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Rheumatology Advance Access originally published online on September 27, 2005
Rheumatology 2006 45(1):79-84; doi:10.1093/rheumatology/kei108
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Factors affecting progression of knee cartilage defects in normal subjects over 2 years

Y. Wang1,2, C. Ding3, A. E. Wluka1,4, S. Davis5, P. R. Ebeling6, G. Jones3 and F. M. Cicuttini1

1 Department of Epidemiology and Preventive Medicine, Monash University, Central and Eastern Clinical School, Alfred Hospital, Melbourne, 2 Graduate School of Integrative Medicine, Swinburne University of Technology, Hawthorn, Victoria, 3 Menzies Research Institute, University of Tasmania, Hobart, Tasmania, 4 The Baker Heart Research Institute, Melbourne, 5 Women's Program, Department of Medicine, Monash University, Melbourne and 6 Departments of Diabetes and Endocrinology, and Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia.

Correspondence to: F. Cicuttini, Department of Epidemiology and Preventive Medicine, Monash University, Central and Eastern Clinical School, Alfred Hospital, Melbourne, Vic. 3004, Australia. E-mail: flavia.cicuttini{at}med.monash.edu.au


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. Cartilage defects are present in subjects with knee osteoarthritis (OA). Although they are often present in healthy subjects, there is little data on the natural history of cartilage defects. The aim of this study was to examine the change in cartilage defects over 2 yr and to identify factors associated with this change.

Methods. One hundred and twenty-four healthy subjects underwent magnetic resonance imaging of their dominant knee at baseline and follow-up. Cartilage defects were scored (0–4) at five sites. Bone size was determined at medial and lateral tibial plateau and patella. Height, weight, body mass index and physical activity were measured by standard protocols.

Results. Eighty-six subjects completed the study. The mean cartilage defect score of each tibiofemoral compartment increased over time. However, medial and lateral tibiofemoral defect score decreased in 5% of the subjects. Cartilage defects were more likely to progress in males than females in each individual compartment (P<0.001 for medial tibiofemoral, P=0.005 for lateral tibiofemoral and P=0.01 for patellar cartilage). Baseline cartilage defect score was negatively associated with the progression of cartilage defects in each compartment (all P<0.001).

Conclusion. Although knee cartilage defects progressed over time in the majority of normal subjects, those of the highest severity tended to regress. Male gender and baseline cartilage defect score were the main factors associated with the progression of cartilage defects. Larger studies will be required to identify factors associated with the progression and regression of lesions.

KEY WORDS: Cartilage defects, Knee, Magnetic resonance imaging (MRI), Normal, Progression


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Cartilage defects are commonly found in the subjects with knee osteoarthritis (OA) [1, 2] and those with knee pain requiring arthroscopy [3]. Full-thickness cartilage defects in conjunction with subchondral cortical bone defects are more likely to be associated with pain in subjects with radiographic OA [4]. Cartilage defects have been shown to be associated with radiographic features, including Kellgren–Lawrence score and the presence of osteophytes [1, 2, 5]. It has been shown that femoral condylar defects may lead to knee OA in an experimental model [6].

Cartilage defects may be found in healthy subjects, without knee pain or radiographic OA [3, 7, 8]. Little is known about their determinants, although they may be related to trauma [9]. We have shown that the prevalence and severity of knee cartilage defects increased with age and body mass index (BMI) in a cross-sectional study of healthy subjects [10, 11]. The severity and prevalence of knee cartilage defects were also significantly and independently associated with tibiofemoral osteophytes, tibial bone area, knee cartilage volume and urinary levels of C-terminal crosslinking telopeptide of type II collagen, suggesting an important role of knee cartilage defects in early OA [12].

Longitudinal studies of cartilage defects in healthy asymptomatic knees to determine whether they are potential risk factors for OA have not been performed. A retrospective cohort study evaluated the progression of knee cartilage defects using magnetic resonance imaging (MRI) in 43 patients with knee pain who had undergone repeat MRI of the same knee on two occasions. It was shown that the presence of meniscal and anterior cruciate ligament tears was associated with more rapid cartilage loss. Cartilage lesions identified in the central region of the medial compartment were prone to more rapid progression of cartilage loss when compared with those in the anterior and posterior regions of medial tibiofemoral compartment or the lateral tibiofemoral compartment [13].

