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Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan

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Abstract

Summary

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures.

Introduction

The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors.

Methods

A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible.

Results

Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed.

Conclusions

These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

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Fig. 1

source and validation cohorts used to develop the existing FRAX tool as well as other cohorts that were previously identified but have not been used in any previous analysis; Known cohort: additional publication of a previously identified cohort. *After reviewing 18 reports, 12 cohorts were identified as several reports described the same cohort

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Acknowledgements

We thank the Gothenburg University Library for assistance with the systematic review. We are grateful to Dr Östen Ljunggren for contributing the MrOS Sweden cohort.

Author information

Authors and Affiliations

  1. Mary McKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia

    L. Vandenput, H. Johansson, E. Liu, M. Lorentzon & J. A. Kanis

  2. Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    L. Vandenput & C. Ohlsson

  3. Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, UK

    H. Johansson, E. V. McCloskey & J. A. Kanis

  4. MRC Versus Arthritis Centre for Integrated Research in Musculoskeletal Ageing, Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield, UK

    E. V. McCloskey

  5. Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden

    K. E. Åkesson & M. K. Karlsson

  6. Department of Orthopedics, Skåne University Hospital, Malmö, Sweden

    K. E. Åkesson

  7. GLOW Coordinating Center, Center for Outcomes Research, University of Massachusetts Medical School, Worcester, MA, USA

    F. A. Anderson

  8. Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain

    R. Azagra

  9. Health Center Badia del Valles, Catalan Institute of Health, Barcelona, Spain

    R. Azagra

  10. GROIMAP (Research Group), Unitat de Suport a La Recerca Metropolitana Nord, Institut Universitari d’Investigació en Atenció Primària Jordi Gol, Santa Coloma de Gramenet, Barcelona, Spain

    R. Azagra

  11. Nordic Bioscience A/S, Herlev, Denmark

    C. L. Bager & C. Christiansen

  12. WHO Collaborating Centre for Public Health Aspects of Musculoskeletal Health and Aging, Division of Public Health, Epidemiology and Health Economics, University of Liège, Liège, Belgium

    C. Beaudart & O. Bruyère

  13. Department of Aging Medicine and Aging Research, University Hospital, Zurich, and University of Zurich, Zurich, Switzerland

    H. A. Bischoff-Ferrari

  14. Centre On Aging and Mobility, University of Zurich and City Hospital, Zurich, Switzerland

    H. A. Bischoff-Ferrari

  15. Division of Bone Diseases, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland

    E. Biver & S. Ferrari

  16. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Philadelphia, USA

    J. A. Cauley

  17. Bone Biology, Healthy Ageing Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia

    J. R. Center

  18. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, Australia

    J. R. Center & J. A. Eisman

  19. School of Medicine Sydney, University of Notre Dame Australia, Sydney, NSW, Australia

    J. R. Center & J. A. Eisman

  20. INSERM UMR 1033, University of Lyon, Hôpital Edouard Herriot, Lyon, France

    R. Chapurlat & P. Szulc

  21. MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK

    C. Cooper

  22. National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton and University Hospitals Southampton NHS Foundation Trust, Southampton, UK

    C. Cooper

  23. National Institute for Health Research Oxford Biomedical Research Unit, , University of Oxford, Oxford, UK

    C. Cooper

  24. Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    C. J. Crandall

  25. San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA

    S. R. Cummings

  26. Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    J. A. P. da Silva

  27. Rheumatology Department, University Hospital and University of Coimbra, Coimbra, Portugal

    J. A. P. da Silva

  28. Bone Metabolism Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center On Aging, Tufts University, Boston, MA, USA

    B. Dawson-Hughes

  29. Department of Internal Medicine, Hospital del Mar and CIBERFES, Autonomous University of Barcelona, Barcelona, Spain

    A. Diez-Perez

  30. Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA

    A. B. Dufour & D. P. Kiel

  31. Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    A. B. Dufour & D. P. Kiel

  32. Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, Sydney, NSW, Australia

    J. A. Eisman

  33. Department of General Practice, Amsterdam UMC, Location VUmc, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands

    P. J. M. Elders, T. Merlijn & K. M. A. Swart

  34. Department of Public Health, Faculty of Medicine, Kindai University, Osaka, Japan

    Y. Fujita & M. Iki

  35. Department of Pharmacy, Yasuda Women’s University, Hiroshima, Japan

    S. Fujiwara

  36. Section Biomedical Imaging, Molecular Imaging North Competence Center, Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein Kiel, Kiel University, Kiel, Germany

