Article Text
PDF
Abstract
Objective Mechanical factors, in particular increased medial knee joint load, are believed to be important in the structural progression of knee osteoarthritis. This study evaluated the relationship of medial knee load during walking to indices of structural disease progression, measured on MRI, in people with medial knee osteoarthritis.
Methods A longitudinal cohort design utilising a subset of participants (n=144, 72%) enrolled in a randomised controlled trial of lateral wedge insoles was employed. Medial knee load parameters including the peak knee adduction moment (KAM) and the KAM impulse were measured at baseline using three-dimensional gait analysis during walking. MRI at baseline and at 12 months was used to assess structural indices. Multiple regression with adjustment for covariates assessed the relationship between medial knee load parameters and the annual change in medial tibial cartilage volume. Binary logistic regression was used for the dichotomous variables of progression of medial tibiofemoral cartilage defects and bone marrow lesions (BML).
Results A higher KAM impulse, but not peak KAM, at baseline was independently associated with greater loss of medial tibial cartilage volume over 12 months (β=29.9, 95% CI 6.3 to 53.5, p=0.01). No significant relationships were seen between medial knee load parameters and the progression of medial tibiofemoral cartilage defects or BML.
Conclusion This study suggests knee loading, in particular the KAM impulse, may be a risk factor for loss of medial tibial cartilage volume. As knee load is modifiable, load-modifying treatments may potentially slow disease progression.
Statistics from Altmetric.com
Knee osteoarthritis, particularly of the medial tibiofemoral compartment, is a major public health problem.1 Patients with medial tibiofemoral disease and varus malalignment comprise a common patient subset2 3 that is three to four times more likely to progress to severe disease than that with more neutral knee alignment.4,–,6 Understanding factors associated with structural disease progression in this patient group will assist in developing effective disease-modifying interventions.
Mechanical factors, in particular increased medial knee joint load, play an important role in the structural progression of knee osteoarthritis.4 6,–,8 The external knee adduction moment (KAM) obtained from three-dimensional gait analysis provides a valid and reliable dynamic indicator of compressive load in the medial compartment during walking.9 The most common KAM parameter measured is the peak KAM, which typically occurs during early stance. More recently, the KAM impulse has also been investigated10,–,12 because it incorporates both the magnitude and the duration of the KAM.
The KAM is of particular importance in knee osteoarthritis as it is related to the risk of structural disease progression13 and can be modified by conservative interventions.14,–,16 In the only longitudinal study, Miyazaki et al13 found that for every one unit increase in the peak KAM, there was a 6.5-fold increase in the risk of medial compartment disease progression on x-ray in a cohort of 74 patients. Findings from that widely cited study have not been replicated nor have longitudinal relationships between the KAM and changes in other pathological features of osteoarthritis been examined. Recent cross-sectional studies confirming a relationship between the KAM and bone marrow lesions (BML),17 cartilage defects18 and meniscal pathology12 highlight the need for such evaluations.
This study aimed to evaluate the hypothesis that greater medial knee load at baseline, measured as peak KAM and KAM impulse during walking, would be associated with greater loss of medial cartilage volume and greater progression of both medial cartilage defects and BML over 12 months as measured on MRI in people with medial knee osteoarthritis.
Methods
Study design
This prospective cohort study utilised a subset of participants in a randomised controlled trial comparing the effects of lateral wedge and control insoles.19 Baseline measures of medial knee load were taken before intervention. Data relating to change in joint structure over the 12 months in the lateral wedge and control insole groups were pooled given that the intervention did not affect joint structure or symptom severity.19
Participants
Participants with pain over the medial knee region, Kellgren and Lawrence grades 2–320 and medial osteophytes or joint space narrowing on x-ray21 were recruited from the community by advertisements in local clubs and print and radio media (see supplementary data, available online only, for full inclusion/exclusion criteria). Participants underwent telephone screening, a semiflexed standing posteroanterior knee x-ray and clinical examination to determine eligibility. The most symptomatic knee was deemed the study knee in bilaterally eligible cases. The University of Melbourne Human Research Ethics Committee approved the study. All participants provided written informed consent.
Gait analysis
A Vicon motion analysis system with 8 M2/MX CMOS cameras (1280×1024) operating at 120 Hz (Vicon, Oxford, UK) and a standard plug-in-gait marker set was used. Additional medial knee and ankle markers were applied during the static standing trial to assist in determining knee and ankle joint flexion–extension axes, halfway along which the respective joint centres were placed.
