PROOF COVER SHEET AUTHOR QUERIES. J. A. Kanis, N. C. Harvey, H. Johansson, A. Ode n, W. D. Leslie, and E. V. McCloskey

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1 PROOF COVER SHEET Author(s): Article title: Article no: Enclosures: J. A. Kanis, N. C. Harvey, H. Johansson, A. Ode n, W. D. Leslie, and E. V. McCloskey FRAX and fracture prediction without bone mineral density ICMT_A_ ) Query sheet 2) Article proofs Dear Author, Please check these proofs carefully. It is the responsibility of the corresponding author to check against the original manuscript and approve or amend these proofs. A second proof is not normally provided. Informa Healthcare cannot be held responsible for uncorrected errors, even if introduced during the composition process. The journal reserves the right to charge for excessive author alterations, or for changes requested after the proofing stage has concluded. The following queries have arisen during the editing of your manuscript and are marked in the margins of the proofs. Unless advised otherwise, submit all corrections using the CATS online correction form. Once you have added all your corrections, please ensure you press the Submit All Corrections button. Please review the table of contributors below and confirm that the first and last names are structured correctly and that the authors are listed in the correct order of contribution. Contrib. No. Prefix Given name(s) Surname Suffix 1 J. A. Kanis 2 N. C. Harvey 3 H. Johansson 4 A. Ode n 5 W. D. Leslie 6 E. V. McCloskey AUTHOR QUERIES No Queries

2 CLIMACTERIC 2015; EARLY ONLINE: REVIEW ARTICLE FRAX and fracture prediction without bone mineral density J. A. Kanis 1, N. C. Harvey 2, H. Johansson 1,3, A. Odén 1, W. D. Leslie 4, and E. V. McCloskey 1 1 Centre for Metabolic Bone Diseases, University of Sheffield Medical School, UK, 2 MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK, 3 Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, and 4 University of Manitoba, Winnipeg, Canada ABSTRACT The major application of FRAX in osteoporosis is to direct pharmacological interventions to those at high risk of fracture. Whereas the efficacy of osteoporosis treatment, with the possible exception of alendronate, is largely independent of baseline bone mineral density (BMD), it remains a widely held perception that osteoporosis therapies are only effective in the presence of low BMD. Thus, the use of FRAX in the absence of BMD to identify individuals requiring therapy remains the subject of some debate and is the focus of this review. The clinical risk factors used in FRAX have high evidence-based validity to identify a risk responsive to intervention. The selection of high-risk individuals with FRAX, without knowledge of BMD, preferentially selects for low BMD and identifies a risk that is responsive to pharmacological intervention. The prediction of fractures with the use of clinical risk factors alone in FRAX is comparable to the use of BMD alone to predict fractures and is suitable, therefore, in the many countries where facilities for BMD testing are sparse. In countries where access to BMD is greater, FRAX can be used without BMD in the majority of cases and BMD tests reserved for those close to a probability-based intervention threshold. Thus concerns surrounding the use of FRAX in clinical practice without information on BMD are largely misplaced. Introduction The aim of treatments for osteoporosis is to decrease the risk of fragility fractures. Thus, the ability to assess fracture risk is critical in identifying patients who are eligible for intervention 1,2. In 2008, the World Health Organization (WHO) Collaborating Centre at Sheffield, UK released FRAX Õ the fracture risk assessment tool for estimating individualized 10-year probability of hip and major osteoporotic fracture (hip, clinical spine, distal forearm, and proximal humerus) 3. The FRAX tool integrates eight clinical risk factors (CRFs: prior fragility fracture, parental hip fracture, smoking, systemic glucocorticoid use, excess alcohol intake, body mass index, rheumatoid arthritis, and other causes of secondary osteoporosis), which, in addition to age and sex, contribute to a 10-year fracture risk estimate independently of bone mineral density (BMD) 2,4. BMD from the femoral neck is an optional input variable when FRAX is used to calculate 10-year fracture probability 5. Fracture probability is computed taking both the risk of fracture and the risk of death into account. This is important because some of the risk factors affect both these outcomes. Examples include increasing age, low body mass index (BMI), low BMD, glucocorticoids and Correspondence: Professor J. A. Kanis, w.j.pontefract@shef.ac.uk ß 2015 International Menopause Society ARTICLE HISTORY Received 14 