A review of the methods used to define glucocorticoid exposure and risk attribution when investigating the risk of fracture in a rheumatoid arthritis population.
Glucocorticoid therapy is used widely in patients with rheumatoid arthritis (RA) with good efficacy but concerns about safety including fractures. Estimates of fracture risk for any given patient are complicated by the dynamic pattern of glucocorticoid use, where patients vary in their dose, duration and timing of glucocorticoid use.



To investigate which methods are currently used to attribute fractures to glucocorticoid exposure and investigate whether such methods can consider individual treatment patterns.



Thirty-eight studies used five common definitions of risk attribution to glucocorticoid exposure: "current use", "ever use", "daily dose", "cumulative dose" and "time variant". One study attempted to combine multiple definitions where "cumulative dose" was nested within "daily dose", covering the effects of dose and duration but not timing. The majority of results demonstrated an equivocal or increased risk of fracture with increased exposure, although there was wide variation, with odds ratios, hazard ratios and relative risks ranging from 0.16 to 8.16. Within definitions there was also variability in the results with the smallest range for "time variant", 1.07 to 2.8, and the largest for "cumulative dose", ranging from risk estimates of 0.88 to 8.12.



Many studies have looked into the effect of glucocorticoids on fracture risk in patients with RA. Despite this, there is no clear consensus about the magnitude of risk. This is a consequence of the varied analysis models and their different assumptions. Moreover, no current analysis method allows consideration of dose, duration and timing of glucocorticoid therapy, preventing a clear understanding of fracture risk for patients and their individual treatment patterns.
Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PT, UK.
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DE
Robinson
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK; Victoria University, Wellington, New Zealand.
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Dennison
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK; NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 5UG, UK; NIHR Nutrition Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton SO16 6YD, UK.
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Cooper
Health eResearch Centre, Farr Institute for Health Informatics Research, University of Manchester, Vaughan House, Portsmouth Road, M13 9PL, UK; Utrecht University, Faculty of Science, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht, The Netherlands.
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van Staa
Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PT, UK; Health eResearch Centre, Farr Institute for Health Informatics Research, University of Manchester, Vaughan House, Portsmouth Road, M13 9PL, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Nowgen Building, 29 Grafton Street, Manchester, M13 9WU, UK; Salford Royal NHS Foundation Trust, Stott Ln, Salford, M6 8HD, UK. Electronic address: will.dixon@manchester.ac.uk.
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Dixon
D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D050723:Fractures, Bone / Q000453:epidemiology*; D005938:Glucocorticoids / Q000009:adverse effects* / Q000627:therapeutic use*; D006801:Humans; D016017:Odds Ratio; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors
D005938:Glucocorticoids
Epidemiology; Fracture; Glucocorticoids; Rheumatoid arthritis; Rheumatology