Patterns of femorotibial cartilage loss in knees ... - Wiley Online Library

Arthritis & Rheumatism (Arthritis Care & Research) Vol. 59, No. 11, November 15, 2008, pp 1563–1570 DOI 10.1002/art.24208 © 2008, American College of Rheumatology

ORIGINAL ARTICLE

Patterns of Femorotibial Cartilage Loss in Knees With Neutral, Varus, and Valgus Alignment FELIX ECKSTEIN,1 WOLFGANG WIRTH,2 MARTIN HUDELMAIER,1 VERENA STEIN,3 VERENA LENGFELDER,3 SEPTEMBER CAHUE,4 MEREDITH MARSHALL,4 POTTUMARTHI PRASAD,5 4 AND LEENA SHARMA

Objective. Malalignment is known to alter medial-to-lateral femorotibial load distribution and to affect osteoarthritis (OA) progression in the mechanically stressed compartment. We investigated the pattern of cartilage loss in neutral, varus, and valgus knees. Methods. Alignment was measured from full-limb radiographs in 174 participants with symptomatic knee OA. Coronal magnetic resonance images were acquired at baseline and a mean ⴞ SD of 26.6 ⴞ 5.4 months later. The weight-bearing femorotibial cartilages were segmented from paired images. Cartilage volume, surface area, and thickness were determined in total cartilage plates and defined subregions using proprietary software. Results. The medial-to-lateral ratio of femorotibial cartilage loss was 1.4:1 in neutral knees (n ⴝ 74), 3.7:1 in varus knees (n ⴝ 57), and 1:6.0 in valgus knees (n ⴝ 43). The relative contribution of cartilage thickness change tended to be greater in knees with mild cartilage loss, whereas the increase of denuded area was greater in knees with accelerated cartilage loss. In both varus and neutral knees, the greatest changes were observed in the same subregions of the medial femorotibial compartment (central and external medial tibia, and central medial femur). In valgus and neutral knees, the subregions with the greatest changes in the lateral femorotibial compartment were also similar (internal and central lateral tibia, external lateral femur). Conclusion. The medial-to-lateral rate of femorotibial cartilage loss strongly depended on alignment. Subregions of greater-than-average cartilage loss within the stressed compartment were, however, similar in neutral, varus, and valgus knees. This indicates that the medial-to-lateral loading pattern is different, but that the (sub)regional loading pattern may not differ substantially between neutral and malaligned knees.

INTRODUCTION Malalignment is known to alter the medial-to-lateral load distribution in the femorotibial joint, with greater loads being transferred through the medial femorotibial compartment in neutral and varus knees, and with relatively greater loads through the lateral compartment in valgus knees (1– 6). Malalignment has also been identified as an important risk factor for structural progression of femorotibial osteoarthritis (OA) as observed on weight-bearing Supported by the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants R01-AR-48216, R01-AR-48748, and P60-AR-48098). 1 Felix Eckstein, MD, Martin Hudelmaier, MD: Paracelsus Medical University, Salzburg, Austria, and Chondrometrics, Ainring, Germany; 2Wolfgang Wirth, PhD: Chondrometrics, Ainring, Germany, and Ludwig Maximilians Universita¨t Mu¨nchen, Munich, Germany; 3Verena Stein, MD, Verena Lengfelder, MD: Paracelsus Medical University, Salzburg, Austria; 4September Cahue, MD, Meredith Marshall, MD, Leena Sharma, MD: Feinberg School of Medicine, Northwestern University, Chicago, Illinois; 5Pottumarthi Prasad, MD: Evanston Northwestern Healthcare, Evanston, Illinois.

radiographs (7–10). However, radiography has important limitations. Measurements of joint space narrowing (JSN) in the less-loaded compartment may not be meaningful due to pseudo-widening (11), and JSN measurement may reflect a change not only in cartilage but also in the meniscus (12–14). In contrast, magnetic resonance imaging (MRI) permits one to obtain insight into the pattern of femorotibial cartilage loss in malaligned knees: cartilage morphology can be accurately assessed in the tibia and femur of the medial and lateral compartments, respectively (15–18), and in Dr. Eckstein has received consultant fees, speaking fees, and/or honoraria (less than $10,000) from Novo Nordisk and (more than $10,000 each) from Pfizer, Merck, and Wyeth. Dr. Wirth has served as a freelancer for Chondrometrics, Ainring, Germany, and received a fee (more than $10,000). Address correspondence to Felix Eckstein, MD, Institute of Anatomy and Musculoskeletal Research, Paracelsus Medical University, Strubergasse 21, A5020 Salzburg, Austria. E-mail: [email protected]. Submitted for publication March 13, 2008; accepted in revised form July 14, 2008.