July 2015 Accepted 10 August 2015 Published online 222 KEYWORDS Frax, fracture probability, clinical risk factors, intervention thresholds, risk assessment smoking. Other risk engines calculate the risk of a clinical event without taking into account the possibility of death from other causes 6,7. Fracture probability differs markedly in different regions of the world 8 and FRAX models are calibrated to the epidemiology of fracture and death in different countries. Models are currently available for 57 countries comprising 79% of the world population 9. The model is available in 27 languages and the website ( receives approximately 3 million visits annually. The importance of this tool in clinical practice is highlighted by the many published clinical guidelines and health technology assessments recommending treatment on the basis of 10-year fracture probability Despite the wide acceptance of FRAX, there has been controversy surrounding its use in clinical practice without information on BMD The argument runs that efficacy for agents to reduce fracture risk has not been tested in patients selected on the basis of FRAX probabilities. Rather, the entry criteria for most clinical trials of primary prevention in osteoporosis have been based upon the presence of a reduced BMD. Moreover, it has been suggested that such agents do not work in Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK;

3 2 KANIS ET AL patients not selected on the basis of BMD 29,30. Thus, with some exceptions (e.g. a prior hip or spine fracture), it is argued that FRAX should not be used in the absence of information on BMD. The view is sufficiently pervasive that the National Osteoporosis Foundation and the International Society for Clinical Densitometry called on the manufacturers of BMD equipment in 2009 to introduce a FRAX filter in the US that, by default, suppressed the output of fracture probabilities on the densitometry report in patients with a T-score of -1 SD or greater 25,31. The effect of this is to undermine confidence in the use of FRAX (and indeed any treatment) in the absence of a BMD measurement. This paper briefly reviews the evidence for and against this view. A fuller account is presented elsewhere 32. Other uses of FRAX, for example, in guideline development, drug registration and health economic applications are reviewed elsewhere The notion that treatment should not be recommended in the absence of a BMD test demands a consideration of current treatment guidelines that use FRAX without BMD, the identification of susceptible risk, the performance characteristics of FRAX, and the clinical justification for undertaking a BMD test in the presence of FRAX. Risk factors and reversibility of risk There are a number of factors to be considered in the selection of risk factors for case-finding 32. An important consideration is the reversibility of risk, i.e. is there evidence that the risk identified by a risk factor is amenable to therapeutic intervention. It is important to draw the distinction between reversible risk and reversibility of risk. An example of the latter ad absurdum, is the high risk of fracture when jumping to the ground from a high-rise building. Although the fracture risk is high, there is little reason to believe that a pharmacological intervention would in any way affect the risk. It would be inappropriate, therefore, to identify such populations in a case-finding strategy. Age is an example of an irreversible risk factor, but the risk of fracture identified by age has reversibility in that interventions induce reductions in fracture risk irrespective of age. The risk factor that is best evaluated in this way is BMD. In recent years, other trials have recruited patients on the basis of age, sex, a prior vertebral fracture, and current exposure to glucocorticoids irrespective of BMD, and have shown therapeutic effects similar to those noted in randomized, controlled trials (RCTs) based on BMD selection For other risk factors, comparable data are lacking. In the absence of such data, an alternative approach is to demonstrate that the presence (or absence) of a risk factor does not adversely influence therapeutic efficacy against fractures. Systematic studies of RCTs have shown no or limited significant interactions between response to treatment and the presence or absence of any of the risk factors used in FRAX, including age, height, family history of fracture, low body weight or BMI, smoking, alcohol intake, or prior non-vertebral fracture 32, In contrast, some commonly used risk factors 6,7 may be associated with less reversibility of risk. For example, patients selected on the basis of risk factors for falling may respond less completely to agents that preserve bone mass than those selected on the basis of low