    C.-C. Glüer

  37. Maccabitech Institute of Research and Innovation, Maccabi Healthcare Services, Tel Aviv, Israel

    I. Goldshtein

  38. Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    I. Goldshtein

  39. Department of Medicine, McGill University and McGill University Health Centre, Montreal, Canada

    D. Goltzman

  40. Icelandic Heart Association, Kopavogur, Iceland

    V. Gudnason & K. Siggeirsdottir

  41. University of Iceland, Reykjavik, Iceland

    V. Gudnason

  42. MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK

    J. Hall

  43. Centre of Bone Diseases, Bone and Joint Department, Lausanne University Hospital, Lausanne, Switzerland

    D. Hans

  44. Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway

    M. Hoff

  45. Department of Rheumatology, St Olavs Hospital, Trondheim, Norway

    M. Hoff

  46. Aberdeen Centre for Arthritis and Musculoskeletal Health, Epidemiology Group, University of Aberdeen, Aberdeen, UK

    R. J. Hollick

  47. Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands

    M. Huisman & N. M. van Schoor

  48. Department of Sociology, VU University, Amsterdam, The Netherlands

    M. Huisman

  49. Endocrine Clinic, Elisha Hospital, Haifa, Israel

    S. Ish-Shalom

  50. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia

    G. Jones

  51. Department of Orthopaedics, Skåne University Hospital, Malmö, Sweden

    M. K. Karlsson

  52. Robert and Arlene Kogod Center On Aging and Division of Endocrinology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA

    S. Khosla

  53. Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    W.-P. Koh

  54. Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore

    W.-P. Koh

  55. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

    F. Koromani, F. Rivadeneira & M. C. Zillikens

  56. Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

    F. Koromani

  57. IMPACT (Institute for Mental and Physical Health and Clinical Translation), Deakin University, Geelong, VIC, Australia

    M. A. Kotowicz

  58. Barwon Health, Geelong, VIC, Australia

    M. A. Kotowicz

  59. Department of Medicine - Western Health, The University of Melbourne, St Albans, Victoria, Australia

    M. A. Kotowicz

  60. Department of Orthopedics and Traumatology, Kuopio University Hospital, Kuopio, Finland

    H. Kröger

  61. Kuopio Musculoskeletal Research Unit, University of Eastern Finland, Kuopio, Finland

    H. Kröger & R. Sund

  62. Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong

    T. Kwok

  63. Jockey Club Centre for Osteoporosis Care and Control, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong

    T. Kwok

  64. Centre of Bone Diseases, Lausanne University Hospital, Lausanne, Switzerland

    O. Lamy

  65. Service of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland

    O. Lamy

  66. Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, HUNT Research Centre, Norwegian University of Science and Technology, Trondheim, Norway

    A. Langhammer

  67. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

    B. Larijani

  68. Department of Osteoporosis, Bern University Hospital, University of Bern, Bern, Switzerland

    K. Lippuner

  69. Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    D. Mellström

  70. Geriatric Medicine, Sahlgrenska University Hospital Mölndal, Mölndal, Sweden

    D. Mellström

  71. Division of Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

    A. Nordström

  72. School of Sport Sciences, Arctic University of Norway, Tromsø, Norway

    A. Nordström

  73. Unit of Geriatric Medicine, Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden

    P. Nordström

  74. National Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

    T. W. O’Neill

  75. Centre for Epidemiology Versus Arthritis, University of Manchester, Manchester, UK

    T. W. O’Neill

  76. Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University Graz, Graz, Austria

    B. Obermayer-Pietsch

  77. Center for Biomarker Research in Medicine, Graz, Austria

    B. Obermayer-Pietsch

  78. Department of Drug Treatment, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden

    C. Ohlsson

  79. Department of Medicine, Oregon Health and Science University, Portland, OR, USA

    E. S. Orwoll

  80. Institute for Physical and Mental Health and Clinical Translation (IMPACT), Deakin University, Geelong, Australia

    J. A. Pasco

  81. Department of Medicine-Western Health, The University of Melbourne, St Albans, Australia

    J. A. Pasco

  82. Barwon Health, Geelong, Australia

    J. A. Pasco

  83. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia

    J. A. Pasco

  84. Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway

    B. Schei

  85. Department of Gynecology, St Olavs Hospital, Trondheim, Norway

    B. Schei

  86. Université Claude Bernard Lyon 1, U INSERM 1290 RESHAPE, Lyon, France

    A.-M. Schott

  87. Laboratory of Epidemiology and Population Sciences, National Institute On Aging, Baltimore, MD, USA

    E. J. Shiroma

  88. Janus Rehabilitation, Reykjavik, Iceland

    K. Siggeirsdottir

  89. Translational Gerontology Branch, National Institute On Aging Intramural Research Program, Baltimore, MD, USA

    E. M. Simonsick

  90. INSERM Research Unit 1033, Lyon, France

    E. Sornay-Rendu

  91. Department of Hygiene and Public Health, Faculty of Medicine, Educational Foundation of Osaka Medical and Pharmaceutical University, Osaka, Japan

