Efficacy of reduced-dose gadobutrol versus standard-dose gadoterate in contrast-enhanced MRI for the evaluation of diabetic foot osteomyelitis

Abstract

Background

Gadobutrol is a macrocyclic gadolinium-based contrast agent (GBCA) with higher relaxivity than other GBCAs, suggesting the potential for dose reduction without compromising image quality.

Purpose

To evaluate whether a 30% reduced dose of gadobutrol is as effective as the standard dose of gadoterate for lesion visualization and enhancement in diabetic foot osteomyelitis.

Methods

This study included 132 patients with preoperative contrast-enhanced foot MRIs prior to amputation surgery for diabetic foot osteomyelitis from November 2020 to January 2023. Sixty-six enhanced foot MRIs with reduced dose gadobutrol (0.07 mmol/kg) and 66 MRIs with standard dose gadoterate (0.1 mmol/kg) were reviewed by two radiologists. For the primary study objective, two parameters (lesion border visualization and subjective lesion enhancement) for qualitative lesion visualization were assessed between the two agents using a noninferiority analysis. In the quantitative assessment of lesion enhancement, lesion-to-background ratio and enhancement percentage were compared between the two agents.

Results

The mean scores for lesion border delineation and the visual degree of contrast enhancement were nearly identical between the two groups. For both readers, the lower limit of the 95% confidence interval (CI) for the difference did not drop below −0.35, which is above the noninferiority margin. Regarding quantitative analysis, no significant differences were observed in the enhancement percentage and lesion-to-background ratio between the two agents (p > 0.5).

Conclusion

A 30% reduced dose of gadobutrol (0.07 mmol/kg) is as effective as the standard gadoterate dose (0.1 mmol/kg) for lesion visualization in contrast-enhanced MRI of diabetic foot osteomyelitis, with similar enhancement efficacy.

Keywords

Diabetic foot diabetic foot ulcer osteomyelitis gadobutrol gadoterate MRI

Introduction

Diabetic foot is one clinical manifestation of diabetes, with a wide range of symptoms, including ulceration, osteomyelitis, osteoarticular destruction, and gangrene, as a consequence of advanced disease. Some diabetic foot cases present general indications for amputation, including limb necrosis, life-threatening infections, severe pain, or loss of function (1). Diabetic foot osteomyelitis arises from a soft tissue infection that spreads into the bone, initially affecting the cortex and subsequently the marrow. The presence of osteomyelitis impedes infection control and raises the need for medical treatment and surgery (2). Since osteomyelitis requires surgery to remove portions of bone that are infected or dead, it is important to determine the extent of infection before surgery (1). Magnetic resonance imaging (MRI) is currently the imaging modality of choice in the assessment of osteomyelitis and soft tissue complications in the diabetic foot. In particular, contrast material-enhanced MRI has advantages in evaluating soft-tissue complications such as sinus tracts, abscesses, and necrosis and is useful for distinguishing between Charcot arthropathy and osteomyelitis, so is increasingly available (3 –5).

Gadolinium-based contrast agents (GBCAs) for contrast-enhanced MRI have been considered safe in most cases, with adverse reactions reported in 0.07%–2.4% of cases, and most being mild (6,7). Nevertheless, free gadolinium is toxic and can be retained in the body (i.e., brain, bone, and skin tissues) (8,9). Such gadolinium deposition is more likely to occur in patients who received linear GBCAs, rather than macrocyclic GBCAs, and was attributed to the lower kinetic stability of linear agents (9). Furthermore, in patients with impaired renal function (ie, a glomerular filtration rate (GFR) below 60 mL/min/1.73 m2 ), linear GBCAs can therefore lead to nephrogenic systemic fibrosis (NSF) (10). However, regardless of renal clearance, there is evidence that traces of GBCAs, linear and macrocyclic alike, will leak from the intravascular space into the cerebrospinal fluid and along the deep perivascular spaces into the deep brain areas (8 –11) Since both intracranial gadolinium deposition and NSF have been observed to be dose-dependent (11–13), the need to use the lowest effective dose of GBCAs for diagnostic purposes has been emphasized.

