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Rheumatology Advance Access published online on July 7, 2008
Rheumatology, doi:10.1093/rheumatology/ken237
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Bone marrow lesions predict progression of cartilage defects and loss of cartilage volume in healthy middle-aged adults without knee pain over 2 yrs

A. E. Wluka1,2, Y. Wang1, M. Davies-Tuck1, D. R. English3,4, G. G. Giles4 and F. M. Cicuttini1

1Department of Epidemiology and Preventive Medicine, Monash University Medical School, Alfred Hospital, Prahran, 2Baker Heart Research Institute, Melbourne, 3School of Population Health, The University of Melbourne, Parkville and 4Cancer Epidemiology Centre, The Cancer Council of Victoria, Carlton, Victoria, Australia.

Correspondence to: A. E. Wluka, Department of Epidemiology and Preventive Medicine, Monash University Medical School, Alfred Hospital, Prahran, Melbourne, Victoria 3004, Australia. E-mail: anita.wluka{at}med.monash.edu.au


   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. In knee OA, the presence of bone marrow lesions (BMLs) predicts pain and progression of disease. Their occurrence has been described in healthy, pain-free subjects, but whether their presence affects change in cartilage is unknown.

Methods. Two hundred and seventy-one healthy community-dwelling adults with no history of knee injury, knee pain or clinical knee OA had an MRI performed on their dominant knee at baseline and 2 yrs later to assess the relationship between the presence of BMLs at baseline and change in tibiofemoral cartilage defects and tibial cartilage volume over 2 yrs.

Results. BMLs were present in 37 (14%) subjects. Cartilage defects were more likely to progress rather than remain stable or regress in subjects with BMLs compared with those without BMLs (P = 0.04). The odds of cartilage defects progressing in the tibiofemoral compartment of the knee where BMLs were present compared with where BMLs were absent was 2.6 (95% CI 1.2, 5.3; P = 0.01). Where ‘very large’ BMLs were present, there was a trend for increased annual tibial cartilage volume loss (46.4 mm3/yr; P = 0.07).

Conclusions. These data suggest that BMLs are associated with change in knee cartilage over 2 yrs in asymptomatic subjects. Increased progression of cartilage defects is seen with increasing size of BMLs. It will be important to determine in future studies whether BMLs directly cause change in cartilage over 2 yrs, or act as a marker of another factor that facilitates these changes.

KEY WORDS: Osteoarthritis, Cartilage, Bone marrow lesions, Cartilage defects, Cartilage volume


   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
There is an increasing interest in the role of bone marrow lesions (BMLs) in the pathogenesis of knee OA [1,2]. In knee OA, the presence of BMLs has been related to increased cartilage loss, measured by biomarkers and using MRI [3,4]. Recently, the presence of BMLs in healthy populations without knee pain or a history of significant knee trauma has been described [5,6]. Whether the presence of BMLs in healthy, pain-free subjects is associated with effects on cartilage is unknown. Previous studies have been performed to examine this relationship only in subjects with OA or at high risk for OA [1,2].

In healthy adults without symptomatic or established radiographic knee OA, the early structural changes of knee OA may be present [7–9]. In middle-aged adults without knee pain, there is a tendency for cartilage defects to develop and progress, as well as cartilage volume to be lost [10,11]. It is likely that as these changes progress, the risk of knee OA increases. In established knee OA, these changes predict pain and joint replacement [12–14]. Identifying factors that relate to change in cartilage may be important in preventing knee OA.

We performed a longitudinal cohort study to assess the relationship between the presence of a BML at baseline and change in cartilage defects and cartilage volume in healthy adults, without knee pain or a history of significant knee trauma.


   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Acknowledgements
 References
 
Subjects
The study was conducted within the Melbourne Collaborative Cohort Study (MCCS), a prospective cohort study of 41 528 people, assembled to examine the role of lifestyle and genetic factors in the risk of cancer and chronic diseases in Melbourne, Australia [15]. Participants for the current study were recruited from this cohort in 2003–04, as described [16]. Briefly, participants were eligible if they were aged between 50 and 79 yrs without any of the following exclusion criteria: a clinical diagnosis of knee OA as defined by American College of Rheumatology criteria, which require the presence of pain [17]; knee pain lasting for >24 h in the last 5 yrs; a previous knee injury requiring non-weight-bearing treatment for >24 h or surgery (including arthroscopy); a history of any form of arthritis diagnosed by a medical practitioner or a contraindication to MRI [16]. Radiographs were not obtained, hence it is unknown whether participants had radiographic OA. The study was approved by The Cancer Council Victoria's Human Research Ethics Committee and the Standing Committee on Ethics in Research Involving Humans of Monash University. All participants gave written informed consent.

