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Bisphosphonates to reduce bone fractures in stage 3B+ chronic kidney disease: a propensity score-matched cohort study.
Health Technol Assess. 2021 03; 25(17):1-106.HT

Abstract

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.

Links

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Authors+Show Affiliations

Robinson DE
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Oxford, Oxford, UK.
Ali MS
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.
Strauss VY
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Oxford, Oxford, UK.
Elhussein L
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Oxford, Oxford, UK.
Abrahamsen B
Open Patient data Explorative Network (OPEN), Department of Clinical Research, University of Southern Denmark, Odense, Denmark. Department of Medicine, Holbæk Hospital, Holbæk, Denmark.
Arden NK
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.
Ben-Shlomo Y
Population Health Sciences, University of Bristol, Bristol, UK.
Caskey F
School of Social and Community Medicine, University of Bristol, Bristol, UK. UK Renal Registry, Bristol, UK.
Cooper C
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Oxford, Oxford, UK. Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK.
Dedman D
Clinical Practice Research Datalink, Medicines and Healthcare products Regulatory Agency, London, UK.
Delmestri A
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Oxford, Oxford, UK.
Judge A
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Oxford, Oxford, 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.
Javaid MK
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Oxford, Oxford, UK. Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK.
Prieto-Alhambra D
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Oxford, Oxford, UK. Grup de Recerca en Malalties Prevalents de l'Aparell Locomotor (GREMPAL) Research Group and Centro de Investigación Biomédica 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.

MeSH

Cohort StudiesDiphosphonatesFractures, BoneHumansPropensity ScoreRenal Insufficiency, Chronic

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33739919

Citation

Robinson, Danielle E., et al. "Bisphosphonates to Reduce Bone Fractures in Stage 3B+ Chronic Kidney Disease: a Propensity Score-matched Cohort Study." Health Technology Assessment (Winchester, England), vol. 25, no. 17, 2021, pp. 1-106.
Robinson DE, Ali MS, Strauss VY, et al. Bisphosphonates to reduce bone fractures in stage 3B+ chronic kidney disease: a propensity score-matched cohort study. Health Technol Assess. 2021;25(17):1-106.
Robinson, D. E., Ali, M. S., Strauss, V. Y., Elhussein, L., Abrahamsen, B., Arden, N. K., Ben-Shlomo, Y., Caskey, F., Cooper, C., Dedman, D., Delmestri, A., Judge, A., Javaid, M. K., & Prieto-Alhambra, D. (2021). Bisphosphonates to reduce bone fractures in stage 3B+ chronic kidney disease: a propensity score-matched cohort study. Health Technology Assessment (Winchester, England), 25(17), 1-106. https://doi.org/10.3310/hta25170
Robinson DE, et al. Bisphosphonates to Reduce Bone Fractures in Stage 3B+ Chronic Kidney Disease: a Propensity Score-matched Cohort Study. Health Technol Assess. 2021;25(17):1-106. PubMed PMID: 33739919.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bisphosphonates to reduce bone fractures in stage 3B+ chronic kidney disease: a propensity score-matched cohort study. AU - Robinson,Danielle E, AU - Ali,M Sanni, AU - Strauss,Victoria Y, AU - Elhussein,Leena, AU - Abrahamsen,Bo, AU - Arden,Nigel K, AU - Ben-Shlomo,Yoav, AU - Caskey,Fergus, AU - Cooper,Cyrus, AU - Dedman,Daniel, AU - Delmestri,Antonella, AU - Judge,Andrew, AU - Javaid,Muhammad Kassim, AU - Prieto-Alhambra,Daniel, PY - 2021/3/19/entrez PY - 2021/3/20/pubmed PY - 2021/10/26/medline KW - BISPHOSPHONATES KW - CHRONIC KIDNEY DISEASE KW - CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER KW - FRACTURE KW - PHARMACOEPIDEMIOLOGY SP - 1 EP - 106 JF - Health technology assessment (Winchester, England) JO - Health Technol Assess VL - 25 IS - 17 N2 - 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. SN - 2046-4924 UR - https://www.unboundmedicine.com/medline/citation/33739919/Bisphosphonates_to_reduce_bone_fractures_in_stage_3B+_chronic_kidney_disease:_a_propensity_score_matched_cohort_study_ DB - PRIME DP - Unbound Medicine ER -