We have recently shown that the presence of tibiofemoral cartilage defects is associated with reduced cartilage volume in the respective compartment in healthy middle-aged adults, and cartilage defects were prospectively associated with knee cartilage loss in the medial tibiofemoral compartment [8]. This suggests that interventions aimed at reducing or reversing cartilage defects may reduce the risk of subsequent knee OA [8]. Given the clinical importance of cartilage defects, it is important to identify the risk factors affecting the progression of cartilage defects over time. We performed a longitudinal cohort study of healthy subjects to examine the change in cartilage defects over 2 yr, and to identify the factors associated with this change.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Normal subjects were recruited through advertising in newspapers, through sporting clubs, and through the hospital staff association, as previously described [14, 15]. Exclusion criteria included: any form of arthritis other than OA, including chondrocalcinosis on plain films, those experiencing significant knee pain, previous significant knee injury requiring non-weight-bearing treatment for >24 h or surgery (including arthroscopy), contraindication to MRI (including pacemaker, metal sutures, presence of shrapnel, iron filings in eye or claustrophobia), hemiparesis of either lower limb or planned total knee replacement. The study was approved by the Alfred Hospital Human Research Ethics Committee in Melbourne, Australia. All participants gave written informed consent.

Subjects completed a questionnaire that included demographic data, past medical and surgical history, and current physical activity [16]. Weight was measured to the nearest 0.1 kg using a single pair of electronic scales with shoes, socks and bulky clothing removed. Height was measured to the nearest 0.1 cm using a stadiometer with shoes and socks removed. BMI (weight/height2, kg/m2) was calculated. Current physical activity was a composite score of total amount of walking (0–4) plus activity at home (0–4) plus sporting activity (0–4) [16].

Each subject had an MRI performed on their dominant knee, defined as the lower limb from which they step off when walking, at baseline and approximately 2 yr later. Knees were imaged in the sagittal plane on a 1.5-T whole-body magnetic resonance unit (Signa Advantage Echospeed; GE Medical Systems, Milwaukee, WI, USA) using a commercial transmit–receive extremity coil. The following sequence and parameters were used: a T1-weighted fat-suppressed 3D gradient recall acquisition in the steady state; flip angle 55°; repetition time 58 ms; echo time 12 ms; field of view 16 cm; 60 partitions; 512 (frequency direction, superior–inferior) x 512 (phase encoding direction, anterior–posterior) matrix; one acquisition, time 11 min 56 s. Sagittal images were obtained at a partition thickness of 1.5 mm and an in-plane resolution of 0.31 x 0.31 mm (512 x 512 pixels).

Cartilage defects were graded on the above MRIs with a modification of a previous classification system [17–19], as we have previously described [8, 12, 20, 21], at medial tibial, medial femoral, lateral tibial, lateral femoral and patellar sites as follows: grade 0, normal cartilage; grade 1, focal blistering and intracartilaginous low-signal intensity area with an intact surface and bottom; grade 2, irregularities on the surface or bottom and loss of thickness of less than 50%; grade 3, deep ulceration with loss of thickness of more than 50%; grade 4, full-thickness cartilage wear with exposure of subchondral bone. We found that cartilage surface in some images was still regular but cartilage adjacent to subchondral bone became irregular, so we included these changes in the classification system. A cartilage defect also had to be present in at least two consecutive slices. The cartilage was considered to be normal if the band of intermediate signal intensity had a uniform thickness. A trained observer (C.D.) scored cartilage defects from the participants’ MRIs. The baseline and follow-up cartilage defects were graded in duplicate (the cartilage defects were regraded 1 month later), unpaired and blinded to the sequence. The defect scores at medial tibiofemoral (0–8), lateral tibiofemoral (0–8) and patellar (0–4) compartments were used in the study. A prevalent cartilage defect was defined as a cartilage defect score of ≥2 at any site within that compartment. Intraobserver reliability (expressed as intraclass correlation coefficient, ICC) was 0.90 for the medial tibiofemoral compartment, 0.89 for the lateral tibiofemoral compartment, and 0.94 for the patellar compartment. Interobserver reliability was assessed in 50 MRIs and yielded an ICC of 0.90 for the medial tibiofemoral compartment, 0.85 for the lateral tibiofemoral compartment, and 0.93 for the patellar compartment [10, 11].