Using GBCAs with high relaxivity is one strategy to reduce the amount of gadolinium (14,15). Among the macrocyclic GBCAs which show high stability, two macrocyclic GBCAs in widespread clinical use are gadobutrol and gadoterate (16). While both gadobutrol and gadoterate are macrocyclic agents with similar pharmacokinetic parameters, variation exists between these two agents. Gadobutrol is the only gadolinium chelate to be prepared commercially as a 1.0 M formulation (1.0 mol/L), unlike other GBCAs (0.5 mol/L). More important, gadobutrol has a T1 relaxivity of 4.6–5.3 L/(mmol · s) at 1.5 T and 3.5–5.0 L/(mmol · s) at 3 T, whereas gadoterate has a T1 relaxivity of 3.3–4.2 L/(mmol · s) at 1.5 T and 2.7–3.5 L/(mmol · s) at 3 T (17). This approximately 26–39% higher relaxivity of gadobutrol compared to gadoterate suggests the possibility that a lower dose of gadobutrol may offer comparable efficacy to a standard dose of gadoterate (16,18).

The FDA's recommended dose for both gadobutrol and gadoterate is 0.1 mmol/kg of body weight (16). Given the difference in T1 relaxivity, even with a 30% dose reduction (0.07 mmol/ kg) of gadobutrol should provide practically equivalent diagnostic efficacy as a standard dose (0.1 mmol/kg) of gadoterate. Therefore, the aim of this study was to investigate whether a 30% reduced dose of gadobutrol (0.07 mmol/kg) is noninferior to the standard dose of gadoterate (0.1 mmol/kg) in terms of lesion visualization and enhancement efficacy in contrast-enhanced foot MRI for evaluating diabetic foot osteomyelitis.

Materials and Methods

Patients

This retrospective study was approved by our institutional review board (IRB No. GAIRB2019-092) and informed consent was waived. In our institution, for diabetic foot ulcer patients with an estimated GFR (eGFR) greater than 30 ml/min/1.73 m2 contrast-enhanced MRI has been performed to assess the presence and characteristics of associated infection, including its extent. Since October 2019, a 30% reduced dose of gadobutrol and the standard dose of gadoterate have been used alternately every day for patients with diabetic foot ulcer, based on mutual agreement between orthopedic surgeons and radiologists.

We conducted an electronic search to identify patients who underwent amputation surgery due to diabetic foot osteomyelitis between November 2020 and January 2023. This initial search found 308 cases. Ninety-five cases were excluded owing to the following reasons: absence of preoperative MRI scan (n = 23), MRI performed but no contrast-enhanced images available (n = 57), MRI taken outside the 5-day preoperative window (n = 9), insufficient quality of MRI scans for evaluation (n = 4), and missing surgical records (n = 2). Subsequently, preoperative contrast-enhanced MRI taken within 5 days before the surgery were selected (n = 213). Among them, 110 MRI scans with a 30% reduced dose of gadobutrol and 103 MRI scans with a standard dose of gadoterate were identified. To better observe the effects of the different doses, 66 image pairs were matched based on the level of foot amputation. These matched groups were included in the study (Fig. 1). Based on the amputation level, surgical procedures were classified into the following 6 categories : 1) partial toe amputation—part of a toe, 2) toe amputation—entire toe, 3) ray amputation : toe and corresponding metatarsal bone, 4) transmetatarsal amputation—partial foot across the metatarsal bones, 5) tarsometatarsal (Lisfranc) amputation—forefoot amputation across the tarsometatarsal line, 6) midtarsal (Chopart) amputation—forefoot and midfoot amputation sparing the proximal talus and calcaneus. Patients who underwent the same procedure in both groups were matched, and their preoperative images were compared.

Fig. 1.

Flowchart of the study population.

