteria Used to Assign Levels of Evidence: Studies of Treatment and Intervention Level Criteria 1+ Systematic overview of meta-analysis of RCTs 1 One RCT with adequate power 2+ Systematic overview or meta-analysis of Level 2 RCTs 2 RCT that does not meet Level 1 criteria 3 5 Non-RCT or cohort study Before/after study, cohort study with non-contemporaneous controls, case-control study Case series without controls 6 Case report or case series of < 10 patients 4 RCT = randomized, controlled study

2010 Guidelines Criteria Used to Assign Levels of Evidence: Studies of Prognosis Level Criteria i ii 1 Inception cohort of patients with the condition of interest, but free of the outcome of interest Reproducible inclusion and exclusion criteria iii Follow-up of at least 80% of participants iv Statistical adjustment for confounders v Reproducible description of the outcome measures 2 Meets criterion i and three of the other four Level 1 criteria 3 Meets criterion i and two of the other four Level 1 criteria 4 Meets criterion i and one of the other four Level 1 criteria Return to main presentation

2010 Guidelines Criteria Used to Assign Grades of Recommendation Level Criteria A Need supportive level 1 or 1+ evidence plus consensus* B Need supportive level 2 or 2+ evidence plus consensus* C Need supportive level 3 evidence plus consensus D Any lower level of evidence supported by consensus * As appropriate level of evidence was necessary, but not sufficient to assign a grade in recommendation; consensus was required in addition. Return to main presentation

2010 Guidelines 10 -year Risk Assessment for Women (CAROC Basal Risk) Age Low Risk Moderate Risk High Risk 50 above -2. 5 to -3. 8 below -3. 8 55 above -2. 5 to -3. 8 below -3. 8 60 above -2. 3 to -3. 7 below -3. 7 65 above -1. 9 to -3. 5 below -3. 5 70 above -1. 7 to -3. 2 below -3. 2 75 above -1. 2 to -2. 9 below -2. 9 80 above -0. 5 to -2. 6 below -2. 6 85 above +0. 1 to -2. 2 below -2. 2 Return to main presentation Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

2010 Guidelines 10 -year Risk Assessment for Men (CAROC Basal Risk) Age Low Risk Moderate Risk High Risk 50 above -2. 5 to -3. 9 below -3. 9 55 above -2. 5 to -3. 9 below -3. 9 60 above -2. 5 to -3. 7 below -3. 7 65 above -2. 4 to -3. 7 below -3. 7 70 above -2. 3 to -3. 7 below -3. 7 75 above -2. 3 to -3. 8 below -3. 8 80 above -2. 1 to -3. 8 below -3. 8 85 above -2. 0 to -3. 8 below -3. 8 Return to main presentation Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].