Abstract
Summary
A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX.
Introduction
The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD).
Methods
We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted β-coefficients.
Results
A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72–2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69–2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63–2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62–2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination.
Conclusion
A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies.
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Acknowledgements
We are grateful to Dr. Östen 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.
Funding
The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005.
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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.
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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.
Conflict of interest
J.A. Kanis led the team that developed FRAX as director of the WHO Collaborating Centre for Metabolic Bone Diseases. E.V. McCloskey, W.D. Leslie, M. Lorentzon, N.C. Harvey, E. Liu, L. Vandenput, and H. Johansson are members of the FRAX team. J.A. Kanis, N.C. Harvey, and E.V. McCloskey are members of the advisory body to the National Osteoporosis Guideline Group. J.A. Kanis reports no additional competing interests. K.E. Åkesson has no financial interest related to FRAX; chaired the National SALAR Group for Person-Centered Care Pathway Osteoporosis. F.A. 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. C.L. Bager is employed at Nordic Bioscience and owns stock in Nordic Bioscience. She declares no competing interests in relation to this work. H.A. 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. Further, 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. J.R. 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. J.A. Eisman declares consulting and research support from Actavis, Amgen, Aspen, Lilly, Merck Sharp and Dohme, Novartis, Sanofi-Aventis, Servier, and Theramex. P.J.M. Elders has no financial interest in FRAX. P.J.M. 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. Claus-C. Glüer reports honoraria and research support from AgNovos, Amgen, Osteolabs, and UCB unrelated to this work. N.C. 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. D.P. 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. E.V. 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. E.S. Orwoll reports consulting fees from Amgen, Biocon, Radius, and Bayer, and research support from Mereo. J.A. 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. K.M.A. Swart is an employee of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related healthcare authorities and several pharmaceutical companies. N.C. Wright sits on the Board of Trustee of the US Bone Health and Osteoporosis Foundation and has received consulting fees from Radius and ArgenX. M.C. 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, J.A. Cauley, C.J. Crandall, S.R. Cummings, J.A.P. da Silva, B. Dawson-Huges, A.B. Dufour, S. Ferrari, Y. Fujita, S. Fujiwara, I. Goldshtein, D. Goltzman, V. Gudnason, J. Hall, D. Hans, M. Hoff, R.J. Hollick, M. Huisman, M. Iki, S. Ish-Shalom, H. Johansson, G. Jones, M.K. Karlsson, S. Khosla, W.-P. Koh, F. Koromani, H. Kröger, T. Kwok, O. Lamy, A. Langhammer, B. Larijani, W.D. Leslie, K. Lippuner, E. Liu, D. Mellström, T. Merlijn, A. Nordström, P. Nordström, T.W. O’Neill, B. Obermayer-Pietsch, F. Rivadeneira, A.-M. Schott, E.J. Shiroma, K. Sigeirsdottir, E.M. Simonsick, E. Sornay-Rendu, R. Sund, K.M.A. Swart, P. Szulc, J. Tamaki, D.J. Torgerson, L. Vandenput, N.M. van Schoor, T.P. van Staa, J. Vila, N.J. Wareham, and N. Yoshimura declare no competing interests in relation to this work.
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Appendix
Fig. 3
Forest plot showing effect size on osteoporotic fracture risk (left panel) and any clinical fracture (right panel) associated with a prior fracture in men and women combined adjusted for age and time since baseline
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Kanis, J., Johansson, H., McCloskey, E. et al. Previous fracture and subsequent fracture risk: a meta-analysis to update FRAX. Osteoporos Int 34, 2027–2045 (2023). https://doi.org/10.1007/s00198-023-06870-z
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DOI: https://doi.org/10.1007/s00198-023-06870-z