MRI examinations

All MRI examinations were performed using a 3-T system with a dedicated ankle coil (MAGNETOM Skyra, Siemens Healthineers). Unenhanced 2D sequences included axial fat-suppressed (FS) turbo spin-echo (TSE) T2-weighted, axial/coronal/sagittal TSE T1-weighted, sagittal TSE T2-weighted, coronal FS proton density (PD)-weighted. Then, axial, coronal, and sagittal contrast-enhanced spin-echo T1-weighted imaging was performed. The sequence parameters are shown in Table 1.

Table 1.

MRI sequence parameters.

Parameter	Precontrast FS TSE T2-weighted	Preconstrast TSE T1-weighted	Precontrast TSE T2-weighted	Precontrast FS TSE PD-weighted	Postcontrast T1-weighted
FOV (mm)	130 × 89 −240 × 143	130 × 89–240 × 143	130 × 89–240 × 143	130 × 89–240 × 143	130 × 89 –240 × 143
Plane or Planes	Axial	Axial, coronal, sagittal	Sagittal	Coronal	Axial, coronal, sagittal
Slice thickness (mm)	2.5–3	2.5–3	2.5–3	2.5–3	2.5–3
Interslice gap (mm)	0–0.3	0–0.3	0–0.3	0–0.6	0–0.3
Matrix	≥384 × ≥264	≥384 × ≥264	≥384 × ≥228	≥384 × ≥264	≥384 × ≥264
No. of excitations	2	1	1	2	1 (axial, sagittal), 2 (coronal)

Note: TSE = turbo spin-echo, FS = fat-suppressed, PD = Proton density.

Contrast-enhanced T1-weighted sequences were obtained using two GBCAs: gadobutrol (Gadobrix^®, Taejoon Pharm Co., Ltd, Seoul, Korea) and gadoterate (Dotarem^®, Guerbet, Roissy, France). The dose of gadobutrol was reduced by 30% to 0.07 mmol/kg, while gadoterate was administered at the standard dose of 0.1 mmol/kg. Both GBCAs were administered intravenously, followed by a saline flush using a power injector.

Image evaluation

All contrast-enhanced foot MRIs were independently reviewed by two musculoskeletal (MSK) radiologists (YMJ and TRA; 14 and 9 years of experience with MSK imaging, respectively) who were blinded to the respective contrast agent used. All images were displayed digitally on monitors with a picture archiving and communication system (PACS) software (INFINITT Healthcare, Korea) in a randomized order. The readers were aware that they were evaluating images of diabetes-related osteomyelitis and were provided with clinical information regarding the location of the ulcer and the surgical site. For each examination, the readers reviewed pre-contrast and post-contrast images together to identify bone marrow lesions. This is because, in patients with diabetic foot infections, the main role of MRI is to identify osteomyelitis, which is the most critical factor for preoperative planning of limited limb resection (1,19). The most characteristic feature indicating osteomyelitis on MRI is the presence of low signal intensity in the bone marrow on T1-weighted images, high signal intensity in the bone marrow on T2-weighted images, and marrow enhancement following the administration of contrast material (3,20,21). Noticeably low signal intensity on T1-weighted images is a primary sign of osteomyelitis (4,5). In accordance with our clinical routine, reviewers were free to choose the appropriate planes— axial, sagittal, or coronal and allowed to modify window width and level. After localizing the bone marrow lesion, qualitative and quantitative assessment regarding osteomyelitis were evaluated by the two readers. When multiple bones were involved, the assessment focused on the most proximal bone lesion among those adjacent to an ulcer or sinus tract, as this would be useful in determining the level of amputation.

Qualitative assessment of lesion visualization

The noninferiority of contrast-enhanced MRI with gadobutrol versus gadoterate for lesion visualization was the primary study objective.

Lesion visualization assessment of osteomyelitis was based on two parameters: border delineation and the visual degree of contrast enhancement. Border delineation was assessed on a four-point scale as follows: 1 = none (no or unclear delineation), 2 = moderate (some areas of clear delineation but also with some significant areas of indistinct delineation), 3 = good (almost clear but not complete delineation), and 4 = excellent (clear and complete delineation). The degree of contrast enhancement was also graded on a four-point scale: 1 = none (no enhancement), 2 = moderate (weak enhancement), 3 = good (clear enhancement), and 4 = excellent (clear and bright enhancement).