Ground reaction forces were measured by two 0R6-6-2000 force plates (Advanced Mechanical Technology, Watertown, Massachusetts, USA) embedded in the floor midway along a 10-m walkway at 1080 Hz, in synchrony with the cameras. Participants walked at a self-selected pace in their usual low-heeled footwear. Although footwear influences the KAM magnitude,22 footwear was permitted rather than barefoot testing in order to replicate real-life walking and daily activity conditions. Practice trials ensured that participants walked naturally and landed the whole foot on the force plate. Walking speed was monitored by two photoelectric beams.
External joint moments were calculated by inverse dynamics in the distal segment coordinate system (Vicon Plug-In-Gait v1.9; Vicon) and normalised for body weight and height. The variables of interest were the peak KAM in the first half of stance (Nm/BW*HT%), which was equivalent to the absolute peak in 92% of cases, and the positive KAM angular impulse (Nm.s/BW*HT%) representing the positive area under the KAM–time curve. Both variables were averaged over five trials.
Structural outcomes
The knee was imaged in the sagittal plane on 1.5-T whole-body MRI units using a commercial transmit–receive extremity coil at baseline and approximately 12 months later. The following sequences were used: a T1-weighted fat suppressed three-dimensional gradient recall acquisition in the steady state and a coronal T2-weighted fat-saturated acquisition (see supplementary data, available online only, for details of MRI parameters).
The volume of the medial tibial cartilage plate was defined by manually drawing disarticulation contours around the cartilage boundary on each section. Data were re-sampled by bilinear and cubic interpolation for final three-dimensional rendering. The volume of the medial tibial cartilage plate was determined by summing the pertinent voxels within the resultant binary volume. Measurements were made independently by two trained blinded observers. The coefficient of variation for the medial tibial cartilage volume measure was 3.4%.23 Annual change was determined by subtracting the follow-up volume from the baseline volume and dividing by the time between scans. We analysed the medial tibia rather than the medial femur given that there are clear anatomical boundaries that define the medial tibial cartilage plate, change in cartilage volume at both sites is strongly correlated,24 and tibial cartilage is related to both structural features25 and the need for joint replacement.26 While absolute changes in cartilage may be greater in the weight-bearing femur,27 the Standard Deviation (SD) are also much higher.28
Other structural outcomes included cartilage defects for medial tibial and femoral compartments, as graded using a classification system previously described:29 30 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. Measurements were performed by a single observer in duplicate on separate occasions. Intraobserver and interobserver reliability assessed in 50 MRI images (expressed as the intraclass correlation coefficient) was 0.90 for both.30 Progression of medial tibiofemoral cartilage defects was determined if the cartilage defect score increased by at least 1 from baseline to follow-up in either the medial tibial or medial femoral compartment.
BML in either the medial distal femur or proximal tibia were defined as areas of increased signal intensity adjacent to subcortical bone, present in either the medial distal femur or proximal tibia and their size was graded as previously described from coronal T2 fat-saturated images:31 grade 0, absence of a lesion; grade 1, lesion up to 25% of the width of the subchondral bone underlying the cartilage plate; grade 2, lesion more than 25% of the width of the subchondral bone underlying the cartilage plate. The number of slices the BML encompassed was also recorded. The BML score was calculated by multiplying the BML grade (0–2) by the number of slices for the medial femoral and medial tibial compartment separately, which was then summed to provide the medial tibiofemoral BML score. Reproducibility for determination of BML was assessed using 60 randomly selected knee MRI (к value 0.88, p<0.001). Progression of BML was defined if there was an increase in the BML score of 1 or more over the time period (ie, follow-up tibiofemoral BML score–baseline tibiofemoral BML score ≥1). This scoring system is a reliable and valid measure of BML as it has been shown to be sensitive to change and to detect clinically important outcomes.32 33
Two different MRI machines were used: Philips (Eindhoven, The Netherlands) initially, followed by GE (Signa Advantage HiSpeed GE Medical Systems, Milwaukee, Wisconsin, USA) as a result of decommissioning of the Philips machine. A validity study confirmed no systematic difference resulted due to the change in machines. Fifteen participants underwent MRI of a single knee using both machines. The mean (SD) medial tibial cartilage volume as measured on the Philips and GE machines was 1706.3 mm3 (361.2) and 1719.3 mm3 (394.4), respectively (p>0.05). The mean of the pairwise systematic differences (Phillips−GE) was −13 mm3, the mean of the pairwise random differences was 56.6 mm3 and measures on the two scanners were not significantly different (p=0.49). The intraclass correlation coefficient was 0.98 (95% CI 0.95 to 0.99) showing excellent absolute agreement between measures. A Bland–Altman plot of difference (Philips−GE) versus average measurements with 95% limits of agreement showed the mean to be −13 mm3 with limits of −152 to +126 mm3. The standard error of measurement was calculated as 49.3 mm3. In order to compare between-machine versus within-machine repeatability, 12 of these 15 participants underwent a second measurement on the Phillips machine, yielding a standard error of measurement of 33.3 mm3 with 95% limits of agreement of −75.6 to 106.5 mm3. These indicate comparable, but slightly less, reproducibility between than within machines.
