Elemental Imaging of Long-term Gadolinium Retention in Rodent Femur

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Background Gadolinium-based contrast agents (GBCAs) are applied to enhance magnetic resonance imaging. Gadolinium (Gd), a rare earth metal, is used in a chelated form when administered as GBCA to patients. There is an ongoing scientific debate about the clinical significance of Gd retention in tissues after administration of GBCAs. It is known that bone serves as Gd reservoir, but only sparse information on localization of Gd in bone is available. Purpose The aim of this study was to compare Gd tissue concentration and spatial distribution in femoral epiphysis and diaphysis 10 weeks after single-dose injection of linear and macrocyclic GBCAs in a large animal model. Materials and Methods In this prospective animal study, Swiss-Alpine sheep (n = 36; age range, 4–10 years) received a single injection (0.1 mmol/kg) of macrocyclic (gadobutrol, gadoteridol, and gadoterate meglumine), linear (gadodiamide and gadobenate dimeglumine) GBCAs, or saline. Ten weeks after injection, sheep were killed, and femur heads and shafts were harvested. Gadolinium spatial distribution was determined in 1 sample of each treatment group by laser ablation–inductively coupled plasma–mass spectrometry. All bone specimens were analyzed histopathologically. Results Injection of GBCAs in female Swiss-Alpine sheep (n = 36) resulted in Gd localization at the endosteal and periosteal surface and in a subset of GBCAs additionally at the cement lines and the bone cartilage junction. No histopathological alterations were observed in the investigated tissue specimens. Conclusions Ten weeks after single injection of a clinically relevant dose in adult sheep, both linear species of GBCA resulted in considerably higher accumulation than macrocyclic GBCAs. Gadolinium deposits were restricted to distinct bone and cartilage compartments, such as in bone linings, cement lines, and bone cartilage junctions. Tissue histology remained unaffected.

Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 88%

Section: La-icp-ms Analysismentioning

confidence: 99%

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Elemental Bioimaging of Sheep Bone and Articular Cartilage After Single Application of Gadolinium-Based Contrast Agents

Richter,

Verlemann,

Jeibmann

et al. 2023

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“…Initially demonstrated by Kanda et al 7 in 2014 and further confirmed in the literature by numerous clinical 42,43 and preclinical studies, [44][45][46] small quantities of Gd were observed in tissues including the brain (with no blood-brain barrier disruption) of subjects with or without normal renal function who received cumulative doses of GBCAs (especially linear). Although it remains unclear whether these findings have any clinical relevance [47][48][49] (no enough evidence to demonstrate that dechelated Gd is present in any tissue long enough to manifest a toxicologic event), the retention of Gd in healthy patients has evoked safety concerns surrounding the application of GBCAs.…”

Section: Discussionmentioning

confidence: 85%

“…In their rat study, Schlatt et al 64 have shown that linear GBCAs accumulated significantly more Gd than macrocyclic GBCAs, but they have also observed, for the first time, that the Gd found in bone samples was mostly present as dechelated Gd or otherwise bound to endogenous components, but not complexed to its initial ligand, which is not the case in other tissues, even for macrocyclic GBCAs. The retention of unchelated Gd ion may be important clinically, because Gd is not a naturally occurring biological constituent, and once within the tissues, it persists for long periods with almost no washout, as observed in preclinical studies 45,65 but also in patients. 66 Despite the long-term retention of Gd observed in this tissue, no toxic effects were attributed to this specificity.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Safety Assessment of Gadopiclenol: A High-Relaxivity Macrocyclic Gadolinium-Based MRI Contrast Agent

