Duration, dose, and responsiveness to erythropoiesis-stimulating agents and risk of osteoporotic fracture among patients with chronic kidney disease in Hong Kong: a nested case-control study.

Background: Anaemia is a common complication of chronic kidney disease (CKD), often treated with erythropoiesis-stimulating agents (ESAs). The association between erythropoietin use and osteoporotic fractures in humans is yet to be fully elucidated. It is also unclear whether responsiveness to ESA treatment independently contributes to fracture risk. We aimed to evaluate the risk of osteoporotic fractures associated with ESA use in patients with chronic kidney disease (CKD). Methods: In this nested case-control study, we identified 19,720 patients newly diagnosed with CKD between 2005 and 2017 who received ESA treatment before Dec 31, 2022 from the Clinical Data Analysis and Reporting System, the territory-wide electronic health record database in Hong Kong. Patients were included irrespective of dialysis status (peritoneal dialysis, haemodialysis, and non-dialysis). Fracture cases were matched with up to 10 fracture-free controls, according to age, sex, and year of fracture, to investigate associations with ESA use. Fracture cases were defined as major osteoporotic fractures, including overall fractures and specific types (spine, humerus, wrist, and hip fractures), identified using ICD-9-CM codes. Main exposures of interest were duration of ESA treatment before fracture (index date), cumulative defined daily dose of ESA before index date, and ESA responsiveness. Responsiveness was defined as haemoglobin increase ≥1 g/dL within 2 months of ESA initiation. Conditional logistic regression was used to estimate odds ratios (ORs) adjusted for time since CKD diagnosis, comorbidities, fracture-related medications, frailty, CKD-related procedures, and laboratory values. Findings: In total, 959 osteoporotic fracture cases were matched with 9262 controls. Among the fracture types, the majority of cases were hip fractures (n = 622), followed by wrist (n = 164), humerus (n = 154), and spine fractures (n = 80). Fracture patients had a longer ESA treatment duration (mean 2.1 years [SD 2.1] vs. 1.4 years [SD 1.7]) and received a higher cumulative defined daily dose (mean 14,559.8 [SD 21,270.1] vs. 9610.3 [SD 15,702.0]) than their matched controls. Longer ESA treatment duration, but not cumulative dose, was independently associated with increased risks of overall fracture (OR per additional year 1.31; 95% CI 1.23-1.39) and hip fracture (1.28; 1.18-1.39). Results remained largely consistent after adjusting for anaemia severity, excluding patients with hyperparathyroidism, and in subgroup analyses. Additionally, ESA responders had a significantly higher fracture risk compared to non-responders (OR 1.36; 95% CI 1.14-1.63). Interpretation: Our findings suggest that prolonged ESA use and ESA responsiveness are associated with increased osteoporotic fracture risk in patients with CKD, highlighting the need for optimisation of treatment regimens for anaemia in patients with CKD to balance treatment benefits against fracture risk. Further research is warranted to better understand this association. Funding: None.