Anthropometric data
Height (in centimetres) was measured using a stadiometer with shoes removed at MCCS baseline (1990–94). Weight (in kilograms) was measured with bulky clothing removed at the time of baseline MRI. BMI was calculated from these data [weight (kg)/height2 (m2)].

MRI and the measurement of cartilage volume, defects and BML
MRI
An MRI of the dominant knee of each participant was performed between October 2003 and December 2004 and ~2 yrs later, as described on a 1.5-T whole body MRI unit (Phillips, Eindhoven, Holland) [18]. The following sequence and parameters were used on both occasions: 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 x 512 matrix; and one acquisition time of 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 mm2 (512 x 512 pixels). In addition, a coronal T2-weighted fat-saturated acquisition, repetition time 2500–3000 ms, echo time 40 ms, with a slice thickness of 3.0 mm, a 0.3 mm inter-slice gap, 1 excitation, a field of view of 11–12 cm and a matrix of 512 x 512 pixels was also obtained [18].

Assessment of BMLs
BMLs were defined as areas of increased signal intensity immediately underlying subcortical bone in either the medial or lateral distal femur or proximal tibia on T2-weighted coronal images [19]. Two trained observers, who were blinded to patient characteristics, as well as image sequence, together assessed the presence of BMLs for each subject [1]. The presence or absence of BMLs was determined. A BML was defined as ‘large’ if it appeared on two or more adjacent slices and encompassed at least one-quarter of the quadrant of the tibial or femoral cartilage being examined from coronal images [1,20]. This is comparable with the previously described ‘Grade 2’ BML by Felson [1,20]. A BML was further classified as ‘very large’ if it appeared on three or more adjacent slices (Fig. 1) [1]. This is comparable with the previously described ‘Grade 3’ BML by Felson [1,20]. The reproducibility for determination of BMLs was assessed using 60 randomly selected knee MRIs ({kappa}-value 0.88; P < 0.001).


Figure 1
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  		FIG. 1. A T2-weighted image of a very large medial tibial BML.

 
Assessment of cartilage defects
Cartilage defects were graded on the T1-weighted sagittal MR images with a classification system that has been previously described [9,14,21], in the medial and lateral tibial and femoral cartilages (Fig. 2). Intra-observer reliability (expressed as intra-class correlation coefficient, ICC) was 0.90 for the medial tibiofemoral compartment and 0.89 for the lateral tibiofemoral compartment [22]. Change in cartilage defects in a compartment was classified as to whether or not they progressed (i.e. an increase in cartilage defect score), regressed (i.e. a reduction in cartilage defect score) or remained stable (i.e. no change in cartilage defect score).


Figure 2
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  		FIG. 2. T1-weighted MRI of Grade 3 femoral cartilage defect (A) and Grade 2 tibial cartilage defect (B).

 
Cartilage volume measurement
The volumes of the individual cartilage plates (medial and lateral tibial) were measured from the total volume by manually drawing disarticulation contours around the cartilage boundaries on each section on a workstation as described on the T1-weighted sagittal images [16]. The coefficients of variation (CVs) for the medial and lateral cartilage volume measures were 3.4 and 2.0%, respectively [8,23]. Annual change in cartilage volume was calculated as: (follow-up cartilage volume subtracted from initial cartilage volume) divided by the period of time between MRI scans, as described [23].

Statistical methods
Baseline characteristics were compared between subjects in whom BMLs were present and absent, using unpaired t-test for continuous variables, chi-square for dichotomous variables and eta test for ordinal variables. Ordinal regression was used to examine the likelihood of defect progression, remaining stable or regressing according to whether a BML was present. Change in cartilage defects was described as progression or not (including remaining stable or regressing). Logistic regression was used to determine the odds of cartilage defect progression vs regression/stability depending on the presence of a BML, and to adjust for potential confounding. After the distribution of annual change in cartilage volume was examined for normality, linear regression techniques were used to examine the relationship between BML and change in cartilage volume adjusting for potential confounding. Analysis of residuals was performed to exclude non-linearity. A P-value <0.05 (two-tailed) was regarded as statistically significant. All analyses were performed using the SPSS statistical package (version 15.0.0, SPSS, Cary, NC, USA).