Quantitative assessment of lesion enhancement

For the quantitative assessment of lesion enhancement, lesion-to-background ratio and enhancement percentage were calculated for the most representative lesion in each patient. Regions of interest (ROI) placement was performed using a picture archiving and communication system (PACS) software (INFINITT G3, Seoul, Korea). The ROI was positioned to include the entire area of the enhancing lesion. The ROI data were used to calculate the lesion-to-background ratio and enhancement percentage of the lesion as detailed below (8):

Lesion-to-background ratio = postcontrast SI of lesion (SI _post ) / SI of healthy tissue surrounding the lesion (SI _b )

Enhancement percentage (%) = (SI _post −SI _b )×100 / SI _b

We tried to draw ROIs (SI _post and SI _b ) in as similar areas as possible for each patient to minimize measurement errors.

Statistical analysis

For the primary study objective, two parameters (lesion border visualization and subjective lesion enhancement) for qualitative lesion visualization were compared between the two agents. A noninferiority analysis used reader's mean scored of the two parameter. To demonstrate the noninferiority of gadobutrol versus gadoterate, we utilized paired t tests and 95% CIs, with a noninferiority margin of 0.35; that is, the lower limit of the 95% CI of the difference in mean scores between reduced-dose gadobutrol and standard-dose gadoterate needed to above the value of −0.35 (8,16). Quantitative enhancement analyses (the enhancement percentage and lesion-to-background ratio) between the two groups were compared using a t test. Data were analyzed using SPSS software (SPSS Statistics for Windows version 21; IBM, Armonk, NY, USA) and MedCalc software (MedCalc version 11.3.0.0, Mariakerke, Belgium). All statistical tests were two sided at the significance level of 0.05.

Results

Demographic characteristics

Each group consisted of 66 patients. The reduced-dose gadobutrol group included 56 men and 10 women with a mean age of 60.33 ± 16.30 (SD) years, while the standard-dose group consisted of 55 men and 11 women with a mean age of 55.45 ± 12.52 (SD) years. There were no significant differences in age or sex between the two groups (p > 0.1). Among 66 pairs of patients, 11 pairs underwent partial toe amputation, 27 pairs had toe amputation, 21 pairs had ray amputation, 6 pairs had transmetatarsal amputation, and 1 pair had Lisfranc amputation.

Qualitative assessment of lesion visualization

Lesion border delineation was similar between the reduced-dose gadobutrol group and the standard-dose gadoterate group, with reader 1 scoring 3.64 ± 0.49 compared to 3.73 ± 0.55, and reader 2 scoring 3.67 ± 0.47 compared to 3.70 ± 0.53. Visual degree of contrast enhancement (subjective lesion enhancement) was similar for reduced-dose gadobutrol and standard-dose gadoterate for both readers, ranging from 3.55 ± 0.56 (mean ± SD) to 3.58 ± 0.50 for reduced-dose gadobutrol and from 3.58 ± 0.61 to 3.61 ± 0.62 for standard-dose gadoterate. The differences in the mean scores for lesion border delineation and visual contrast enhancement were close to zero between the two groups (Figs. 2 and 3). The lower limit of the 95% CI of the difference did not fall below −0.35 (above the noninferiority margin of −0.35) for both readers (Table 2). Therefore, the qualitative lesion visualization of a 30% reduced-dose of gadobutrol (0.07 mmol/kg) was noninferior to that of standard-dose of gadoterate (0.1 mmol/kg) (p < .01).

Fig. 2.

A 55-year-old man who underwent his first toe amputation due to a diabetic foot ulcer and osteomyelitis. Axial T1-weighted image (A) and contrast-enhanced fat-suppressed axial T1-weighted image obtained using reduced-dose gadobutrol (B), taken 2 days before surgery. The mean scores of both readers for lesion visualization were 4, with 4 for border delineation and 4 for contrast enhancement.

Fig. 3.