Statistical analysis
Dependent variables were the annual change in medial tibial cartilage volume and progression of medial tibiofemoral cartilage defects and BML. As the change in tibial cartilage volume was normally distributed, a multiple regression model was constructed. Progression of tibiofemoral cartilage defects and BML were dichotomous variables thus binary logistic regression was used. Models were performed unadjusted and then adjusted for age, gender, body mass index, MRI machine, static knee alignment, baseline structural measure and treatment group. All analyses were performed using SPSS (version 17.0).
Results
For this study, 144 of the 200 (72%) participants enrolled in the randomised controlled trial were included. The remaining participants were excluded from the present analyses as they did not have complete datasets. Of the 144 participants, 40 (28%) had their baseline and follow-up MRI on a different machine. Characteristics of the cohort are shown in table 1. In general, participants were overweight and presented with mild to moderately severe radiographic and symptomatic disease and some degree of varus malalignment.
Baseline characteristics of study participants
Both the unadjusted and adjusted results (table 2) showed that a higher KAM impulse at baseline was associated with significantly greater loss of cartilage over the 12 months. This relationship was not seen for the peak KAM. Analysis of the subset of 104 participants scanned on the same MRI machine at baseline and follow-up showed a similar trend for KAM impulse (adjusted β=1.7, 95% CI −0.2 to 3.5, p=0.07).
Relationships between baseline mechanical loading and change in medial tibial cartilage volume over 12 months
The number (%) of participants showing progression of medial cartilage defects and BML was 45 (33%, data available on 138 participants) and 47 (33%, data available on 143 participants), respectively. The results showed no significant relationship between either of the KAM parameters and the progression of medial cartilage defects or BML (table 3). Further analyses excluding those with grade 4 baseline cartilage defects (n=56) and grade 2 BML (n=54) (and thus no scope for progression) yielded similar results. There were also no significant relationships between KAM parameters and medial cartilage defects or BML when analysed separately at the tibia and femur.
Relationship between mechanical loading and change in medial cartilage defects and BML over 12 months
Discussion
This study provides insight into the genesis of structural progression in knee osteoarthritis and validates the important role of dynamic knee loading during walking first reported by Miyazaki et al13 in 2002. In particular, we found that a higher medial knee load at baseline was predictive of greater annual loss of medial tibial cartilage volume in a large cohort with medial knee osteoarthritis.
The relationship with medial tibial cartilage volume was evident for medial knee load as measured by the KAM impulse but not by the peak KAM. While there is a moderate correlation between the two KAM measures (r=0.55, p<0.001 in our cohort), it is likely that the KAM impulse provides a more comprehensive indicator of knee load. KAM impulse takes into account not only load magnitude but also load duration, which will contribute to total knee load exposure.34 Given that during stance, different parts of the cartilage will be loaded,35 the KAM impulse may better reflect loading across the whole medial tibial cartilage plate, our outcome measure. Conversely, peak KAM is measured at one point during stance (typically approximately 20–40% of stance) and will indicate loading on only one specific cartilage region. The KAM impulse may also be more sensitive as studies have found that the KAM impulse is related to a greater number of osteoarthritis structural features17 18 and is better able to differentiate between osteoarthritis radiographic disease severities36 than peak KAM.
There are currently few clearly identified prognostic factors for disease progression in knee osteoarthritis,37 with the strongest evidence being for static knee malalignment.38 While varus malalignment increases medial compressive forces and is correlated with KAM measures (in our study r=0.24, p=0.005 for peak KAM and r=0.40, p<0.001 for KAM impulse), we showed that the KAM impulse was independently associated with changes in cartilage volume even after adjusting for knee malalignment. This highlights the additional contribution of dynamic loading as a risk factor for disease progression.