Gendron,

Bourrinet,

Dencausse

et al. 2023

Objective Gadopiclenol is a new high-relaxivity macrocyclic gadolinium-based contrast agent for magnetic resonance imaging of the central nervous system and other body regions. The product has been approved by US Food and Drug Administration and is currently being evaluated by European Medicines Agency. For risk assessment of the single diagnostic use in humans, the safety profile of gadopiclenol was evaluated with a series of preclinical studies. Materials and Methods With exception of dose-ranging studies, all safety pharmacology and toxicology studies were performed in compliance with Good Laboratory Practice principles. Safety pharmacology studies were conducted to assess potential effects on cardiovascular (in vitro and in dogs), respiratory (in rats and guinea pigs), neurological (in rats), and renal endpoints (in rats). Toxicology studies were also performed to investigate acute toxicity (in rats and mice), extended single-dose (in rats and dogs) and repeated-dose toxicity (in rats and dogs), reproductive (in rats), developmental (in rats and rabbits) and juvenile toxicity (in rats), as well as genotoxicity (in vitro and in rats), local tolerance (in rabbits), potential immediate hypersensitivity (in guinea pigs), and potential tissue retention of gadolinium (in rats). Results Safety pharmacology studies conducted at high intravenous (IV) doses showed a satisfactory tolerance of gadopiclenol in the main body systems. After either single or repeated IV dosing (14 and 28 days) in rats and dogs, gadopiclenol was well tolerated even at high doses. The no-observed-adverse-effect level values (ie, the highest experimental dose without adverse effects) representing between 8 times in rats and 44 times in dogs (based on the exposure), the exposure achieved in humans at the intended diagnostic dose, provide a high safety margin. No or only minor and reversible effects on body weight, food consumption, clinical signs, clinical pathology parameters, or histology were observed at the highest doses. The main histological finding consists in renal tubular vacuolations (exacerbated after repeated exposure), which supports a well-known finding for this class of compounds that has no physiological consequence on kidney function. Reproductive toxicity studies showed no evidence of effects on reproductive performance, fertility, perinatal and postnatal development in rats, or reproductive development in rats or rabbits. The safety profile of gadopiclenol in juvenile rats was satisfactory like in adults. Gadopiclenol was not genotoxic in vitro in the Ames test, a mouse lymphoma assay, and a rat in vivo micronucleus test. There were no signs of local intolerance at the injection site after IV and intra-arterial administration in rabbits. However, because of minor signs of intolerance after perivenous administration, misadministration must be avoided. Gadopiclenol exhibited no signs of potential to induce immediate hypersensitivity in guinea pigs. Conclusions High safety margins were observed between the single diagnostic dose of 0.05 mmol/kg in humans and the doses showing effects in animal studies. Gadopiclenol is, therefore, well tolerated in various species (mice, rats, dogs, rabbits, and guinea pigs). All observed preclinical data support the clinical approval.

Gadolinium-Based Contrast Agents and Free Gadolinium Inhibit Differentiation and Activity of Bone Cell Lineages

Strunz,

Stähli,

Heverhagen

et al. 2023

Objectives Administration of gadolinium-based contrast agents (GBCA) in magnetic resonance imaging results in the long-term retention of gadolinium (Gd) in tissues and organs, including the bone, and may affect their function and metabolism. This study aims to investigate the effects of Gd and GBCA on the proliferation/survival, differentiation, and function of bone cell lineages. Materials and Methods Primary murine osteoblasts (OB) and osteoclast progenitor cells (OPC) isolated from C57BL/6J mice were used to test the effects of Gd3+ (12.5–100 μM) and GBCA (100–2000 μM). Cultures were supplemented with the nonionic linear Gd-DTPA-BMA (gadodiamide), ionic linear Gd-DTPA (gadopentetic acid), and macrocyclic Gd-DOTA (gadoteric acid). Cell viability and differentiation were analyzed on days 4–6 of the culture. To assess the resorptive activity of osteoclasts, the cells were grown in OPC cultures and were seeded onto layers of amorphous calcium phosphate with incorporated Gd. Results Gd3+ did not affect OB viability, but differentiation was reduced dose-dependently up to 72.4% ± 6.2%–73.0% ± 13.2% (average ± SD) at 100 μM Gd3+ on days 4–6 of culture as compared with unexposed controls (P < 0.001). Exposure to GBCA had minor effects on OB viability with a dose-dependent reduction up to 23.3% ± 10.2% for Gd-DTPA-BMA at 2000 μM on day 5 (P < 0.001). In contrast, all 3 GBCA caused a dose-dependent reduction of differentiation up to 88.3% ± 5.2% for Gd-DTPA-BMA, 49.8% ± 16.0% for Gd-DTPA, and 23.1% ± 8.7% for Gd-DOTA at 2000 μM on day 5 (P < 0.001). In cultures of OPC, cell viability was not affected by Gd3+, whereas differentiation was decreased by 45.3% ± 9.8%–48.5% ± 15.8% at 100 μM Gd3+ on days 4–6 (P < 0.05). Exposure of OPC to GBCA resulted in a dose-dependent increase in cell viability of up to 34.1% ± 11.4% at 2000 μM on day 5 of culture (P < 0.001). However, differentiation of OPC cultures was reduced on day 5 by 24.2% ± 9.4% for Gd-DTPA-BMA, 47.1% ± 14.0% for Gd-DTPA, and 38.2% ± 10.0% for Gd-DOTA (P < 0.001). The dissolution of amorphous calcium phosphate by mature osteoclasts was reduced by 36.3% ± 5.3% upon incorporation of 4.3% Gd/Ca wt/wt (P < 0.001). Conclusions Gadolinium and GBCA inhibit differentiation and activity of bone cell lineages in vitro. Thus, Gd retention in bone tissue could potentially impair the physiological regulation of bone turnover on a cellular level, leading to pathological changes in bone metabolism.