Increased Risk of Fracture Among Patients With Iron Overload: A Population-based Matched Cohort Study

Abstract

Introduction: Iron overloading disorders are associated with decreased bone mineral density. However, evidence on fracture risk is scarce. Therefore, we evaluated the risk of fracture associated with iron overload disorders compared to matched controls.

Methods: Using The Healthcare Improvement Network, a Cegedim database of UK general practice data, we identified patients >18 years with elevated iron (ferritin value >1000 µg/L) or an eligible diagnosis code for iron overloading disorders between 2010 and 2022. The first date of elevated iron or a diagnosis code defined the index date for iron overload patients, who were matched with up to 10 controls. Time-varying confounder-adjusted Cox proportional hazard models estimated the hazard ratios (HRs) and 95% confidence intervals. Analyses were stratified by osteoporotic fracture site (hip, vertebral, humerus, forearm) and evidence of elevated serum ferritin at baseline (ferritin >1000 µg/L), and sex.

Results: We identified 20 264 eligible patients and 192 956 controls. Overall, there was a 55% increased risk of any fracture among iron overload patients (HR 1.55 [1.42-1.68]). Fracture risk was increased at all sites, with the highest risk observed for vertebral fractures (HR 1.97 [1.63-2.10]). Patients with ferritin >1000 µg/L had a 91% increased risk of any fracture (HR 1.91 [1.73-2.16]) and a 2.5-fold increased risk of vertebral fractures (HR 2.51 [2.01-3.12]). There was no increased risk among patients without elevated serum ferritin at any site. Fracture risk was similar between sexes.

Discussion: This large population-based cohort study found a 55% increased risk of fracture associated with iron overload. The risk was highest among patients with laboratory-confirmed iron overload, highlighting the importance for clinicians to consider initiating osteoporosis therapy in patients with serum ferritin >1000 µg/L to minimize fracture risk.

Keywords: erythropoiesis; fracture; iron; iron overload; osteoporosis; red cells.

Figure 1.

Patients flow diagram. Cases are those patients with an eligible diagnosis code for an iron overloading disorder [Supplementary Table S1 (23)] or a recorded serum ferritin value >1000 µg/L. The first date of the diagnosis or serum ferritin was considered the index date for inclusion into the study.