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specific subregions within the femorotibial cartilage plates (19 –21). Subregional cartilage loss in OA may be related to the specific pattern of mechanical stress within the femorotibial cartilage plates, and its analysis may support the development of targeted strategies to improve the load/ stress distribution and to prevent OA progression in malaligned knees. Using MRI, Cicuttini et al (22) demonstrated a significant relationship between femoral cartilage loss and varus angulation, with less evidence of this relationship in tibial cartilage, whereas another (cross-sectional) study showed a higher correlation between malalignment and femoral cartilage loss (23). Recently, we reported that varus malalignment increased the risk of cartilage loss in medial cartilage surfaces after adjusting for age, sex, body mass index, medial meniscal damage and extrusion, and lateral laxity (24). The spatial pattern of femorotibial cartilage loss, specifically changes in anatomically defined subregions, however, has not been previously examined. In the present study, we investigated whether 1) magnitudes of tibial and femoral cartilage loss are affected differently by alignment in the stressed femorotibial compartment, 2) loss of cartilage in malaligned knees is primarily due to reductions in cartilage thickness or cartilage area, and 3) the subregional pattern of femorotibial cartilage loss differs between neutral and malaligned knees.

PARTICIPANTS AND METHODS Participants were recruited from the community and were members of a cohort of participants in a natural history study of knee OA (Mechanical Factors in Arthritis of the Knee Study, second cycle) (24). Inclusion criteria were as follows: definite tibiofemoral osteophyte presence (Kellgren/Lawrence [K/L] radiographic grade 2 or higher) in 1 or both knees and Likert category of at least “a little difficulty” for ⱖ2 items on the Western Ontario and McMaster Universities Osteoarthritis Index physical function scale (24). Approval was obtained from the Office for the Protection of Research Subjects-Institutional Review Boards of Northwestern University and Evanston Northwestern Healthcare. To determine the K/L grade, bilateral, anteroposterior, semiflexed, weight-bearing knee radiographs with fluoroscopic control were obtained for all participants at baseline (25). To assess the hip-knee-ankle angle, a single anteroposterior radiograph of both legs was obtained (8,26). Alignment was analyzed as a continuous variable (hipknee-ankle angle) as described previously (24). Knees with a hip-knee-ankle angle of ⫺2° to ⫹2° were classified as neutral, those with an angle ⬎2° as varus, and those with an angle less than ⫺2° as valgus. All participants underwent MRI of both knees using a commercial knee coil and 1 of 2 whole-body scanners, either a 1.5 Tesla Symphony at Northwestern University (Siemens, Erlangen, Germany) or a 3.0 Tesla Genesis Signa Scanner at Evanston Northwestern Healthcare (GE Healthcare Technologies, Waukesha, WI). Baseline and followup MRIs were always performed on the same scanner. The mean ⫾ SD observation interval was 26.6 ⫾ 5.4 months

Figure 1. Coronal magnetic resonance image, acquired with a spoiled gradient echo sequence with water excitation. The top image shows the femorotibial cartilage plates: MT ⫽ medial tibia; LT ⫽ lateral tibia; cMF ⫽ medial weight-bearing femur; cLF ⫽ lateral weight-bearing femur. The bottom image shows an enlarged part of the top image in the medial compartment: the top bracket shows over which region the area of the cartilage surface (AC) is segmented in the MT. The bottom brackets show where the total area of subchondral bone (tAB) is segmented in the MT. The part of the tAB that is covered by AC is the cartilaginous area of bone (cAB). The part not coverd by AC is the denuded area of bone (dAB). Cartilage thickness is measured both over the cAB and over the entire tAB, with inclusion of dAB areas with 0-mm cartilage thickness.