A 62-year-old man who underwent his second toe amputation due to a diabetic foot ulcer and osteomyelitis. Axial T1-weighted image (A) and contrast-enhanced fat-suppressed axial T1-weighted image obtained using standard-dose gadoterate (B), taken 2 days before surgery. The mean scores of both readers for lesion visualization were 4, with 4 for border delineation and 4 for contrast enhancement.

Table 2.

Comparison of lesion visualization at contrast-enhanced foot MRI with gadobutrol (0.07 mmol/kg) versus gadoterate (0.1 mmol/kg).

Parameter and Reader	Gadobutrol	Gadoterate	Difference	95% CI of the Difference	P value*
Border delineation
Reader 1	3.64 ± 0.49	3.73 ± 0.55	−0.09 ± 0.12	−0.33, 0.15	<.01
Reader 2	3.67 ± 0.47	3.70 ± 0.53	−0.03 ± 0.12	−0.28, 0.22	<.01
Contrast enhancement
Reader 1	3.55 ± 0.56	3.58 ± 0.61	−0.03 ± 0.14	−0.32, 0.26	<.01
Reader 2	3.58 ± 0.50	3.61 ± 0.62	−0.03 ± 0.13	−0.30, 0.24	<.01

*P value for noninferiority test.

Quantitative assessment of lesion enhancement

Regarding quantitative parameters analyzed, no significant differences were observed in the enhancement percentage and lesion-to-background ratio between the two agents for both readers (p > 0.5) (Table 3).

Table 3.

Quantitative analysis of lesion enhancement at MRI with gadobutrol (0.07 mmol/kg) versus gadoterate (0.1 mmol/kg).

Parameter and Reader	Gadobutrol	Gadoterate	Difference	P value
Enhancement percentage
Reader 1	405.28 ± 20.27	404.54 ± 16.37	0.74 ± 0.45	0.84
Reader 2	401.82 ± 35.03	402.70 ± 28.50	−0.87 ± 0.12	0.77
Lesion-to-background ratio
Reader 1	5.05 ± 0.35	5.04 ± 0.28	0.01 ± 0.14	0.98
Reader 2	4.39 ± 0.24	4.41 ± 0.24	−0.02 ± 0.19	0.91

Discussion

In our study, a 30% reduced gadobutrol dose (0.07 mmol/kg) was as effective as a standard gadoterate dose (0.1 mmol/kg) for visualizing diabetes-related osteomyelitis in contrast-enhanced foot MRI, with a lower limit of the 95% CI of the difference of at least −0.33, which is above the noninferiority margin of −0.35 (P < .01). This result was consistent with the primary objective of our study. In additional quantitative contrast enhancement analysis, the two GBCAs did not demonstrate a significant difference. The efficacy of a 30% dose reduction of gadobutrol may be attributed to the higher T1 relaxivity of gadobutrol compared with gadoterate (16,17). In principle, GBCAs that offer higher relaxivity could potentially reduce the amount of gadolinium needed to yield the same image contrast, thereby possibly reducing the gadolinium dose required for contrast-enhanced MRI.

The value of contrast-enhanced MRI for detecting and characterizing lesions is well-recognized across several medical conditions. Since the first reports of gadolinium deposition in patients with normal kidney function following the use of linear GBCAs, this issue has raised concerns (22,23). Although the likelihood of such deposition is low with macrocyclic GBCAs due to the stability of the chelate, it remains crucial to use the lowest possible dose of gadolinium to achieve diagnostic image quality.

Diabetic foot ulcers are considered one of the most serious complications of diabetes, leading to significant morbidity and mortality and resulting in a reduced quality of life. Osteomyelitis is an important cause of delayed healing of foot ulcers in diabetics, increasing the risk of amputation. In diabetic foot, MRI is the modality of choice for the evaluation of pedal osteomyelitis, with sensitivity of 93% and specificity of 75% (24). Furthermore, contrast material—enhanced imaging is useful for the evaluation of soft-tissue complications such as sinus tracts, abscesses, and necrosis, and it provides invaluable information for preoperative planning of limited limb resection (4,5,20). Previous researches on diabetic foot have reported that the recurrence rate of diabetic foot ulcers within 1 year after healing was 40%, the recurrence rate was 60% within 3 years and 65% within 5 years (25). Given these relatively high recurrence rates of diabetic foot ulcers, the necessity for repetitive contrast-enhanced MRI is inevitable. Therefore, using the lowest effective dose of GBCAs in patients with diabetic foot, especially in younger individuals, would be desirable. Also, since diabetes and chronic kidney disease are closely related, using the lowest possible dose of GBCAs in diabetic foot patients may reduce the risk of NSF or gadolinium deposition in other body tissues.

