BMI; FRAX; epidemiology; hip fracture; major osteoporotic fracture; meta-analysis; osteoporosis; Humans; Female; Male; Risk Factors; Middle Aged; Bone Density; Aged; Body Mass Index; Osteoporotic Fractures/epidemiology; Fractures, Bone/epidemiology; Fractures, Bone; Osteoporotic Fractures; Endocrinology, Diabetes and Metabolism; Orthopedics and Sports Medicine
Abstract :
[en] The aim of this international meta-analysis was to quantify the predictive value of BMI for incident fracture and relationship of this risk with age, sex, follow-up time, and BMD. A total of 1 667 922 men and women from 32 countries (63 cohorts), followed for a total of 16.0 million person-years were studied. 293 325 had FN BMD measured (2.2 million person-years follow-up). An extended Poisson model in each cohort was used to investigate relationships between WHO-defined BMI categories (Underweight: <18.5 kg/m2; Normal: 18.5-24.9 kg/m2; Overweight: 25.0-29.9 kg/m2; Obese I: 30.0-34.9 kg/m2; Obese II: ≥35.0 kg/m2) and risk of incident osteoporotic, major osteoporotic and hip fracture (HF). Inverse-variance weighted β-coefficients were used to merge the cohort-specific results. For the subset with BMD available, in models adjusted for age and follow-up time, the hazard ratio (95% CI) for HF comparing underweight with normal weight was 2.35 (2.10-2.60) in women and for men was 2.45 (1.90-3.17). Hip fracture risk was lower in overweight and obese categories compared to normal weight [obese II vs normal: women 0.66 (0.55-0.80); men 0.91 (0.66-1.26)]. Further adjustment for FN BMD T-score attenuated the increased risk associated with underweight [underweight vs normal: women 1.69 (1.47-1.96); men 1.46 (1.00-2.13)]. In these models, the protective effects of overweight and obesity were attenuated, and in both sexes, the direction of association reversed to higher fracture risk in Obese II category [Obese II vs Normal: women 1.24 (0.97-1.58); men 1.70 (1.06-2.75)]. Results were similar for other fracture outcomes. Underweight is a risk factor for fracture in both men and women regardless of adjustment for BMD. However, while overweight/obesity appeared protective in base models, they became risk factors after additional adjustment for FN BMD, particularly in the Obese II category. This effect in the highest BMI categories was of greater magnitude in men than women. These results will inform the second iteration of FRAX®.
Disciplines :
Geriatrics
Author, co-author :
Harvey, Nicholas C ; MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, SO16 6YD, United Kingdom ; NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, United Kingdom
Johansson, Helena; Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, United Kingdom
McCloskey, Eugene V ; Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, United Kingdom ; MRC Versus Arthritis Centre for Integrated Research in Musculoskeletal Ageing, Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield, United Kingdom
Liu, Enwu ; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia
Åkesson, Kristina E ; Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden ; Department of Orthopedics, Skåne University Hospital, Malmö, Sweden
Anderson, Fred A; GLOW Coordinating Center, Center for Outcomes Research, University of Massachusetts Medical School, Worcester, MA, United States
Azagra-Ledesma, Rafael; Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain ; Docencia Atenció Primària, Metropolitana Nord, Institut Català de la Salut, Barcelona, Spain ; GROIMAP/GROICAP (research groups), Unitat de Suport a la Recerca de Girona, Institut Universitari d'Investigació en Atenció Primària Jordi Gol, Girona, Spain ; PRECIOSA-Fundación para la investigación, Barberà del Vallés, Barcelona, Spain
Beaudart, Charlotte; Public Health Aging Research and Epidemiology (PHARE) Group, Research Unit in Clinical Pharmacology and Toxicology (URPC), NAmur Research Institute for LIfe Sciences (NARILIS), Faculty of Medicine, University of Namur, 5000 Namur, Belgium
Bischoff-Ferrari, Heike A; Department of Aging Medicine, Felix Platter, University of Basel, 4055 Basel, Switzerland ; Centre on Aging and Mobility, University of Zurich and City Hospital, Zurich, Switzerland
Biver, Emmanuel ; Division of Bone Diseases, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
Bruyère, Olivier ; Université de Liège - ULiège > Département des sciences de la santé publique > Santé publique, Epidémiologie et Economie de la santé