(range 14 –50 months). Previously validated (16 –18,27) coronal spoiled gradient echo sequences with water excitation were acquired with a slice thickness of 1.5 mm and an in-plane resolution of 0.31 mm ⫻ 0.31 mm. The repetition time, echo time, and flip angle, respectively, were 18.6 msec, 9.3 msec, and 15° at 1.5T and 12.2 msec, 5.8 msec, and 9° at 3.0T. The MRI data were sent to the image analysis center, quality controlled, and converted to a proprietary format (Chondrometrics, Ainring, Germany). One knee per participant was studied. When good-quality baseline and followup data sets without artifacts were available for both knees, the dominant knee was included (157 dominant, 17 nondominant, 145 right, and 29 left). The mean ⫾ SD age of the 174 participants (76% women, 24% men) was 66 ⫾ 11.1 years and the mean body mass index was 30.1 ⫾ 5.9 kg/m2. Most knees had a K/L grade of 2 (41%) or 3 (33%) at baseline. A total of 74 knees showed

Femorotibial Cartilage Loss Patterns in Malaligned Knees

Figure 2. Image showing femorotibial subregions. A, Posterior view of femorotibial subchondral bone areas (tibia at the bottom, weight bearing femur at the top), with subregions displayed by different gray values. B, Superior view of the tibial subchondral bone area, with subregions labeled. C, Inferior view of the femoral subchondral bone area, with subregions labeled. cMF ⫽ central (weight-bearing) medial femoral condyle; ccMF ⫽ central cMF; ecMF ⫽ external cMF; icMF ⫽ internal cMF; MT ⫽ medial tibia; cMT ⫽ central MT; eMT ⫽ external MT; iMT ⫽ internal MT; aMT ⫽ anterior MT; pMT ⫽ posterior MT; LT ⫽ lateral tibia; pLT ⫽ posterior LT; aLT ⫽ anterior LT; eLT ⫽ external LT; iLT ⫽ internal LT; cLT ⫽ central LT; cLF ⫽ central lateral femoral condyle; ecLF ⫽ external cLF; ccLF ⫽ central cLF; icLF ⫽ internal cLF.

neutral alignment (mean ⫾SD 0.2 ⫾ 1.3°), 57 showed varus malalignment (6.5 ⫾ 4.1°, maximum 19°), and 43 showed valgus malalignment (⫺5.3 ⫾ 2.5°, minimum ⫺13°). Segmentation of the femorotibial cartilages was performed by 10 readers with formal training in cartilage segmentation using proprietary software (Chondrometrics). Images were read in pairs with blinding to acquisition order. Segmentation involved manual tracing (Figure 1) of the total subchondral bone area and the cartilage joint surface area of the medial tibia, the lateral tibia, the central (weight-bearing) medial femoral condyle, and the central lateral femoral condyle (28 –32). Quality control of all segmentations was performed by one reader (FE). The segmentations were used to compute the total area of subchondral bone, the cartilage surface area, the part of the subchondral bone covered with cartilage, the denuded subchondral bone area, the cartilage volume, the cartilage thickness over the cartilage covered area not including denuded areas, and the cartilage thickness over the entire subchondral bone area, including denuded areas with 0-mm cartilage thickness (Figure 1) (28). Changes were computed for the medial femorotibial compartment

1565 (MFTC) and lateral femorotibial compartment (LFTC) by summing values of the medial tibia and femur and the lateral tibia and femur, respectively, at baseline and followup (30,31). In a next step, 5 subregions (central, internal, external, anterior, posterior) were determined based on the subchondral bone area in the tibiae (Figure 1), with the central subregion occupying 20% of the total subchondral bone area (Figures 2A and B) (21). The central tibial region was defined by a perpendicular cylinder around the center of gravity of the tibial subchondral bone area, the diameter being adapted to its individual shape (21). Because the weight-bearing femoral condyles are limited in their anteroposterior extension (femoral trochlea anteriorly and posterior femoral condyle posteriorly), they were divided into a central, internal, and external strip-like region of interest, respectively (Figures 2A and C), each occupying 33.3% of the subchondral bone area (21). Cartilage thickness was determined in all subregions. The correlation between cartilage loss and the hip-kneeankle angle was determined across all knees by computing the Pearson correlation coefficient. The mean ⫾ SD of the change from baseline to followup, the standardized response mean (SRM; mean/SD of change), and the significance of change (paired t-test, without correction for multiple testing) were calculated for each cartilage plate, subregion, parameter, and alignment group after adjusting individual changes to a 12-month observation period. The percentage mean change was obtained by relating the mean changes (i.e., mm) to the mean baseline values. Differences in changes of cartilage thickness between varus and neutral knees and between valgus and neutral knees were tested using an unpaired 2-sided t-test. Differences (in changes) between subregions of each cartilage plate were tested using an analysis of variance (ANOVA) of repeated measures.

