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Safety of oral bisphosphonates in moderate-to-severe chronic kidney disease: a bi-national cohort analysis

Safety of oral bisphosphonates in moderate-to-severe chronic kidney disease: a bi-national cohort analysis
Safety of oral bisphosphonates in moderate-to-severe chronic kidney disease: a bi-national cohort analysis

Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997–2016) and SIDIAP (2007–2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m 2, aged 40 years or older were identified. New bisphosphonate users were propensity score–matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD.

ANTIRESORPTIVES, FRACTURE PREVENTION, GENERAL POPULATION STUDIES, OSTEOPOROSIS, STATISTICAL METHODS
0884-0431
820-832
Robinson, Danielle E.
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Ali, M. Sanni
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Pallares, Natalia
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Tebé, Cristian
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Elhussein, Leena
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Abrahamsen, Bo
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Arden, Nigel
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Ben-Shlomo, Yoav
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Caskey, Fergus J.
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Cooper, Cyrus
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Delmestri, Antonella
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Judge, Andrew
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Pascual, Julio
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Nogués, Xavier
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Diez-Perez, Adolfo
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Strauss, Victoria Y.
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Kassim Javaid, M.
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Prieto-Alhambra, Daniel
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Robinson, Danielle E.
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Ali, M. Sanni
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Pallares, Natalia
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Tebé, Cristian
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Elhussein, Leena
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Abrahamsen, Bo
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Arden, Nigel
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Ben-Shlomo, Yoav
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Caskey, Fergus J.
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Cooper, Cyrus
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Dedman, Daniel
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Delmestri, Antonella
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Judge, Andrew
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Perez-Saez, Maria Jose
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Nogués, Xavier
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Diez-Perez, Adolfo
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Strauss, Victoria Y.
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Kassim Javaid, M.
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Robinson, Danielle E., Ali, M. Sanni, Pallares, Natalia, Tebé, Cristian, Elhussein, Leena, Abrahamsen, Bo, Arden, Nigel, Ben-Shlomo, Yoav, Caskey, Fergus J., Cooper, Cyrus, Dedman, Daniel, Delmestri, Antonella, Judge, Andrew, Perez-Saez, Maria Jose, Pascual, Julio, Nogués, Xavier, Diez-Perez, Adolfo, Strauss, Victoria Y., Kassim Javaid, M. and Prieto-Alhambra, Daniel (2021) Safety of oral bisphosphonates in moderate-to-severe chronic kidney disease: a bi-national cohort analysis. Journal of Bone and Mineral Research, 36 (5), 820-832. (doi:10.1002/jbmr.4235).

Record type: Article

Abstract

Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997–2016) and SIDIAP (2007–2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m 2, aged 40 years or older were identified. New bisphosphonate users were propensity score–matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD.

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Accepted/In Press date: 1 December 2020
e-pub ahead of print date: 29 December 2020
Published date: 12 June 2021
Additional Information: Funding Information: Funding was provided by Health Technology Assessment Programme Assessment project number 14/36/02. The project was partially funded by Centro de Investigaci?n Biom?dica en Red Fragilidad y Envejecimiento Saludable. Funding Information: Funding was provided by Health Technology Assessment Programme Assessment project number 14/36/02. The project was partially funded by Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable. JP and MJP‐S are supported by PI19/00037 (Spanish Ministry of Health ISCIII FIS‐FEDER) and RD16/0009/0013 (Instituto de Salud Carlos III (ISCIII) FEDER REDinRen). This work was supported by the NIHR Oxford Biomedical Research Centre. AJ was supported by the NIHR Biomedical Research Centre at University Hospitals BristolandWestonNHS Foundation Trust and the University of Bristol. No funder was directly involved in any aspect of this work. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Funding Information: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: DPA reports grants and other from AMGEN; grants, non‐financial support, and other from UCB Biopharma; grants from Les Laboratoires Servier, outside the submitted work. DPA also reports that Janssen, on behalf of the IMI‐funded EHDEN and EMIF consortiums, and Synapse Management Partners have supported training programs that are organized by DPA's department and are open to external participants. AJ reports personal fees from Freshfields Bruckhaus Derringer and Anthera Pharmaceuticals Inc., outside the submitted work. CC reports personal fees from Alliance for Better Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda, and UCB. KJ reports grants from NIHR HTA during the conduct of the study and personal fees from UCB and AMGEN, outside the submitted work. NA reports grants from Merck and personal fees from Merck, Regeneron, Pfizer/Eli Lilly, and Flexion, outside the submitted work. VS reports consultancy fees from Janssen Pharmaceutica NV, during the conduct of the study. XN reports advisory boards for Amgen, Eli Lilly, and Formation, and talks for Amgen, Eli Lilly, FAES, and ITALFARMACO. ADP reports personal fees from AMGEN‐UCB, Eli Lilly, Gilead, and Sandoz; other from Active Life Sci; and personal fees and non‐financial support from EchoLight, outside the submitted work. BA reports institutional research contracts and personal consulting fees from UCB Biopharma sprl, institutional research contracts from Novartis, personal speaker's fees from Eli Lilly and Amgen, and personal consulting fees from Kyowa‐Kirin Plc. CT reports personal fees from Boehringer Ingelheim and Amgen, outside the submitted work. Publisher Copyright: © 2020 American Society for Bone and Mineral Research (ASBMR) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
Keywords: ANTIRESORPTIVES, FRACTURE PREVENTION, GENERAL POPULATION STUDIES, OSTEOPOROSIS, STATISTICAL METHODS

Identifiers

Local EPrints ID: 446303
URI: http://eprints.soton.ac.uk/id/eprint/446303
ISSN: 0884-0431
PURE UUID: 0f71957d-c814-46bd-af11-220eb2ad6dd4
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709

Catalogue record

Date deposited: 04 Feb 2021 17:30
Last modified: 02 Nov 2021 02:36

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Contributors

Author: Danielle E. Robinson
Author: M. Sanni Ali
Author: Natalia Pallares
Author: Cristian Tebé
Author: Leena Elhussein
Author: Bo Abrahamsen
Author: Nigel Arden
Author: Yoav Ben-Shlomo
Author: Fergus J. Caskey
Author: Cyrus Cooper ORCID iD
Author: Daniel Dedman
Author: Antonella Delmestri
Author: Andrew Judge
Author: Maria Jose Perez-Saez
Author: Julio Pascual
Author: Xavier Nogués
Author: Adolfo Diez-Perez
Author: Victoria Y. Strauss
Author: M. Kassim Javaid
Author: Daniel Prieto-Alhambra

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