    J. Tamaki

  92. York Trials Unit, Department of Health Sciences, University of York, York, UK

    D. J. Torgerson

  93. Centre for Health Informatics, Faculty of Biology, Medicine and Health, School of Health Sciences, University of Manchester, Manchester, UK

    T. P. van Staa

  94. Statistics Support Unit, Hospital del Mar Medical Research Institute, CIBER Epidemiology and Public Health (CIBERESP), Barcelona, Spain

    J. Vila

  95. MRC Epidemiology Unit, University of Cambridge, Cambridge, UK

    N. J. Wareham

  96. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA

    N. C. Wright

  97. Department of Preventive Medicine for Locomotive Organ Disorders, The University of Tokyo Hospital, Tokyo, Japan

    N. Yoshimura

  98. Health Center Can Gibert del Plà, Catalan Institute of Health, Girona, Spain

    M. Zwart

  99. Department of Medical Sciences, University of Girona, Girona, Spain

    M. Zwart

  100. GROIMAP (Research Group), Institut Universitari d’Investigació en Atenció Primària Jordi Gol, Barcelona, Spain

    M. Zwart

  101. MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK

    N. C. Harvey

  102. NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK

    N. C. Harvey

  103. Sahlgrenska Osteoporosis Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden

    M. Lorentzon

  104. Geriatric Medicine, Region Västra Götaland, Sahlgrenska University Hospital, Mölndal, Sweden

    M. Lorentzon

  105. Department of Medicine, University of Manitoba, Winnipeg, MB, Canada

    W. D. Leslie

  106. Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK

    J. A. Kanis

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  1. L. Vandenput
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  85. J. A. Kanis
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Corresponding author

Correspondence to J. A. Kanis.

Ethics declarations

Human and animal rights

This review does not contain any original studies with human participants or animals performed by any of the authors.

Ethics

All individual cohorts with candidate risk factors available have been approved by their local ethics committees and informed consent has been obtained from all study participants. General ethics approval for the use of these cohorts is also given by the University of Sheffield. Participant data will be stored in coded, de-identified form. Only summary statistics and aggregate data will be published, not allowing for identification of individual study participants.