To our knowledge, multiple studies have validated the clinical efficacy of reduced doses of gadobutrol, including 0.08 mmol/kg (26), 0.075 mmol/kg (16), 0.05 mmol/kg (27,28), and below 0.04 mmol/kg (29,30). These studies focus on breast cancer (26,27), brain tumor (16), and MRA (28 –30) rather than on infected lesions like osteomyelitis. Melsaether et al. (27) investigated half-dose gadobutrol (0.05 mmol/kg) in 41 patients with breast cancer, assessing lesion conspicuity and size. Cozzi et al. (26) investigated accuracy and interreader reproducibility of tumor size measurements on breast MRI using 0.08 mmol/kg of gadobutrol in 36 women. Liu et al. (16) compared efficacy of a 25% reduced dose of gabobutrol (0.075 mmol/kg) and standard dose of gadoterate in 141 patients with brain tumor. Hansmann et al. (29) compared gadobutrol versus gadoterate, both performed at a one-third dose (0.03 mmol/kg), in MRA of the calf in 100 patients. Bayrak et al. (28) compared half-dose versus standard-dose gadobutrol for renal MRA in 13 patients. The above studies generally reveal that reduced doses of gadobutrol did not show significant difference in terms of image quality in contrast-enhanced MRI. However, in clinical practice, contrast-enhanced examinations are frequently performed due to infections. Therefore, although this study is retrospective, it is noteworthy that the noninferiority of gadobutrol at 0.07 mmol/kg compared to gadoterate at 0.1 mmol/kg, especially in diabetic foot patients, has been demonstrated for bone infection.

Our study had several limitations. First, its retrospective design may have introduced selection bias, as the study population consisted of selected cases under controlled conditions. However, because the study population did not require multiple contrast-enhanced examinations for surveillance, as is the case with tumor patients, it was very challenging to design a prospective comparative study. Second, traditional ROI measurements were used for quantitative assessment of contrast enhancement, which have relatively high variability and are user-dependent. If an automated measurement algorithm is available, it would strengthen the reliability of the current results. Third, other soft tissue lesions such as sinus tract or abscess were not assessed. Clinically, in diabetes-related infection, osteomyelitis is the most critical lesion for determining treatment policy and patient care, so we focused on bone infection. Hence, further larger studies are warranted to investigate the efficacy of a reduced dose of gadobutrol for all infectious lesions in patients with diabetic foot. Finally, our study did not delve into the diagnostic performance of the two contrast agents. There have been various studies that consistently demonstrated the strong performance of MRI in diagnosing osteomyelitis (20,21,24,31). In a preliminary study conducted prior to the initiation of our current research, where approximately 50 MRIs were reviewed, no cases of osteomyelitis were overlooked, irrespective of the contrast agent used. Therefore, our research focused on comparing the subjective and quantitative enhancement profiles of the two agents.

In conclusion, a 30% reduced dose of gadobutrol (0.07 mmol/kg) is as effective as the standard dose of gadoterate (0.1 mmol/kg) for lesion visualization in contrast-enhanced MRI of diabetic foot osteomyelitis, with comparable enhancement efficacy.

Footnotes

Acknowledgements

This work was supported by the Gachon University research fund of 2023 (GCU-202308830001) and 2024 (GCU-202410420001).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the TAEJOON Pharmaceutical Co., Ltd, Gachon University research fund, (grant number GCU-202308830001, GCU-202410420001).

ORCID iDs

Tae Ran Ahn

Ji Young Jeon

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