   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Acknowledgements
 References
 
Two hundred and ninety-seven subjects entered the study, 271 (91%) of whom completed the follow-up MRI. The baseline characteristics of the 271 subjects with and without BMLs at baseline are compared in Table 1. There were no significant differences between these groups. The reasons for loss to follow-up for 26 subjects were death (n = 3), poor health (n = 4), withdrawal of consent (n = 10), ineligible for follow-up (n = 4) and being unable to be contacted (n = 5). The characteristics of subjects who were lost to follow-up tended to be similar to those who completed the study apart from their tendency to overweight [mean BMI 27.9 kg/m2 (S.D. 5.4)], compared with those who completed the study [mean BMI 25.7 kg/m2 (S.D. 4.1); P = 0.01 for difference], and to have very large BMLs (4 ‘very large’ BMLs; P = 0.01).


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  		TABLE 1. Characteristics of participants with and without BMLs at baseline

 
BMLs were present in 37 subjects (13.7%), comprising of 26 large BMLs and 11 ‘very large’ BMLs. There were 25 large BMLs in the medial compartment, of which 6 were ‘very large’. In the lateral compartment, there were 14 large BMLs, of which 5 were ‘very large.’ Two subjects had a BML in both the medial and lateral compartments.

Whether in a knee total baseline cartilage defect progressed, remained stable or regressed according to whether or not a large or very large BML was present, and according to the initial severity of cartilage defects, is presented in Tables 2 and 3, respectively. We examined the relationship between change in cartilage defects (comparing those which progressed/deteriorated with those that remained stable and those that showed improvement/regressed) and the presence of a BML at baseline using ordinal regression (Table 4). There was a tendency for those with a BML to show progression/deterioration of cartilage defects rather than for them to remain stable or to show improvement/regress compared with subjects where no BML was present initially (P = 0.04 where a large BML was present and P = 0.05 where a very large BML was present).


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  		TABLE 2. The outcome of total tibiofemoral cartilage defects, according to baseline cartilage defect score and presence or not of a large BML at baseline

 

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  		TABLE 3. The outcome of total tibiofemoral cartilage defects, according to baseline cartilage defect score and presence or not of a very large BML at baseline

 

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  		TABLE 4. Proportion of cartilage defects progressing (deteriorating), remaining stable or improving (regressing) depending on whether a large or very large BML was present at baselinea

 
The odds of cartilage defect progressing were examined according to whether or not a BML was present at baseline (Table 5). Where a ‘large’ or ‘very large’ BML was present in the knee, cartilage defects were more likely to progress in both univariate and multivariate analyses, compared with where no BML was present, adjusting for the potential confounders of age, gender, BMI and initial cartilage defect score (P = 0.01–0.04, Table 5). When these relationships were examined in the medial and lateral compartments individually in multivariate analysis, whilst the direction of effect was the same throughout, the results only reached statistical significance in the lateral compartment (large BML P = 0.003, very large BML P = 0.03).


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  		TABLE 5. Odds ratios of progression of cartilage defect score depending on whether any BML or a large BML is present

 
The relationship between the presence of a BML and annual change in total tibial cartilage volume was examined. In univariate analysis, the presence of a ‘very large’ BML trended towards predicting increased annual tibial cartilage loss (49.5 mm3/yr; P = 0.07). After adjusting for the potential confounders of age, gender, BMI and initial cartilage volume, although the direction of effect remained, the significance of this result diminished (regression coefficient 39.4 mm3/yr; 95% CI –13.0, 91.7; P = 0.14). When these relationships were examined in the medial and lateral compartments individually, whilst the direction of effect was similar in both the compartments it only reached statistical significance in the lateral compartment (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Acknowledgements
 References
 
These data suggest that the presence of a BML in knees of adults without knee pain or history of significant trauma is associated with cartilage changes over 2 yrs. In tibiofemoral compartments in which a ‘large’ or a ‘very large’ BML was present, cartilage defects were more likely to progress rather than remain stable or regress, and the odds of cartilage defect progression were increased. The odds of progression increased with increasing BML size. Where a ‘very large’ BML was present, there was a trend towards increased annual tibial cartilage volume loss compared with where no BMLs were present.