Conflicts of interest

JA 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. EV McCloskey, WD Leslie, M Lorentzon, NC Harvey, E Liu, L Vandenput and H Johansson are members of the FRAX team. JA Kanis, NC Harvey and EV McCloskey are members of the advisory body to the National Osteoporosis Guideline Group. JA Kanis reports no additional competing interests. KE Åkesson has no financial interest related to FRAX; chaired the National SALAR Group for Person-Centered Care Pathway Osteoporosis. FA Anderson led the team that developed GLOW, while director of the Center for Outcomes Research at the University of Massachusetts Medical School; he has no financial interest in FRAX. R Azagra has received funding for research from Instituto Carlos III of Spanish Ministry of Health, IDIAP Jordi Gol of Catalan Government and from Scientific Societies SEMFYC and SEIOMM. CL Bager is employed at Nordic Bioscience and owns stock in Nordic Bioscience. She declares no competing interests in relation to this work. HA Bischoff-Ferrari has no financial interest in FRAX. For the DO-HEALTH trial cohort, Prof. Bischoff-Ferrari reports independent and investigator-initiated grants from European Commission Framework 7 Research Program, from the University of Zurich, from NESTEC, from Pfizer Consumer Healthcare, from Streuli Pharma, plus non-financial support from DNP. For the study cohort extension, she reports independent and investigator-initiated grants from Pfizer and from Vifor. Furthermore, Prof. Bischoff-Ferrari reports non-financial support from Roche Diagnostics and personal fees from Wild, Sandoz, Pfizer, Vifor, Mylan, Roche, Meda Pharma, outside the submitted work with regard to speaker fees and travel fees. JR Center has received honoraria for speaking at educational meetings and for advisory boards from Amgen and honoraria for an advisory board from Bayer. R Chapurlat has no financial interest in FRAX. He has received grant funding from Amgen, UCB, Chugai, MSD, Mylan and Medac. He has received honoraria from Amgen, UCB, Chugai, Galapagos, Biocon, Abbvie, Haoma Medica, Pfizer, Amolyt, MSD, Lilly, BMS, Novartis, Arrow, PKMed, Kyowa-Kirin and Sanofi. C Christiansen owns stock in Nordic Bioscience. He declares no competing interests in relation to this work. C Cooper reports personal fees from Alliance for Better Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda and UCB. A Diez-Perez reports personal fees from Amgen, Lilly, Theramex and grants from Instituto Carlos III and owns shares of Active Life Scientific, all outside the submitted work. JA Eisman declares consulting and research support from Actavis, Amgen, Aspen, Lilly, Merck Sharp and Dohme, Novartis, Sanofi-Aventis, Servier and Theramex. PJM Elders has no financial interest in FRAX. PJM Elders reports support for the SOS study by Stichting Achmea Gezondheidszorg, Achmea and VGZ zorgverzekeraar. Additional support was given by the stichting Artsenlaboratorium en Trombosedienst. Outside the submitted work, she did receive independent investigator driven grants by Zonmw, the Netherlands, de Hartstichting, the Netherlands, the European foundation for the study of Diabetes, Amgen the Netherlands, TEVA, the Netherlands and Takeda, the Netherlands. NC Harvey has received consultancy/lecture fees/honoraria/grant funding from Alliance for Better Bone Health, Amgen, MSD, Eli Lilly, Radius Health, Servier, Shire, UCB, Consilient Healthcare and Internis Pharma. DP Kiel has no financial interest in FRAX but has received support for his work in the Framingham Study over the past 30 years by the National Institutes of Health, Astra Zeneca, Merck, Amgen and Radius Health. MA Kotowicz has received funding from the National Health and Medical Research Council (NHMRC) Australia, and the Medical Research Future Fund (MRFF) Australia. He has served on advisory boards for Amgen Australia, Novartic and Eli Lilly — all unrelated to this work and is the Director of the Geelong Bone Densitometry Service. M Lorentzon has received lecture fees from Amgen, Lilly, Meda, Renapharma and UCB Pharma and consulting fees from Amgen, Radius Health, UCB Pharma, Renapharma and Consilient Health, all outside the presented work. EV McCloskey has received consultancy/lecture fees/grant funding/honoraria from AgNovos, Amgen, AstraZeneca, Consilient Healthcare, Fresenius Kabi, Gilead, GSK, Hologic, Internis, Lilly, Merck, Novartis, Pfizer, Radius Health, Redx Oncology, Roche, Sanofi Aventis, UCB, ViiV, Warner Chilcott and I3 Innovus. C Ohlsson is listed as a coinventor on two patent applications regarding probiotics in osteoporosis treatment. ES Orwoll reports consulting fees from Amgen, Biocon, Radius and Bayer, and research support from Mereo. JA Pasco has received funding from the National Health and Medical Research Council (NHMRC) Australia, and the Medical Research Future Fund (MRFF) Australia, all unrelated to this work. MC Zillikens has received honoraria in the past for lectures or advice from Alexion, Amgen, Eli Lilly, Kyowa Kirin, Shire and UCB, unrelated to the current work. M Zwart has received research funding from national societies (SEMFYC and SEIOMM). C Beaudart, E Biver, O Bruyère, JA Cauley, CJ Crandall, SR Cummings, JAP da Silva, B Dawson-Huges, AB Dufour, S Ferrari, Y Fujita, S Fujiwara, C–C Glüer, I Goldshtein, D Goltzman, V Gudnason, J Hall, D Hans, M Hoff, RJ Hollick, M Huisman, M Iki, S Ish-Shalom, H Johansson, G Jones, MK Karlsson, S Khosla, W–P Koh, F Koromani, H Kröger, T Kwok, O Lamy, A Langhammer, B Larijani, WD Leslie, K Lippuner, E Liu, D Mellström, T Merlijn, A Nordström, P Nordström, TW O´Neill, B Obermayer-Pietsch, F Rivadeneira, B Schei, A-M Schott, EJ Shiroma, K Sigeirsdottir, EM Simonsick, E Sornay-Rendu, R Sund, KMA Swart, P Szulc, J Tamaki, DJ Torgerson, L Vandenput, NM van Schoor, TP van Staa, J Vila, NJ Wareham, NC Wright and N Yoshimura declare no competing interests in relation to this work.

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Table 3 Excluded cohorts
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3 and

Table 4 Additional risk factors for consideration for the update of FRAX
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Vandenput, L., Johansson, H., McCloskey, E.V. et al. Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan. Osteoporos Int 33, 2103–2136 (2022). https://doi.org/10.1007/s00198-022-06435-6

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