BMD 30. Evidence for reversibility of risk is also available from the phase 3 of RCTs in which FRAX-based probabilities were calculated in post hoc analyses. These studies examined the interaction between FRAX-based probabilities (rather than the FRAX risk factors) with effectiveness. Two of these re-analyses of clinical trial data have shown greater efficacy against fracture in individuals at higher risk treated with clodronate or bazedoxifene 48,53,54 whereas others have shown benefit of strontium ranelate, teriparatide or raloxifene across the range of fracture probabilities (with greater absolute risk reductions in those at higher risk In a further preplanned analysis of the FREEDOM trial, greater efficacy against fracture was shown in individuals at higher risk treated with denosumab 49. These RCT data strongly suggest that FRAX (with and without BMD) identifies high-risk patients who respond to pharmaceutical interventions. A second consideration relates to the effects of treatment in patients in whom BMD is unknown or who have normal BMD. It might be argued that treatment will be ineffective in those patients with normal BMD, but at high risk when assessed by FRAX in the absence of BMD. There are several lines of evidence that suggest that responses to treatment are independent of BMD. First, many studies have shown no significant interaction between response to treatment and the baseline BMD. The lack of an interaction with BMD has been shown for risedronate 44,59,60, raloxifene 46,52,55, bazedoxifene 54, zoledronate 45, strontium ranelate 51,56, clodronate 40, teriparatide 47,58,61 and denosumab 49,62. It is relevant to note that several of these studies preferentially enrolled patients with low BMD (e.g. a T-score of -2.0 standard deviations (SD) or less), but one trial enrolled patients with osteopenia in which efficacy for raloxifene was demonstrated for vertebral fracture risk 46 and another was a random population sample in which efficacy for clodronate was shown for non-vertebral fracture risk 48. One study, the FIT II study with alendronate, suggested in a post hoc analysis that

4 CLIMACTERIC treatment efficacy was BMD-dependent 29. In another sub-group analysis, efficacy of denosumab on nonvertebral fracture risk was confined to patients with osteoporosis at the femoral neck 50, findings that were not reproduced when BMD was considered as a continuous variable 49. Moreover, the efficacy of denosumab in breast cancer patients on aromatase inhibitors was similar over the entire range of BMD 62. This large body of data on a wide variety of interventions indicates that treatment effects, with the possible exception of alendronate, are not dependent on baseline BMD. Supporting evidence for this conclusion is that intervention in the general population or populations not selected on the basis of low BMD induces therapeutic results similar to those expected in individuals selected to be at high risk 39,40,42,63,64. These data indicate that efficacy is not downgraded when patients are allocated to treatment on the basis of FRAX CRFs. BMD in patients selected by FRAX without BMD The CRFs used in FRAX are not totally independent of BMD. Indeed there is a weak but significant correlation between the clinical risk factor score for hip fracture (assessed without BMD) and BMD at the femoral neck (r ¼ 0.25) 5. This indicates that the selection of individuals with the use of FRAX, without knowledge of BMD, will preferentially select those with low BMD; and that the higher the fracture probability, the lower will be the BMD. This inference has been addressed in a randomly drawn sample of elderly women (aged 75 years or more) from Sheffield, UK 65. Approximately 2000 women were assessed at baseline for risk factors for fracture, had a baseline BMD test performed at the femoral neck and were followed up 6-monthly to record fractures and deaths for 6700 patient-years. In women characterized by fracture probability (a precursor of FRAX but not FRAX itself) without the inclusion of BMD in the model, mean BMD values were progressively lower with increasing 10-year probability of a major fracture (Figure 1). In women above an arbitrary risk threshold (30% 10-year fracture probability in Figure 1), the mean BMD was approximately 1 SD lower than in women below the threshold. Similar finding were reported in a large referral population from Manitoba, Canada 66. In this study, the minimum T-score (of measurements at the femoral neck, total hip, trochanter or lumbar spine) decreased progressively with increasing FRAX probability measured without BMD. Thus, in patients categorized at low risk using FRAX without BMD (510% probability of a major BMD (g/cm 2 ) Interval of 10-year probability (%) Figure 1. Mean bone mineral density (BMD) at the femoral neck (with 95% confidence intervals) in randomly selected women aged 75 years or more according to their 10-year probability of a major fracture calculated without BMD. Data from Table fracture), the mean minimum T-score was 1.5 SD. In those at intermediate risk (10 19% probability), the T-score was 2.2 SD, and in those at high risk ( 20% probability) it was 2.8 SD. These findings consistently indicate that the categorization of patients at high risk on the basis of FRAX without BMD selects patients with low BMD, and the higher the probability, the lower the BMD. Performance of FRAX without BMD For the purpose of risk assessment diagnosis, a characteristic of major importance is the ability of a technique to predict fractures. This is traditionally expressed as the increase in relative risk per SD unit decrease in risk score termed the gradient of risk. The performance characteristics of FRAX have been determined using information derived from the primary data of nine population-based cohorts from around the world 3 and validated in many independent cohorts with a similar geographic distribution with in excess of 1 million patient-years 5,67. The gradient of risk is shown in Table 1 for the use of the clinical risk factors alone, femoral neck BMD and the combination. The principal finding is that the use of clinical risk factors alone provides some discriminative value in the categorization of fracture risk. The use of clinical risk factors alone provided a gradient of risk/sd that lay between 1.4 and 2.1, depending upon age and the type of fracture predicted. These gradients are comparable to the use of BMD alone to predict fractures 68,69. These data suggest that clinical risk factors alone are of value and

5 4 KANIS ET AL Table 1. Gradients of risk per standard deviation change in risk score (with 95% confidence intervals) with the use of bone mineral density (BMD) at the femoral neck, clinical risk factors or the combination 5. With kind permission from Springer Science and Business Media. Age (years) Gradient of risk BMD only might be used, therefore, in the many countries where DXA facilities are sparse 70. Case finding with FRAX Clinical risk factors alone Clinical risk factors + BMD Hip fracture ( ) 2.05 ( ) 4.23 ( ) ( ) 1.95 ( ) 3.51 ( ) ( ) 1.84 ( ) 2.91 ( ) ( ) 1.75 ( ) 2.42 ( ) ( ) 1.66 ( ) 2.02 ( ) Other osteoporotic fractures ( ) 1.41 ( ) 1.44 ( ) ( ) 1.48 ( ) 1.52 ( ) ( ) 1.55 ( ) 1.61 ( ) ( ) 1.63 ( ) 1.71 ( ) ( ) 1.72 ( ) 1.81 ( ) The use of FRAX in clinical practice demands a consideration of the fracture probability at which to intervene, both for treatment (an intervention threshold) and for BMD testing (assessment thresholds). Many approaches have been used to set intervention thresholds with FRAX 11,12,14,17,18,20,22 24, The thresholds used have varied since they depend critically on local factors such as reimbursement issues, health economic assessment, willingness to pay for health care in osteoporosis and access to DXA. For this reason, it is not possible or desirable to recommend a unified intervention strategy. A general approach is shown in Figure 2. The management process begins with the assessment of fracture probability and the categorization of fracture risk on the basis of age, sex, BMI and the clinical risk factors. On this information alone, some patients at high risk may be offered treatment without recourse to BMD testing. Many guidelines 15,28,77 81 recommend treatment in the absence of information on BMD in women with a previous fragility fracture (a prior vertebral or hip fracture in North America). Many physicians would also perform a BMD test, but frequently this is for reasons other than to decide on intervention, for example, as a baseline to monitor treatment. There will be other instances where the probability will be so low that a decision not to treat can be made without BMD. An example might be the well woman at menopause with no clinical risk factors. Thus, not all individuals require a BMD test. The size of the intermediate category in Figure 3 will vary in different countries. In the US, this CRFs Fracture probability High Intermediate Low Treat High Treat BMD Reassess probability will be a large category, whereas, in a large number of countries with limited or no access to densitometry, the size of the intermediate group will necessarily be small. In other countries (e.g. the UK), where provision for BMD testing is sub-optimal 70, the intermediate category will lie between the two extremes. It has been conservatively estimated that a minimum of 10 DXA units are required per million of the population and such provision is available for less than 20 countries world-wide 70. Use of FRAX without BMD Low Figure 2. Management algorithm for the assessment