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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.

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Correspondence to J. A. Kanis.

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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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Appendix

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Tables

Table 3 Excluded cohorts

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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