The mechanisms by which increased mechanical loading adversely influences cartilage are unclear but may involve chondrocyte death, disruption of the extracellular matrix and/or microfractures within the subchondral cortical endplate.39 40 Meniscal lesions may also play a role as they are common in people with knee osteoarthritis, and are an important contributing factor to progression of cartilage damage, particularly in the medial compartment.41 42 Whether meniscal lesions mediated the relationship between mechanical loading and the cartilage loss we observed in our study is unknown given that the MRI sequences we employed were not suitable for evaluation of the meniscus.
Given that we did not correct for multiple statistical tests, our significant findings may simply reflect chance. However, despite some methodological differences, our findings generally corroborate those of the only other comparable prospective study.13 In the study by Miyazaki et al13 only peak KAM was assessed and the structural outcome was joint space narrowing on radiographs over 6 years. The results of that paper have been used to justify the clinical relevance of KAM measures in osteoarthritis research and the use of load-modifying interventions in knee osteoarthritis management. Our results are an important extension of that isolated study given the larger sample size and the use of MRI to assess several structural features.
There was no significant multivariate relationship between knee loading and progression of cartilage defects and/or BML. This is somewhat surprising given that we have previously reported cross-sectional relationships between these parameters,17 18 and in the current study we observed a relationship between loading and loss of cartilage volume. It could be argued that the MRI sequence we used is less suited than fluid-sensitive sequences to depict focal cartilage defects as it is susceptible to artefacts.43 This may have led to a degree of misclassification and reduced our ability to detect a relationship. However, as our measure of cartilage defects has been shown to be reliable and to be associated with a variety of clinically important outcomes,44,–,46 we believe that our findings are valid. A relationship between KAM and cartilage volume but not cartilage defects or BML also concurs with findings that a quantitative structural measure was more sensitive at revealing mechanical risk factor relationships than semiquantitative structural measures.8
Our results highlight a modifiable risk factor for identifying individuals with medial knee osteoarthritis at risk of disease progression. However, as KAM measures are currently confined to gait laboratories with sophisticated and expensive equipment, their clinical usefulness is limited. There is interest in defining surrogate clinical parameters that may be used to estimate knee load,47 and further research using mobile technologies may lead to devices that can be used in the clinic. Our results also support the current focus on designing and evaluating load-modifying interventions such as gait-retraining strategies,48,–,50 braces,51 footwear14 and exercise52 with the aim of slowing structural disease progression. Given our results, interventions that reduce the KAM impulse in particular are likely to be more effective.
The strengths of our study include its prospective design, large sample size, particularly given the time intensive nature of three‑dimensional gait measurements, and the use of MRI to assess joint structure. A limitation was the need to use a different MRI machine for follow-up assessment in 28% of participants as this may have increased the error in the rate of change in cartilage volume measurements. However, this potentially systematic bias should not affect risk factor relationships and our re-analysis of the 104 participants who were tested using the same MRI machine showed comparable regression coefficients for KAM impulse but with a trend towards significance due to a reduced sample size. Furthermore, our cross-calibration and repeatability studies found that measures taken on the two machines were not significantly different and showed excellent agreement. Differences in measurements between the two machines were generally comparable to those expected with repeated measurements taken from the same machine. Second, limiting the cohort to those with mild to moderate disease and excluding those with more severe disease may have restricted our ability to find significant relationships. The 12-month follow-up was also relatively short, and a longer duration may be needed to characterise the relationship between knee loading and structural changes fully. Finally, although we cannot exclude the possibility that the baseline load parameters changed over the course of the study thereby influencing the results, others have found no significant changes over testing intervals of 3–6 months.52,–,54
In summary, this study provides support for knee loading, in particular the KAM impulse, as a risk factor for the loss of medial tibial cartilage volume. However, as statistical confidence in the results is reduced given the number of statistical tests, our findings require confirmation in other cohorts. Increasing our knowledge of the predictors of progression will enhance our ability to identify high-risk groups and to design appropriate and effective load-modifying treatments to slow progression.
Acknowledgments
The authors would like to thank the project personnel including Ben Metcalf and Georgina Morrow, who assisted with recruitment and database management.
References
Supplementary materials
Web Only Data
Files in this Data Supplement:
Footnotes
-
Funding This study was supported by a project grant from the National Health and Medical Research Council (NHMRC project #350297). KLB is partly funded by an Australian Research Council Future Fellowship (#FT0991413). YW is the recipient of an NHMRC public health (Australia) fellowship (#465142).
-
Competing interests None.
-
Patient consent Obtained.
-
Ethics approval This study was conducted with the approval of the University of Melbourne Human Research Ethics Committee.
-
Provenance and peer review Not commissioned; externally peer reviewed.