Cauley, Jane A; Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
Center, Jacqueline R ; Garvan Institute of Medical Research, Sydney, NSW, Australia ; St Vincent's Clinical School, School of Medicine and Health, University of New South Wales Sydney, Sydney, NSW, Australia
Chapurlat, Roland; INSERM UMR 1033, Université Claude Bernard-Lyon1, Hôpital Edouard Herriot, Lyon, France
Cooper, Cyrus ; MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, SO16 6YD, United Kingdom ; NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, United Kingdom ; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
Crandall, Carolyn J ; Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine, University of California, Los Angeles, CA, United States
Cummings, Steven R; San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, United States
da Silva, José A P; Centre for Innovative Biomedicine and Biotechnology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal ; Rheumatology Department, University Hospital and University of Coimbra, Coimbra, Portugal
Dawson-Hughes, Bess ; Bone Metabolism Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA, United States
Diez-Perez, Adolfo; Department of Internal Medicine, Hospital del Mar and CIBERFES, Autonomous University of Barcelona, Barcelona, Spain
Dufour, Alyssa B ; Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, United States ; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
Eisman, John A ; St Vincent's Clinical School, School of Medicine and Health, University of New South Wales Sydney, Sydney, NSW, Australia ; Skeletal Diseases Program, Garvan Institute of Medical Research, Sydney, NSW, Australia ; School of Medicine Sydney, University of Notre Dame Australia, Sydney, NSW, Australia
Elders, Petra J M; Department of General Practice, Amsterdam UMC, location AMC, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands
Ferrari, Serge ; Division of Bone Diseases, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland
Fujita, Yuki; Department of Hygiene and Public Health, Faculty of Medicine, Kansai Medical University, Osaka, Japan
Fujiwara, Saeko; Department of Pharmacy, Yasuda Women's University, Hiroshima, Japan
Glüer, Claus-Christian; Section Biomedical Imaging, Molecular Imaging North Competence Center, Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein Kiel, Kiel University, Kiel, Germany
Goldshtein, Inbal; Maccabitech Institute of Research and Innovation, Maccabi Healthcare Services, Tel Aviv, Israel ; Department of Epidemiology and Preventive Medicine, Sackler Faculty of Medicine, School of Public Health, Tel Aviv University, Tel Aviv, Israel
Goltzman, David; Department of Medicine, McGill University and McGill University Health Centre, Montreal, QC, Canada
Gudnason, Vilmundur; Icelandic Heart Association, Kopavogur, Iceland ; University of Iceland, Reykjavik, Iceland
Hall, Jill; MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, United Kingdom
Hans, Didier ; Interdisciplinary Centre of Bone Diseases, Bone and Joint Department, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
Hoff, Mari; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway ; Department of Rheumatology, St. Olavs Hospital, Trondheim, Norway
Hollick, Rosemary J; Aberdeen Centre for Arthritis and Musculoskeletal Health, Epidemiology Group, University of Aberdeen, Aberdeen, United Kingdom
Huisman, Martijn; Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands ; Department of Sociology, VU University, Amsterdam, The Netherlands
Iki, Masayuki ; Department of Public Health, Kindai University Faculty of Medicine, Osaka, Japan
Ish-Shalom, Sophia; Endocrine Clinic, Elisha Hospital, Haifa, Israel
Jones, Graeme; Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
Karlsson, Magnus K ; Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden ; Department of Orthopaedics, Skåne University Hospital, Malmö, Sweden
Khosla, Sundeep ; Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, United States
Kiel, Douglas P ; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States ; Marcus Institute for Aging Research, Hebrew Senior Life, Boston, MA, United States
Koh, Woon-Puay; Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore ; Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore
Koromani, Fjorda ; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands ; Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