RESULTS The correlation of the hip-knee-ankle angle (continuous variable) with cartilage volume loss and reduction in cartilage thickness across all medial tibiae was r ⫽ 0.36 and r ⫽ 0.40, respectively (both P ⬍ 0.001), whereas the coefficients were 0.10 and 0.11, respectively (not significant), in the medial weight-bearing femur. The correlation was 0.07 and 0.10, respectively (not significant), in the lateral tibia, and 0.18 (P ⬍ 0.05) and 0.21 (P ⬍ 0.01), respectively, in the lateral femur. Neutral knees. A significant reduction in cartilage volume was observed in all 4 femorotibial cartilage plates, ranging from ⫺0.8% (lateral tibia) to ⫺1.5% (medial femur) (Table 1). Changes in cartilage thickness tended to be greater than changes in cartilage volume (P ⫽ 0.047 for the medial tibia), with annual rates between ⫺0.9% (lateral tibia) and ⫺1.7% (medial femur). The highest SRM was observed for changes in cartilage thickness in the medial tibia (⫺0.50; P ⫽ 0.0001). The medial-to-lateral ratio of cartilage loss (MFTC versus LFTC) was 1.4:1. In all 4 plates, the reduction in cartilage thickness exclusive of denuded areas tended to make a relatively stron-

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Table 1. Changes in cartilage morphology parameters from baseline to followup in neutral knees* Medial femorotibial compartment

Total cartilage plate

Cartilage subregions

Lateral femorotibial compartment

Parameter

MC%

SRM

P†

Parameter

MC%

SRM

P†

MT.VC cMF.VC MFTC.VC MT.ThCtAB cMF.ThCtAB MFTC.ThCtAB MT.ThCcAB cMF.ThCcAB MT.cAB cMF.cAB cMT.ThCtAB eMT.ThCtAB iMT.ThCtAB aMT.ThCtAB pMT.ThCtAB ccMF.ThCtAB ecMF.ThCtAB icMF.ThCtAB

⫺0.9 ⫺1.5 ⫺1.1 ⫺1.1 ⫺1.7 ⫺1.4 ⫺0.7 ⫺1.3 ⫺0.3 ⫺0.5 ⫺1.5 ⫺1.7 ⫺0.1 ⫺1.4 ⫺0.7 ⫺2.2 ⫺1.2 ⫺1.5

⫺0.35 ⫺0.34 ⫺0.44 ⫺0.50 ⫺0.37 ⫺0.50 ⫺0.35 ⫺0.32 ⫺0.17 ⫺0.20 ⫺0.49 ⫺0.41 ⫺0.06 ⫺0.41 ⫺0.15 ⫺0.34 ⫺0.21 ⫺0.42

⬍ 0.01 ⬍ 0.01 ⬍ 0.001 ⬍ 0.001 ⬍ 0.01 ⬍ 0.001 ⬍ 0.01 ⬍ 0.01

LT.VC cLF.VC LFTC.VC LT.ThCtAB cLF.ThCtAB LFTC.ThCtAB LT.ThCcAB cLF.ThCcAB LT.cAB cLF.cAB cLT.ThCtAB eLT.ThCtAB iLT.ThCtAB aLT.ThCtAB pLT.ThCtAB ccLF.ThCtAB ecLF.ThCtAB icLF.ThCtAB

