Point of no return for improvement of cartilage quality indicated by dGEMRIC before and after weight loss in patients with knee osteoarthritis: a cohort study

Abstract

Background

It has been demonstrated that weight loss improves symptoms in obese subjects with knee osteoarthritis (KOA). A parallel change in cartilage morphology remains to be demonstrated.

Purpose

To demonstrate a parallel change in cartilage morphology.

Material and Methods

Obese patients with KOA were examined before and after weight loss over 16 weeks. Target knee joints were radiographically assessed by the Kellgren/Lawrence grading (KLG) system. Patients with KLG-1 and 2 changes in the lateral compartment were included. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) was performed using intra-articular contrast.

Results

Nine patients with lateral KLG-1 and ten patients with lateral KLG-2 were studied. There were no group differences regarding the lateral compartment baseline dGEMRIC T1 values: median = 497 ms (KLG-1) and 533 ms (KLG-2) (P = 0.12), or regarding reduction in body mass index (BMI) after 16 weeks: 12.8% versus 11.4% (P = 0.74). In the KLG-1 group, several cases of increased dGEMRIC T1 values were seen and median value decreased significantly less than in KLG-2 group (15 ms versus 41 ms, P = 0.03) after weight loss.

Conclusion

Improvement of cartilage quality, assessed with dGEMRIC, after weight loss might be possible in early stage KOA (KLG-1), but not in later stage KOA (KLG-2). The results may suggest a point of no return for improvement of cartilage quality that should be tested in larger trials.

Keywords

Knee osteoarthritis (KOA)weight loss magnetic resonance imaging (MRI)cartilage dGEMRIC

Introduction

Very few risk factors and prognostic markers for knee osteoarthritis (KOA) are modifiable, while consistently, weight loss in obese patients with KOA has been found to relieve symptoms. Several studies have shown a direct relationship between the amount of weight loss and the level of improvement of osteoarthritis (OA) symptoms (1,2).

KOA affects the whole joint. Articular cartilage and meniscal degeneration typical of osteoarthritis of the knee may be measured indirectly as joint-space narrowing on standing radiographs or directly using magnetic resonance imaging (MRI) (3). MRI-related cartilage- and osteoarthritic research has focused on developing reproducible and sensitive methods to diagnose/capture and monitor cartilage degeneration over time and following interventions. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) has shown to be highly reproducible and reflect the glycosaminoglycan (GAG) content of the cartilage and has thus been used to assess the structural quality and changes of cartilage as a surrogate marker of cartilage health in several trials (4).

The dGEMRIC-index is based on the T1 relaxation time following a delayed diffusion of negatively charged gadolinium-contrast-media into cartilage. Proteoglycans and GAGs in the cartilage matrix are also negatively charged; by consequence, an increase in dGEMRIC-index is an indicator of improvement in cartilage health (4). In KOA, the dGEMRIC-index has shown an inverse relationship with Kellgren/Lawrence grading (KLG) in the medial tibiofemoral compartment (5) and in pre-KOA obese patients, weight loss has been associated with an increase in dGEMRIC-index of the medial knee-joint compartment (6).

The aim of this study was to assess if weight loss in obese patients with moderate to severe radiographically defined KOA in the medial compartment could improve the quality of cartilage in the lateral compartment, where cartilage was still preserved, and whether this might be possible in both early and later stages of KOA according to the findings on standing conventional radiographs of the knee.

Material and Methods

Patients

This study included a subgroup of obese KOA patients from the CARtilage in obese knee OsteoarThritis (CAROT) weight loss trial (NCT00655941) (7). Patients were recruited from November 2007 to August 2008 from the outpatient clinic at the Department of Rheumatology, Frederiksberg Hospital, Denmark.

The inclusion criteria were: age > 50 years; body mass index (BMI) ≥ 30 kg/m²; and primary symptomatic KOA, diagnosed according to the American College of Rheumatology (ACR), verified by radiographic criteria (8).

Patients underwent a 16-week supervised formula diet program (Cambridge Weight Plan®, Northants, UK).

Radiographs

Standardized anteroposterior (AP) standing radiographs of the target knee joints were obtained in a semi-flexed position of approximately 30° and scored according to the KLG system (8) in both the medial and lateral tibiofemoral compartments.

Patients with KLG-3 or 4 in the medial compartment in combination with KLG-1 or 2 in the lateral compartment were included in the analysis excluding patients with insufficient quantity of cartilage and late stage KOA (KLG ≥ 3) in the lateral compartment.

