| アブストラクト | BACKGROUND: Bisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects. OBJECTIVES: The aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time. DESIGN: This was a new-user cohort study design with propensity score matching. SETTING AND DATA SOURCES: Data were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1-3 and from the Danish Odense University Hospital Databases for work package 4. PARTICIPANTS: Patients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of < 45 ml/minute/1.73 m(2) were eligible. A second estimated glomerular filtration rate value of < 45 ml/minute/1.73 m(2) within 1 year after the first was requested for work packages 1 and 3. Patients with no Hospital Episode Statistics linkage were excluded from work packages 1-3. Patients with < 1 year of run-in data before index estimated glomerular filtration rate and previous users of anti-osteoporosis medications were excluded from work packages 1-4. INTERVENTIONS/EXPOSURE: Bisphosphonate use, identified from primary care prescriptions (for work packages 1-3) or pharmacy dispensations (for work package 4), was the main exposure. MAIN OUTCOME MEASURES: Work package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change. RESULTS: Bisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users. LIMITATIONS: Confounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively. CONCLUSIONS: Bisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness. FUTURE WORK: Randomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data. STUDY REGISTRATION: This study is registered as EUPAS10029. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 17. See the NIHR Journals Library website for further project information. The project was also supported by the National Institute for Health Research Biomedical Research Centre, Oxford. |
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| 投稿者 | Robinson, Danielle E; Ali, M Sanni; Strauss, Victoria Y; Elhussein, Leena; Abrahamsen, Bo; Arden, Nigel K; Ben-Shlomo, Yoav; Caskey, Fergus; Cooper, Cyrus; Dedman, Daniel; Delmestri, Antonella; Judge, Andrew; Javaid, Muhammad Kassim; Prieto-Alhambra, Daniel |
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| 組織名 | Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences,;National Institute for Health Research (NIHR) Biomedical Research Centre,;University of Oxford, Oxford, UK.;Faculty of Epidemiology and Population Health, Department of Non-communicable;Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.;Open Patient data Explorative Network (OPEN), Department of Clinical Research,;University of Southern Denmark, Odense, Denmark.;Department of Medicine, Holbaek Hospital, Holbaek, Denmark.;Arthritis Research UK Sports, Exercise and Osteoarthritis Centre, University of;Oxford, Oxford, UK.;Medical Research Council Lifecourse Epidemiology Unit, University of Southampton,;Southampton General Hospital, Southampton, UK.;Population Health Sciences, University of Bristol, Bristol, UK.;School of Social and Community Medicine, University of Bristol, Bristol, UK.;UK Renal Registry, Bristol, UK.;Clinical Practice Research Datalink, Medicines and Healthcare products Regulatory;Agency, London, UK.;Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical;School, University of Bristol, Bristol, UK.;National Institute for Health Research (NIHR) Bristol Biomedical Research Centre;(BRC), University Hospitals Bristol NHS Foundation Trust, University of Bristol,;Southmead Hospital, Bristol, UK.;Grup de Recerca en Malalties Prevalents de l'Aparell Locomotor (GREMPAL) Research;Group and Centro de Investigacion Biomedica en Red Fragilidad y Envejecimiento;Saludable (CIBERFes), University Institute for Primary Care Research (IDIAP);Jordi Gol, Universitat Autonoma de Barcelona and Instituto de Salud Carlos III,;Barcelona, Spain. |
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