Bone size was measured by means of image processing on an independent work station using the software program Osiris to determine medial and lateral tibial plateau areas and patellar volume, as previously described [14, 22, 23].

Descriptive statistics for characteristics of the subjects were tabulated. The t-test was used to compare means. The Mann–Whitney U-test was used to compare nominal characteristics between the groups. The principal outcome measure in analyses was the change in cartilage defect score over time, which was obtained by subtracting the baseline cartilage defect score from the follow-up score. Stepwise multiple linear regression techniques were used to explore the possible factors affecting the change in cartilage defect score, including age, gender, BMI, physical activity, baseline bone size, and baseline cartilage defect score. A P-value less than 0.05 (two-tailed) was considered to be statistically significant. All analyses were performed using the SPSS statistical package (standard version 11.5.0; SPSS, Chicago, IL, USA).


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
One hundred and twenty-four subjects entered the study. Baseline characteristics of the study population are presented in Table 1. Females tended to be older than males, had smaller tibial plateau and patellar bone, higher mean physical activity score and a higher proportion of severe tibiofemoral cartilage defects than males. Although a high proportion of subjects had tibiofemoral cartilage defects (35% for medial and 48% for lateral), these were not severe defects, the mean tibiofemoral cartilage defect score being low (2.0 ± 1.0 for medial and 1.9 ± 1.0 for lateral).


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  		TABLE 1. Characteristics of participants

 
Eighty-four (68%, 56 females, 28 males) subjects completed the longitudinal MRI component of the study. There were no significant differences in terms of age (55.8 ± 8.8 vs 54.8 ± 10.3 yr, P = 0.61), BMI (25.7 ± 4.5 vs 26.9 ± 4.8 kg/m2, P = 0.18), tibial plateau bone area (28.7 ± 4.1 vs 30.3 ± 6.1 cm2, P = 0.14), patellar bone volume (20.7 ± 4.4 vs 21.3 ± 6.4 ml, P = 0.63) and cartilage defect score (2.0 ± 1.1 vs 1.9 ± 0.9 for medial tibiofemoral, P = 0.34; 1.9 ± 1.0 vs 1.9 ± 1.1 for lateral tibiofemoral, P = 0.88; 1.2 ± 1.1 vs 1.1 ± 0.9 for patellar, P = 0.45) between the subjects who completed the study and those who did not. However, subjects who completed the study had a significantly higher level of physical activity than those who did not complete the study (7.2 ± 1.8 vs 6.3 ± 1.7, P = 0.009).

Table 2 depicts the natural progression of the cartilage defects. Grade 1 cartilage defects were the most prevalent of the defects, accounting for 47% of the defects found at baseline and 59% of the defects found at follow-up. Among the 117 grade 0 defects identified at baseline, 111 (95%) progressed to grade 1, 2, or 3, six (5%) did not change. Grade 0 defects were most likely to progress to grade 1 defects. In comparison, 112 (57%) of 196 grade 1 defects did not change, 82 (42%) progressed to grade 2 or 3 (Fig. 1) and two (1%) reverted to grade 0. Of the 88 grade 2 defects identified, 53 (60%) did not change, 27 (31%) reverted to grade 1 and eight (9%) progressed to grade 3 or 4 (Fig. 1). Among the 14 grade 3 defects, six (43%) reverted to grade 1 or 2, five (36%) progressed to grade 4 and three (21%) did not change. Of the five grade 4 defects, four (80%) reverted to grade 1, 2 or 3 (Fig. 2) and one (20%) did not change. Severe cartilage defects (grades 3 and 4) were more likely to revert to less severe lesions.


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  		TABLE 2. Natural progression of cartilage defects over 2 yr

 


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  		FIG. 1. Grade 1 and 2 cartilage defects progress. (A) Baseline image, demonstrating a grade 1 cartilage defect in medial femoral cartilage, and a grade 2 cartilage defect in medial tibial cartilage. (B) Follow-up image, showing that the cartilage defects identified at baseline had progressed to severe cartilage defects (grade 3).