MRI protocol

Prior to MRIs, an ultrasound examination was performed at baseline and after 16 weeks of weight loss. The target joint was aspirated for any excessive joint fluid, followed by an ultrasound-guided intra-articular injection of 0.1 mL gadolinium-DPTA (diethylenetriamine penta-acetic acid) (4 mmol/L [Multihance®]) added to 10 mL Lidocain 1%.

Following the injection, the patients walked for 15–20 min on stairs, and after 120 min dGEMRIC of the target knee was performed on a Philips Intera 1.5 T MRI system (software release 12.1.5.0; Philips Medical Systems, Eindhoven, The Netherlands) with patients in the supine position, using a flex sense coil, and the following protocol: three-plane gradient echo (GRE) localizer, coronal T1-weighted (T1W) spin echo (SE), sagittal 2D proton density (PD)-weighted fat-saturated (reference image when fusing dGEMRICimages), and four sagittal inversion recovery T1W measurements (inversion times 50, 350, 650, 1410 ms) in four anatomical locations representing the weight-bearing areas (two in the medial and two in the lateral compartment of the knee). Total scan time was 30 min.

All MRI examinations at baseline and after 16 weeks were performed in the same MRI system and with the same software version. For further MRI details, see supplementary files.

Image analysis

A resident radiologist (SH) performed all image analyses supervised by a senior consultant radiologist (MB). A medical student (MS) contributed to the reproducibility assessment.

The lateral, sagittal image with best preserved cartilage was chosen and used for both baseline and follow-up analysis. Region of interest (ROl) was drawn around the posterior weight-bearing femoral knee cartilage delimited of the posterior menisci on sagittal MRI images as described by Tiderius et al. (9). dGEMRIC T1 values were calculated using MedMap v0.9 (Carl Siversson, Spectronic Medical AB, Helsingborg, Sweden). The reported dGEMRIC-indices are the average of the T1 values in the given ROI.

Statistical analysis

Baseline characteristics, differences in weight loss from baseline to week 16, and the corresponding dGEMRIC T1 values between groups were compared using non-parametric statistical analyses: Wilcoxon Rank Sum test with level of significance of 0.05. All analyses were performed in SAS 9.4.

Results

All 192 patients in the CAROT trial got radiographs and were scanned at baseline, and 172 patients at the 16-week follow-up (10).

In this study, patients with KLG-3 or 4 in the medial compartment in combination with KLG-1 or 2 in the lateral compartment were included in the analysis excluding patients with insufficient quantity of cartilage and late stage KOA (KLG ≥ 3) in the lateral compartment

The majority of dGEMRIC images unfortunately had to be excluded due to motion artifacts between the temporal slice acquisitions. The motion artifacts were probably a result of the 7 min long scanning times between each of the four inversion times. Consequently, we ended up with 19 patients with good image quality at both time points: nine patients with KLG-1 and ten patients with KLG-2 according to the baseline radiograph. Baseline characteristics of the patients are presented in Table 1.

Table 1.

Patient characteristics at baseline and at 16-week follow-up.

	KLG 1	KLG 2	P values
Baseline
Patients (n)	9	10
Age (years)	61.5 (50.9–71.9)	62.5 (54.9–71.5)	0.62
BMI baseline (kg/m²)	34.5 (30.9–40.6)	35.0 (31.0–39.7)	0.68
dGEMRIC index baseline (ms)	497 (345–547)	533 (390–615)	0.12
16-week follow-up
Δ BMI (%)	−12.8 (−22.0 – −8)	−11.4 (−23.6 – −8.8)	0.93
Δ dGEMRIC index (ms)	−15 (–85 – 213)	−41 (−178–32)	0.03

Medians, range, and P values for comparison of the groups.

Reproducibility analyses were performed by SH and MS by scoring all 38 images. Intra-class correlation coefficients were 0.96 for intra-reader and 0.92 for inter-reader variability.

No group differences were found between baseline dGEMRIC-index: median = 497 ms (KLG-1), and 533 ms (KLG-2) (P = 0.12), or BMI reductions after 16 weeks: 12.8% (KLG-1) and 11.4% (KLG-2), respectively (P = 0.74), but the median dGEMRIC T1 value decreased significantly less in the KLG-1 group compared with the KLG-2 group: 15 ms and 41 ms, respectively (P = 0.03) following the weight loss (Fig. 1).

Fig. 1.

The changes in dGEMRIC-indices (measured in ms) in relation to the KLG for the lateral compartment.