No previous studies have examined how the presence of a BML relates to change in cartilage in subjects without painful knee OA. In healthy subjects, where a BML was present, cartilage defects were also more likely to be present [6]. Previous longitudinal studies have examined this relationship in subjects with knee OA [3,4,20]. In established OA, where a BML was present there was increased cartilage loss, as measured by MRI and also by using biomarkers [3,4]. With increased size of BMLs, increased cartilage loss was seen in established OA [3]. The current study suggests that where a BML is present in a person without knee pain or significant trauma, knee cartilage is also more likely to be lost and that with increasing size of a BML, the risk of cartilage defect progression is increased. These data suggest that BMLs lie on one of the pathways of progression of the structural changes in knee OA. However, we cannot determine whether BMLs directly cause the cartilage changes or this is an indirect effect, and their presence is merely a surrogate marker for another causative factor.

In either case, it is possible that targeting factors that affect the presence of BMLs may also affect change in cartilage and the possibility of progression to knee OA. Bone may be a more responsive target in prevention of OA than cartilage, since known risk factors for knee OA such as knee adduction moment have been shown to affect bone before cartilage changes are present in healthy people [24]. In contrast, previous interventions aimed to affect change in cartilage directly have been largely unsuccessful [25,26]. This approach appears promising, since use of osteoprotective therapy has been associated with reduced prevalence of BMLs [27]. In OA, use of bisphosphonates has been shown to reduce cartilage metabolism as measured by biomarkers, as well as to diminish the trabecular changes of OA in subchondral bone whilst reducing progression of cartilage loss over 2 yrs [28,29]. Thus, it may be important to further characterize whether the relationship between BMLs and cartilage change is direct or indirect, with a view to disease prevention.

This study has a number of limitations. There were few BMLs at baseline in this healthy population. Nevertheless, we have demonstrated that even in this population the relationship between the presence of a BML and change in cartilage exists. Although the relationship between the presence of a BML and change in cartilage volume did not attain statistical significance, the direction was consistent with change in defects. This relationship may require a larger sample size or a longer duration of follow-up as we may not have had enough power to show this relationship. Since the number of participants with BMLs was low, our ability to demonstrate compartmental changes was also limited. However, the direction of effect seen in the total tibiofemoral compartment was also present in both medial and lateral compartments, although these results were not always statistically significant. Our study is unable to address whether in subjects with asymptomatic radiographic knee OA, the same relationship exists. However, since cartilage defects and volume have both been shown to correlate strongly with radiographic disease and to be more sensitive to early disease than radiographic changes, we hypothesize that it is likely a continuum that exists in these changes [7,14]. Because we did not obtain measures of knee alignment (radiographic or clinical) we are unable to examine how this affects the relationships described, which has been shown to be important in cross-sectional studies. However, the absence of these measures is likely to result in non-differential misclassification, which is likely to diminish the magnitude of the results obtained, rather than to result in spuriously positive associations.

These data suggest that BMLs, present in healthy asymptomatic individuals with no history of significant knee pain or trauma, are associated with increased risk of cartilage defect progression and loss of cartilage volume. This suggests that either BMLs or a factor associated with their presence may be important as a target for preventive measures for knee OA.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
References
 
We would like to thank the study participants who made this study possible.

Funding: The Melbourne Collaborative Cohort Study recruitment was funded by VicHealth and The Cancer Council Victoria. This study was funded by a program grant from the National Health and Medical Research Council (NHMRC; 209057) and was further supported by infrastructure provided by The Cancer Council Victoria. We would like to acknowledge the NHMRC (project grant 334150) and Colonial Foundation. A.E.W. and Y.W. are the recipients of NHMRC Public Health Fellowships (317840 and 465142, respectively). M.D.-T. is the recipient of an Australian Postgraduate Award PhD Scholarship.

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 3 December 2007; revised version accepted 2 June 2008.
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