of individuals at risk of fracture. CRF, clinical risk factor; BMD, bone mineral density. Adapted from reference 74 with kind permission from Springer Science and Business Media. As noted above, many guidelines recommend that women with a prior fragility fracture may be considered for intervention without the necessity for a BMD test (other than to monitor treatment). Since a prior fracture can be considered to carry a sufficient risk that treatment can be recommended, the intervention threshold in women without a prior fracture can be set at the agespecific fracture probability equivalent to women with a prior fragility fracture 74 and therefore rises with age from a 10-year probability of 8 to 33% in the UK. In other words, the intervention threshold is set at the fracture threshold. This is the approach to intervention thresholds used in France, Switzerland and by the National Osteoporosis Guideline Group (NOGG) for the UK 10,11,75. Incidentally, the same intervention threshold is applied to men, since the effectiveness and cost-effectiveness of intervention in men are broadly similar to those in women for equivalent risk The approach used has

6 CLIMACTERIC been well validated and the intervention strategy shown to be cost-effective 65,66,74, Using the same criteria, the intervention threshold will vary from country to country because the population risks (of fracture and death) vary 8 (Figure 4). The UK guidance of the NOGG is a good example of treatment decisions only partly dependent on BMD testing 11,74. As above, women with a prior fragility fracture may be considered for intervention without the necessity for a BMD test. In women without a fragility fracture, the intervention threshold set by NOGG is also Figure 3. Country-specific intervention thresholds showing the 10-year probability of a major osteoporotic fracture by age in women with a prior fracture and no other clinical risk factors in four countries determined with FRAX (version 3.9 without bone mineral density). Body mass index was set to 25 kg/m 2. ( year probability (%) Treatment zone Safety zone set at the age-specific fracture probability equivalent to women with a prior fragility fracture. The management strategy considers two additional thresholds (Figure 3) 15. Age (years) A threshold probability below which neither treatment nor a BMD test should be considered (lower assessment threshold); A threshold probability above which treatment may be recommended irrespective of BMD (upper assessment threshold). In other words, some patients at high risk may be offered treatment without recourse to BMD testing. Conversely, some patients at low risk will appropriately be denied treatment without a BMD test. The attraction of the approach is that efficient use is made of BMD testing. For example, the NOGG strategy requires only 3.5 scans at the age of 50 years to identify one case of hip fracture, whereas the former guidelines of the Royal College of Physicians required The justification for this parsimonious approach derives from the fact that reclassification of patients from high risk to low risk (and from low risk to high risk) very rarely occurs in individuals that are above the upper assessment threshold (and vice versa) 65,66. Conclusions The use of clinical risk factors alone in FRAX provides some discriminative value in the categorization of fracture, providing a gradient of risk that lies between 1.4 and 2.1, depending upon age and the type of fracture predicted. These gradients are comparable to Consider treatment No treatment Figure 4. Assessment guidelines in Europe based on the 10-year probability of a major fracture (%). The left panel shows the intervention threshold in the absence of a bone mineral density (BMD) test. In the right panel, the dotted line denotes the same intervention threshold. Where assessment is made in the absence of BMD, a BMD test is recommended, where available, for individuals where the probability assessment lies in the orange region. Adapted from reference 15 with kind permission from Springer Science and Business Media

