Incorporation of excess gadolinium into human bone from medical contrast agents

Abstract

We find anomalously high gadolinium (Gd) concentrations in the femoral head bones of patients exposed to chelated Gd, commonly used as a contrast agent for medical imaging. Gd is introduced in chelated form to protect patients from exposure to toxic free Gd(3+), a calcium antagonist which disrupts cellular processes. Recent studies suggest Gd chelates break down in vivo, and Gd accumulation in tissue is linked to medical conditions such as nephrogenic systemic fibrosis (NSF), acute kidney failure, and in some cases death. We measure Gd and other rare earth element (REE) concentrations in 35 femoral heads by solution based ICP-MS. Gd concentrations in patients with documented exposure to Gd-based contrast agents (n = 13: Gd DTPA-BMA (Omniscan) n = 6; Gd HP-DO3A (Prohance) n = 5; unknown type n = 4) are significantly higher (p < 0.001) than the control group (n = 17). We use our control group to establish the 'natural' background level of Gd in human bone (cortical 95% CI: 0.023, 0.041 nmol/g; trabecular 95% CI: 0.054, 0.107 nmol/g). A control group outlier reveals the occurrence of individuals with high concentrations of all REEs, including Gd. Because of this, we calculate Gd anomalies from the concentrations of adjacent REEs and normalize to the control group mean to isolate Gd input from contrast agents. Normalized Gd anomalies, (Gd/Gd*)(N), for exposed patients range up to >800 times the 'natural' level (95% CI: 124, 460). Our data confirm that Gd, introduced in chelated form, incorporates into bone and is retained for more than 8 years. No difference was observed in bone Gd concentrations and anomalies between patients dosed with Gd DTPA-BMA (Omniscan; n = 6) and Gd HP-DO3A (Prohance; n = 5). Osteoporotic fracture patients exposed to Gd have significantly lower Gd concentrations than osteoarthritis patients (p < 0.001). This indicates different mechanisms of metal incorporation and/or retention in osteoporotic bone tissues, and may signal an increased risk of endogenous Gd release for patients with increased rates of bone resorption (e.g. osteoporosis patients and menopausal, pregnant, and lactating women) who are exposed to Gd-based contrast agents.