 


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  		FIG. 2. Grade 4 cartilage defect improves. (A) Baseline image, demonstrating a grade 4 cartilage defect in patellar cartilage. (B) Follow-up image, showing that the grade 4 cartilage defect identified at baseline had improved to grade 2 cartilage defect.

 
The change in cartilage defect scores over 2 yr is presented in Table 3. The mean cartilage defect score in each tibiofemoral compartment increased over the study period. The patellar cartilage defect score did not increase significantly over the study period. The medial and lateral tibiofemoral compartments’ total cartilage defect scores increased in 63 and 65% of the subjects, respectively, remained unchanged in 32 and 30%, respectively, and decreased in 5% in each compartment. The patellar cartilage defect score increased in 36%, remained unchanged in 46% and decreased in 18% of the subjects (Table 3).


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  		TABLE 3. Change in cartilage defect score over 2 yr

 
Factors affecting change in medial and lateral tibiofemoral cartilage defects were similar (Table 4). In both univariate and multivariate analyses, medial and lateral tibiofemoral compartment cartilage defects were more likely to progress in males than in females (in univariate analysis P<0.001 for both medial and lateral; in multivariate analysis, P<0.001 for medial and P = 0.005 for lateral compartment). When the percentages of subjects with scores that were increasing, remaining stable and decreasing were examined using the {chi}2 test (linear by linear association), there was a significant trend for males to progress more than females in all cartilages (P for trend <0.001 for all cartilages except the lateral femoral cartilage, P = 0.026). Baseline medial and lateral tibiofemoral cartilage defect scores were negatively associated with the progression of tibiofemoral cartilage defects (all P<0.001) (Table 4). When the individual cartilages were examined separately, age was positively associated with the progression of cartilage defects in lateral tibiofemoral compartment in multivariate analyses (P = 0.04), and BMI was positively associated with the progression of lateral femoral cartilage defects only (P = 0.03).


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  		TABLE 4. Factors affecting the change in cartilage defect score

 
Factors affecting change in patellar cartilage defects are presented in Table 4. In both univariate and multivariate analyses, patellar cartilage defects were more likely to progress in males compared with females (P = 0.001 and P = 0.01, respectively). Baseline patellar cartilage defect score was negatively associated with the progression of patellar cartilage defects (all P<0.001). Although patellar bone volume was positively associated with the progression of patellar cartilage defects in univariate analyses (P = 0.005), this association was not significant after adjusting for age, gender, BMI, physical activity and baseline cartilage defect score in multivariate analyses (P = 0.92).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
We found that whilst knee cartilage defects tended to progress over 2 yr in most normal subjects, there was a tendency to improve as lesions became more severe. Male gender and baseline cartilage defect score were the main factors that affected the progression of cartilage defects. Cartilage defects were more likely to progress in males compared with females in each knee compartment (medial and lateral tibiofemoral and patellar). The baseline cartilage defect score was negatively associated with cartilage defect progression in each compartment. There was a suggestion that age and BMI may also be positively associated with progression of cartilage defects in the lateral tibiofemoral compartment.

Few previous longitudinal studies have examined the change in cartilage defects in normal subjects. The only published retrospective cohort study evaluated the progression of knee cartilage defects in 43 symptomatic subjects, with serial clinically indicated MRI scans over 52–285 weeks [13]. This study found that the presence of meniscal and anterior cruciate ligament tears was associated with more rapid cartilage loss [13]. Our population was different, being healthy and free of significant pain or injury. It may be that the cartilage defects have a fluctuating course with a significant proportion improving in the absence of factors such as mechanical instability, as seen in those with meniscal and anterior cruciate ligament tears.