Kotowicz, Mark A; Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, Geelong, VIC, Australia ; Barwon Health, Geelong, VIC, Australia ; Department of Medicine-Western Health, The University of Melbourne, St Albans, VIC, Australia
Kröger, Heikki; Department of Orthopedics and Traumatology, Kuopio University Hospital, Kuopio, Finland ; Kuopio Musculoskeletal Research Unit, University of Eastern Finland, Kuopio, Finland
Kwok, Timothy ; Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong ; Jockey Club Centre for Osteoporosis Care and Control, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
Lamy, Olivier ; Centre of Bone Diseases, Lausanne University Hospital, Lausanne, Switzerland ; Service of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland
Langhammer, Arnulf; HUNT Research Centre, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway ; Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
Larijani, Bagher ; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
Lippuner, Kurt; ARTORG Center for Biomedical Engineering Research, Faculty of Medicine, University of Bern, Bern, Switzerland
McGuigan, Fiona E A ; Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
Mellström, Dan; Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden ; Geriatric Medicine, Sahlgrenska University Hospital Mölndal, Mölndal, Sweden
Merlijn, Thomas ; Department of General Practice, Amsterdam UMC, location AMC, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands
Nguyen, Tuan V; School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia ; School of Population Health, UNSW Medicine, UNSW Sydney, Kensington, NSW, Australia ; Tam Anh Research Institute, Tam Anh Hospital, Ho Chi Minh City, Vietnam
Nordström, Anna; School of Sport Sciences, UiT The Arctic University of Norway, Tromsø, Norway ; Department of Health Sciences, Swedish Winter Sports Research Centre, Mid Sweden University, Östersund, Sweden ; Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Nordström, Peter; Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
O'Neill, Terence W; National Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom ; Centre for Epidemiology Versus Arthritis, University of Manchester, Manchester, United Kingdom
Obermayer-Pietsch, Barbara; Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University Graz, Graz, Austria
Ohlsson, Claes ; Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden ; Department of Drug Treatment, Sahlgrenska University Hospital, Gothenburg, Sweden
Orwoll, Eric S ; Department of Medicine, Oregon Health and Science University, Portland, OR, United States
Pasco, Julie A; Institute for Physical and Mental Health and Clinical Translation (IMPACT), Deakin University, Geelong, VIC, Australia ; Department of Medicine-Western Health, The University of Melbourne, St Albans, VIC, Australia ; Barwon Health, Geelong, VIC, Australia ; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia
Rivadeneira, Fernando; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
Schei, Berit; Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway ; Department of Obstetrics and Gynaecology, St Olavs Hospital, Trondheim, Norway
Schott, Anne-Marie; Université Claude Bernard Lyon 1, RESHAPE U INSERM U-1290, Lyon, France
Shiroma, Eric J; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Baltimore, MD, United States
Simonsick, Eleanor M ; Translational Gerontology Branch, National Institute on Aging Intramural Research Program, Baltimore, MD, United States
Sornay-Rendu, Elisabeth; INSERM UMR 1033, University of Lyon, Hôpital Edouard Herriot, Lyon, France
Sund, Reijo ; Kuopio Musculoskeletal Research Unit, University of Eastern Finland, Kuopio, Finland
Swart, Karin M A; Department of General Practice, Amsterdam UMC, location VUmc, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands ; PHARMO Institute for Drug Outcomes Research, Utrecht, The Netherlands
Szulc, Pawel ; INSERM UMR 1033, University of Lyon, Hôpital Edouard Herriot, Lyon, France
Tamaki, Junko ; Department of Hygiene and Public Health, Faculty of Medicine, Educational Foundation of Osaka Medical and Pharmaceutical University, Osaka, Japan
Torgerson, David J; York Trials Unit, Department of Health Sciences, University of York, York, United Kingdom
van Schoor, Natasja M; Department of Epidemiology and Data Science, Amsterdam UMC location Vrije Universiteit, Amsterdam, The Netherlands ; Amsterdam Public Health Research Institute, Aging and Later Life Program, Amsterdam, The Netherlands