7 6 KANIS ET AL the use of BMD alone to predict fractures and suggest that clinical risk factors alone are of value and might be used, therefore, in the many countries where DXA facilities are sparse. The risk factors chosen for incorporation into FRAX have been shown to identify a risk that is responsive to pharmaceutical intervention. Moreover, efficacy has been demonstrated in patients with high FRAX probabilities enrolled into RCTs in post hoc analyses and a pre-planned analysis. A large body of data on a wide variety of interventions indicates that treatment effects, with the possible exception of alendronate, are not dependent on baseline BMD. Moreover, the use of FRAX, without knowledge of BMD, preferentially selects individuals with low BMD; the higher the fracture probability, the lower the BMD. These data strongly suggest that FRAX identifies high-risk patients that respond to pharmaceutical interventions. Controversy surrounding the use of FRAX in clinical practice without information on BMD is largely spurious. Whereas the efficacy for agents to reduce fracture risk has not been tested prospectively in RCTs in patients selected on the basis of FRAX probabilities, there is compelling evidence that FRAX with or without the use of BMD provides a well-validated instrument for targeting patients most likely to benefit from an intervention. Declaration of interest John A. Kanis led the team that developed FRAX as Director of the WHO Collaborating Centre for Metabolic Bone Diseases; he has no financial interest in FRAX. Source of funding Nil. References 1. Kanis JA, Oden A, Johnell O, et al. The burden of osteoporotic fractures: a method for setting intervention thresholds. Osteoporos Int 2001;12: Kanis JA, Borgström F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int 2005;16: Kanis JA, on behalf of the World Health Organization Scientific Group. Assessment of osteoporosis at the primary health-care level. Technical Report. WHO Collaborating Centre, University of Sheffield, UK Available at Kanis JA, Johnell O, Oden A, Johansson H, McCloskey EV. FRAXÔ and the assessment of fracture probability in men and women from the UK. Osteoporos Int 2008;19: Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int 2007;18: Nguyen ND, Frost SA, Center JR, Eisman JA, Nguyen TV. Development of prognostic nomograms for individualizing 5-year and 10-year fracture risks. Osteoporos Int 2008;19: Hippisley-Cox J, Coupland C. Derivation and validation of updated QFracture algorithm to predict risk of osteoporotic fracture in primary care in the United Kingdom: prospective open cohort study. BMJ 2012;344e Kanis JA, Odén A, McCloskey EV, et al. 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Osteoporos Int 2008;19: Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2010;62: Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster J-Y on behalf of the Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2013;24: Kanis JA, Borgström F, Compston J, et al. SCOPE: a scorecard for osteoporosis in Europe. Arch Osteoporos 2013;8: Lekawasam S, Adachi JD, Agnusdei D, et al. A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos Int 2012;23: Lippuner K, Johansson H, Kanis JA, Rizzoli R. FRAX Õ assessment of osteoporotic fracture probability in Switzerland. Osteoporos Int 2010;21: Makras P, Paiopoulos G, Lyritis GP Guidelines for the diagnosis and treatment of osteoporosis in Greece. J Musculoskelet Neuronal Interact 2012;12: Neuprez A, Johansson H, Kanis JA, et al. Rationalisation du remboursement des médicaments de l ostéoporose: de la mesure isolée de la densité osseuse à l intégration des facteurs cliniques de risque fracturaire. Validation de l algorithme FRAX Õ. Rev Med Liege 2009;64: National Institute for Health and Care Excellence NICE. Osteoporosis: assessing the risk of fragility fracture

8 CLIMACTERIC ; CG Accessed 18th May Orimo H, Nakamura T, Hosoi T, et al. Japanese 2011 Guidelines for Prevention and Treatment of Osteoporosis Executive Summary. A Report of the Committee for Developing Guidelines for Prevention and Treatment of Osteoporosis: Japan Osteoporosis Society, Japanese Society for Bone and Mineral Research, and Japan Osteoporosis Foundation. Arch Osteoporos 2012;7: Papaioannou A, Morin S, Cheung AM, et al clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ 2010;182: Socialstyrelsen. Nationella riktlinjer för rörelseorganens sjukdomar 2010 stödför styrning och ledning. Preliminär version. Artikelnr Published at www. socialstyrelsen.se. Accessed 26th June Watts NB, Siris ES, Cummings SR, Bauer DC. Filtering FRAX. Osteoporos Int 2010;21: National Institute for Health and Clinical Excellence. Final appraisal determination. Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. London: NICE, June National Institute for Health and Clinical Excellence. Final appraisal determination. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. London: NICE, June Scottish Intercollegiate Guidelines Network (SIGN). Management of osteoporosis and the prevention of fragility fractures. Edinburgh: SIGN; (SIGN publication no. 142). [March 2015]. Available from URL: Accessed May 11th Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280: McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 2001;344: McCloskey E, Compston J, Cooper C. The US FRAX filter: avoiding confusion or hindering progress? Osteoporos Int 2010;21: Kanis JA, McCloskey E, Johansson H, Oden A, Leslie WD. FRAX Õ with and without BMD. Calcif Tiss Int 2012;90: Kanis JA, Oden A, Johansson H, Borgström F, Ström O, McCloskey E. FRAX Õ and its applications to clinical practice. Bone 2009;44: Kanis JA, Hiligsmann M. The application of health technology assessment in osteoporosis. Best Pract Res Clin Endocrinol Metab 2014;28: Borgström F, Kanis JA. Health economics of osteoporosis. Best Pract Res Clin Endocrinol Metab 2008;22: Ström O, Borgström F, Kleman M, et al. FRAX and its applications in health economics cost-effectiveness and intervention thresholds using bazedoxifene in a Swedish setting as an example. Bone 2010;47: Hernlund E, Svedbom A, Ivergård M, et al. Osteoporosis in the European Union: Medical Management, Epidemiology and Economic Burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 2013;8: Adachi JD, Saag KG, Delmas PD, et al. Two year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomised, double-blind, placebo-controlled extension trial. Arthritis Rheum 2001:44: Chapuy MC, Arlot ME, Delmas PD, Meunier PJ. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. BMJ 1994;308: McCloskey EV, Beneton M, Charlesworth D, et al. Clodronate reduces the incidence of fractures in community dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res 2007;22: Reginster JY, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) study group. Osteoporos Int 2000;11: Roussow JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women s Health Initiative randomized controlled trial. JAMA 2002; 288: Saag KG, Emkey R, Schnitzer TJ, et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-induced Osteoporosis Intervention Study Group. N Engl J Med 1998;339: Kanis JA, Barton I, Johnell O. Risedronate decreases fracture risk in patients selected solely on the basis of prior vertebral fracture. Osteoporos Int 2005;16: Eastell R, Lang T, Boonen S, et al. Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density. J Clin Endocrinol Metab 2009;94: Johnell O, Kanis JA, Black DM, et al. Association between baseline risk factors and vertebral fracture risk in the Multiple Outcomes of Raloxifene Evaluation (MORE) study. J Bone Miner Res 2004;19: Marcus R, Wang O, Satterwhite J, et al. The skeletal response to teriparatide is largely independent of age, initial bone mineral density and prevalent vertebral fractures in postmenopausal women with osteoporosis. J Bone Miner Res 2003;18: McCloskey EV, Johansson H, Oden A, et al. Ten-year fracture probability identifies women who will benefit from clodronate therapy additional results from a double blind, placebo controlled randomised study. Osteoporos Int 2009;20; McCloskey EV, Johansson H, Oden A, et al. Denosumab reduces the risk of all osteoporotic fractures in postmenopausal women, particularly in those with moderate to high fracture risk as assessed with FRAX Õ. J Bone Miner Res 2012;27: McClung M, Boonen S, Torring O, et al. Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis. J Bone Miner Res 2012;27: Roux C, Reginster J-Y, Fechtenbaum J, et al. Vertebral fracture with reduction with strontium ranelate in women

9 8 KANIS ET AL with postmenopausal osteoporosis is independent of baseline risk factors. J Bone Miner Res 2006;21: Kanis JA, Johnell O, Black DM, et al. Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis: a reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial. Bone 2003;33: Kaufman JM, Palacios S, Silverman S, Sutradhar S, Chines A. An evaluation of the fracture risk assessment tool (FRAX Õ ) as an indicator of treatment efficacy: the effects of bazedoxifene and raloxifene on vertebral, nonvertebral, and all clinical fractures as a function of baseline fracture risk assessed by FRAX Õ. Osteoporos Int 2013;24: Kanis JA, Johansson H, Oden A, et al. Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Bone 2009;44: Kanis JA, Johansson H, Oden A, et al. A meta-analysis of the efficacy of raloxifene on all clinical and vertebral fractures and its dependency on FRAX. Bone 2010;47: Kanis JA, Jönsson B, Odén A, McCloskey EV. A metaanalysis of the effect of strontium ranelate on the risk of vertebral and non-vertebral fracture in postmenopausal osteoporosis and the interaction with FRAX Õ. Osteoporos Int 2011;22: With erratum Osteoporos Int 2011;22: Harvey NC, Kanis JA, Odén A, et al. Efficacy of weekly teriparatide does not vary by baseline fracture probability calculated using FRAX. Osteoporos Int 2015;26: Harvey NC, Kanis JA, Odén A, et al. FRAX and the effect of teriparatide on vertebral and non-vertebral fracture. Osteoporos Int 2015 June 20. Epub ahead of print. 59. Adachi JD, Rizzoli R, Boonen S, Li Z, Meredith MP, Chesnut CH Vertebral fracture risk reduction with risedronate in post-menopausal women with osteoporosis: a metaanalysis of individual patient data. 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