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 due to 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 stage 3b-5, based on 2 or more estimated glomerular filtration rate measurements less than 45 ml/min/1.73m2, aged 40 years or older were identified. New bisphosphonate users were propensity-score-matched with up to five non-users to minimise confounding within this population. Our primary outcome was CKD stage worsening (eGFR decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcaemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2,447 bisphosphonate users with 8,931 non-users from CPRD and 1,399 users with 6,547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcaemia. 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.