In this study, we found that baseline cartilage defect score was negatively associated with cartilage defect progression. It is possible that this reflects regression to the mean. However, our results show that progression is less likely in those with more severe defects, and that the progression of cartilage defects is more rapid in the early stages, when the cartilage defects are mild. In our study, few subjects had severe cartilage defects (grade 3 or 4) at baseline, so it is less likely that the negative association resulted from ceiling effect due to severe disease. In fact, most of those with severe cartilage defects improved in our study. Although knee cartilage defect score was found to increase over the 2 yr in most subjects (63% for medial tibiofemoral, 65% for lateral tibiofemoral and 36% for patellar), the defect score remained unchanged in 32% of the subjects for medial tibiofemoral, 30% for lateral tibiofemoral and 46% for patellar compartment, and decreased in 5% for each tibiofemoral compartment and 18% for the patellar compartment. Indeed, when compared according to the severity of defects, the more severe defects showed an increased tendency to improve. Whilst this may have been due to measurement error, our reproducibility was high. The slice thickness of our MRI images was 1.5 mm, and the definition of a cartilage defect is that it had to be present in at least two consecutive slices. The reversion to a lower grade cartilage defect is likely to be explained only in part by the partial volume averaging of the MRI and errors in our grading (including problems with position). Thus, these data suggest that there may be some repair of articular cartilage [24, 25].

In this study, age and gender affected the progression of cartilage defects, which is consistent with our finding that these same factors are associated with cartilage defects in healthy subjects in cross-sectional studies [10, 11]. It has been well established that age and obesity are strong risk factors for knee OA [26]. We have shown that with increased age and BMI, the likelihood of knee cartilage defect progression is increased. It is possible that these changes play a role in the pathogenesis of OA. In this study we showed that cartilage defects were more likely to progress in males compared with females. Males had significantly lower baseline cartilage defect score than females in our study, which might, in part, explain this.

Our study has a number of potential limitations. Firstly, our subjects were generally healthy, with few (four cases) having radiographic knee OA. Repeating our analyses excluding those who had OA did not change the magnitude or direction of our findings. Thus, it is unlikely that our findings are due to significant pre-existing OA. Secondly, our sample size may not be large enough to identify weaker associations between age and cartilage defect progression in the medial tibiofemoral or patellar compartment, or between BMI and cartilage defect progression. Larger studies will be needed. Thirdly, the loss to follow-up in our study may introduce bias. However, there was no significant difference between those who completed the follow-up study and those who did not in terms of previously reported risk factors for cartilage defects (age and BMI) [10, 11]. Fourthly, we were unable to comment on meniscal or cruciate ligamental pathology, the factors shown to be associated with progression in subjects with clinically significant pain, given the sequences used in this study.

This is the first longitudinal study of healthy subjects to examine the natural history of cartilage defects. We have shown that cartilage defects tend to progress in most healthy people and that, in general, the risk factors for progression of cartilage defects are similar to the risk factors for knee OA. There are some data to suggest that articular cartilage defects may lead to OA. Lefkoe et al. [6] performed a study using surgical model of articular condylar defects in rabbits. Progressive OA changes were confirmed by radiographic, histological and biochemical parameters 20 weeks after the creation of 5-mm femoral condylar defects, suggesting that articular condylar defects may lead to knee OA [6]. A recent human cross-sectional study in healthy subjects showed that the severity and prevalence of knee cartilage defects were associated with tibiofemoral osteophytes, a reduction in knee cartilage volume, an increase in tibial bone area and urinary levels of C-terminal crosslinking telopeptide of type II collagen [12], suggesting that knee cartilage defects may play a role in early knee OA. Taken together, these data suggest that interventions aimed at preventing or treating cartilage defects may have an important role in the prevention of knee OA.

Although knee cartilage defects progressed over time in the majority of normal subjects, those of the highest severity tended to regress. Male gender and baseline cartilage defect score were the main factors associated with the progression of cartilage defects. Larger studies will be required to identify factors associated with the progression and regression of lesions. Further studies will be needed to determine the impact of cartilage defects on the development of knee OA and whether interventions aimed at modifying them will affect the risk of knee OA.


   Acknowledgments
 
We would like to acknowledge the Colonial Foundation, Shepherd Foundation and NHMRC Center Clinical Research Excellence for support. Ms Wang is the recipient of a National Health and Medical Research Council Scholarship. Dr Wluka is the recipient of a National Health and Medical Research Council Fellowship, with additional funds from the Royal Australasian College of Physicians (Cottrell Fellowship).

The authors have declared no conflicts of interest.


   References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 19 April 2005; revised version accepted 9 August 2005.
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