van Staa, Tjeerd P; Centre for Health Informatics, Faculty of Biology, Medicine and Health, School of Health Sciences, University of Manchester, Manchester, United Kingdom
Vila, Joan; Statistics Support Unit, Hospital del Mar Medical Research Institute, CIBER Epidemiology and Public Health (CIBERESP), Barcelona, Spain
Wareham, Nicholas J; MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom
Wright, Nicole C ; Center for Health Outcomes, Implementation, and Community-Engaged Sciences, Tulane University, New Orleans, LA, United States
Yoshimura, Noriko; Department of Preventive Medicine for Locomotive Organ Disorders, The University of Tokyo Hospital, Tokyo, Japan
Zillikens, M Carola ; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
Zwart, Marta; PRECIOSA-Fundación para la investigación, Barberà del Vallés, Barcelona, Spain ; Health Center Can Gibert del Pla, Catalan Institute of Health, Girona, Spain ; Department of Medical Sciences, University of Girona, Girona, Spain ; GROICAP (Research Group), Institut Universitari d'Investigació en Atenció Primària Jordi Gol, Girona, Spain
Vandenput, Liesbeth; Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Lorentzon, Mattias ; Sahlgrenska Osteoporosis Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden ; Region Västra Götaland, Geriatric Medicine, Sahlgrenska University Hospital, Mölndal, Sweden
Leslie, William D ; Department of Medicine, University of Manitoba, Winnipeg, MB, Canada
Kanis, John A; Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, United Kingdom
H.A.B.-F. has no financial interest in FRAX. For the DO-HEALTH trial cohort, Prof. H.A.B.-F. 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. Further, Prof. H.A.B.-F. 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.N.C.H. 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, Kyowa Kirin, Theramex, and Internis Pharma.R.A. 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.We are grateful to Dr. \u00D6sten Ljunggren for contributing the MrOS Sweden cohort. UK Biobank data are included under approved access agreement 3593. The authors acknowledge the Manitoba Centre for Health Policy for use of Manitoba data contained in the Population Health Research Data Repository (HIPC 2016/2017-29). The results and conclusions are those of the authors and no official endorsement by the Manitoba Centre for Health Policy, Manitoba Health, Seniors and Active Living, or other data providers is intended or should be inferred. N.C.H. acknowledges funding from the UK Medical Research Council [MC_PC_21003; MC_PC_21001] and the NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, UK. Terence O\u2019Neill is supported by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (BRC) (NIHR203308). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005. The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, R01 AG066671, and UL1 TR002369. Funding for the SOF study comes from the National Institute on Aging (NIA), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), supported by grants (AG05407, AR35582, AG05394, AR35584, and AR35583). Funding for the Health ABC study was from the Intramural research program at the National Institute on Aging under the following contract numbers: NO1-AG-6-2101, NO1-AG-6-2103 and NO1-AG-6-2106. The Longitudinal Aging Study Amsterdam is supported by a grant from the Netherlands Ministry of Health, Welfare and Sport, Directorate of Long-Term Care. Funding for the Framingham Study comes from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) R01 AR041398 and AR061445 and National Heart, Lung, and Blood Institute Framingham Heart Study (N01-HC-25195, HHSN268201500001I). Funding for the GOS was from the Victorian Health Promotion Foundation: ID 91-0095. For the purpose of Open Access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission.J.R.C. has received honoraria for speaking at educational meetings and for advisory boards from Amgen and honoraria for an advisory board from Bayer, all unrelated to this work. R.C. 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.A.D.-P. 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.J.A.P. has received funding from the National Health and Medical Research Council (NHMRC) Australia, and the Medical Research Future Fund (MRFF) Australia, and Amgen, all unrelated to this work.
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