Discussion

The main purpose of this study was to assess if weight loss in obese patients with KOA in the medial compartment could improve the quality of cartilage in the lateral compartment and whether this was possible in both the early and later stages of KOA.

The dGEMRIC results indicate that patients on the brink of developing definite radiographic KOA, corresponding to a KLG-1, might have a possibility to maintain or even improve the content of GAG in their cartilage following 16 weeks of weight loss (Fig. 1). In contrast, only borderline improvement or worsening in cartilage GAG composition was observed in the KLG-2 group. These data suggest that there may be a “point of no return” for improvement of cartilage quality in KOA.

The observed dGEMRIC improvement in the KLG-1 group is in agreement with previous results after weight loss in heavily obese patients without KOA examined before and 12 months after obesity surgery (6). Similar results in healthy knees have also been reported after moderate exercise (11). Together with the results of the present study, these data suggest a possibility for reversibility or at least slowing of cartilage degeneration in areas of preserved cartilage with only subtle radiographic KOA changes. On the other hand, both the Boston Leeds Osteoarthritis Knee score (BLOKS) cartilage changes in the full patient cohort (12) and the observed dGEMRIC decline in the present study in the KLG-2 group indicate a continuation of the degenerative process in the knee cartilage over as short a period as 16 weeks for obese participants with definite KOA. Thus, it may be suggested that the reported symptomatic improvement in the same patient cohort (12) following weight loss is due to other factors than structural cartilage changes. In this context, it was remarkable that even patients with more severe KOA (KLG-3 and 4) in the medial tibiofemoral compartment, seemed to be able to improve the cartilage GAG content in the lateral compartment after 10% weight loss. This might indicate a differentiated cartilage degeneration process in the various compartments – an assumption that is supported by a previous study showing regional dGEMRIC differences between knee-joint compartments in KOA patients (13). Another study examining dGEMRIC changes after exercise in a group of pre-KOA patients following medial meniscectomy also found most pronounced dGEMRIC changes in the lateral posterior weight-bearing cartilage (14).

Other methods have been used to study the cartilage composition in the knees, but compared with T2 mapping, which seems to be influenced by the collagen network of the cartilage, the dGEMRIC method conveys information on the GAG concentration (15) and also seems to be slightly more reproducible (16). dGEMRIC is usually performed using a double dose intravenous injection of gadolinium contrast followed by 10–20 min exercise or stair-walking (17). We, on the other hand, used an ultrasound-guided intra-articular injection of 4 mmol negatively charged gadolinium that in a previous study of the hip has shown similar or even better cartilage delineation (18). The use of intra-articular administered contrast media has not gained common use, even though this method uses a negligible amount of gadolinium corresponding to approximately 1/1000 of the standard intravenous dose. Another advantage of intra-articular contrast administration is that dosing issue related to BMI was minimized (19), as different body composition due to different BMI will influence the intravenous dGEMRIC index (19). This association would have been of particular concern in the present study where patients in 16 weeks decreased their BMI significantly between the dGEMRIC investigations.

A major limitation of our study was the limited number of patients in each group. We had to exclude a substantial part of the participants due to methodological issues including movement artifacts between the four inversion time points needed to construct the dGEMRIC map. The exclusions, however, seemed to be random and evenly distributed over the included KLG groups. In addition, our inclusion criteria of severe medial KOA (KLG-3 and 4) with relatively well preserved lateral joint space cartilage and discrete or early radiographic signs of lateral KOA reduces our ability to generalize the results to the full spectrum of KOA. But as 16 weeks seems to be a too short time frame for registration of subtler morphological cartilage changes in the BLOKS scores (12), our results demonstrated that different radiographic KOA scores seem to reflect cartilages ability to improve the dGEMRIC index.

In conclusion, improvement of knee cartilage quality (GAG content) after weight loss measured by the dGEMRIC method may be possible in very early stages of radiographic KOA (KLG-1), but not in later radiographic KLG-stages. This suggest a “point of no return” for improvement of the cartilage following weight loss that should be tested in larger trials.

Footnotes

Acknowledgments

The authors thank the staff at the Department of Radiology for help in obtaining the images. Special thanks to Carl Siversson for providing the MedMap software, to Birgit Falk Riecke for doing all the ultrasound-guided injections, to Robert GC Riis and Rasmus Bouert for always professional help and input during the study.

Declaration of Conflicting Interests

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

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Parker Institute, Bispebjerg and Frederiksberg Hospital is supported by a core grant from the Oak Foundation (OCAY-13-309). This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors; the Oak Foundation had no role in study design or writing of this manuscript.

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