Bisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease (CKD). However, they are widely used to prevent fragility fractures in stage 3 CKD, despite a lack of good-quality data on their effects.
Work package 1 (WP1): The relationship between bisphosphonate use and CKD progression.
WP2: The association between using bisphosphonates and fracture risk.
WP3: The risks of hypocalcaemia, hypophosphatemia, acute kidney injury, and upper gastrointestinal events associated with using bisphosphonates.
WP4: The association between using bisphosphonates and changes in bone mineral density (BMD) over time.
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 (CPRD) GOLD database) and linked hospital inpatient records (Hospital Episode Statistics, HES) for WP1-3 and from the Danish Odense University Hospital Databases (OUHD) for WP4.
Patients registered in the data sources who had at least one measurement of estimated glomerular filtration rate (eGFR) below 45 were eligible. A second eGFR <45 within 1 year after the first was requested for WP1 and 3. Patients with no HES linkage were excluded for WP1-3. Patients with less than 1 year of run-in data before index eGFR and previous users of anti-osteoporosis medications were excluded for WP1-4.
Bisphosphonate use, identified from primary care prescriptions (WP1-3) or pharmacy dispensations (WP4), was the main exposure.
Main outcome measures
WP1: CKD progression, defined as stage worsening or starting renal replacement.
WP2: Hip fracture.
WP3: Acute kidney injury, hypocalcaemia, and hypophosphatemia identified from HES. Gastrointestinal events identified from CPRD or HES.
WP4: Annualised femoral neck BMD percentage change.
Bisphosphonate use was associated with an excess risk of CKD progression (sub-hazard ratio (HR) [95% confidence interval (CI)]: 1.12 [1.02-1.24]) in WP1, but did not increase the probability of other safety outcomes in WP3. WP2 suggested that bisphosphonate use increased fracture risk (HR: 1.25 [1.13-1.39] for hip fractures), but sensitivity analyses suggested this was related to unresolved confounding. Conversely, WP4 suggested that bisphosphonates improved BMD, with an average 2.65% [1.32% to 3.99%] greater gain in femoral neck BMD per year in bisphosphonate users than matched non-users.
Confounding by indication was a concern for the clinical effectiveness (WP2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. WP3 and WP4 were based on low numbers of events and participants, respectively.
Bisphosphonates were associated with a 12% excess risk of CKD progression in participants with stage 3B+ CKD. No other safety concerns were identified. Bisphosphonate therapy increased BMD, but we failed to demonstrate anti-fracture effectiveness.