⫺0.8 ⫺1.2 ⫺1.0 ⫺0.9 ⫺1.0 ⫺1.0 ⫺0.8 ⫺0.8 0.0 ⫺0.5 ⫺1.1 0.0 ⫺1.8 ⫺1.1 ⫺0.3 ⫺0.9 ⫺1.2 ⫺1.0

⫺0.25 ⫺0.37 ⫺0.37 ⫺0.32 ⫺0.36 ⫺0.42 ⫺0.40 ⫺0.32 0.01 ⫺0.29 ⫺0.25 ⫺0.01 ⫺0.55 ⫺0.36 ⫺0.05 ⫺0.27 ⫺0.26 ⫺0.27

⬍ 0.05 ⬍ 0.01 ⬍ 0.01 ⬍ 0.001 ⬍ 0.01 ⬍ 0.001 ⬍ 0.01 ⬍ 0.01

⬍ 0.001 ⬍ 0.001 ⬍ 0.01 ⬍ 0.01 ⬍ 0.001

⬍ 0.05 ⬍ 0.05 ⬍ 0.001 ⬍ 0.01 ⬍ 0.05 ⬍ 0.05 ⬍ 0.05

* MC% ⫽ mean change (percentage); SRM ⫽ standardized response mean (mean change/SD of change); MT ⫽ medial tibia; VC ⫽ volume of cartilage; LT ⫽ lateral tibia; cMF ⫽ weight-bearing medial femoral condyle; cLF ⫽ weight-bearing lateral femoral condyle; MFTC ⫽ medial femorotibial compartment (MT ⫹ cMF); LFTC ⫽ lateral femorotibial compartment (LT ⫹ cLF); ThCtAB ⫽ thickness of the cartilage over the entire subchondral bone area (including denuded areas with 0-mm cartilage thickness); ThCcAB ⫽ thickness of the cartilage over the entire cAB; cAB ⫽ cartilage covered bone area; cMT ⫽ central MT; cLT ⫽ central LT; eMT ⫽ external MT; eLT ⫽ external LT; iMT ⫽ internal MT; iLT ⫽ internal LT; aMT ⫽ anterior MT; aLT ⫽ anterior LT; pMT ⫽ posterior MT; pLT ⫽ posterior LT; ccMF ⫽ central cMF; ccLF ⫽ central cLF; ecMF ⫽ external cMF; ecLF ⫽ external cLF; icMF ⫽ internal cMF; icLF ⫽ internal cLF. Abbreviations have been chosen in accordance with published nomenclature (28). † Level of significance of change between baseline and followup.

ger contribution to the cartilage loss than the reduction in cartilage area or the increase in denuded area (Table 1). The difference was, however, not statistically significant. In the medial tibia, the rate of change between (sub)regions differed significantly (P ⬍ 0.01 by ANOVA). The central (⫺1.5%, SRM ⫺0.49), external (⫺1.7%, SRM ⫺0.41), and anterior subregions (⫺1.4%, SRM ⫺0.41) showed significant changes between baseline and followup, whereas the posterior and internal subregions did not (Table 1 and Figure 3). In the medial femur, the central subregion displayed the highest rate of change (⫺2.2%) and the internal subregion the highest SRM (⫺0.42), whereas the external subregion failed to show significant changes (Figure 3). There were, however, no significant differences in the rate of change between subregions (P ⫽ 0.12 by ANOVA). In the lateral tibia, the internal (⫺1.8%, SRM ⫺0.55), central (⫺1.1%, SRM ⫺0.25), and anterior subregions (⫺1.1%, SRM ⫺0.36) showed significant change, whereas the posterior and external subregions did not. However, the differences between subregions did not reach statistical significance (P ⫽ 0.07). In the lateral femur, all 3 subregions showed significant rates of change and similar SRMs (⫺0.26 to ⫺0.27), with no significant differences in the rate of change between the subregions (P ⫽ 0.93) (Table 1 and Figure 3).

neutral knees (Table 2). The lateral tibia displayed a significant change between baseline and followup (⫺1.2%, SRM ⫺0.54; P ⫽ 0.001), whereas the lateral femur did not (Table 2). In the medial femur, the lateral tibia, and the lateral femur, the rate of change did not differ significantly from that in neutral knees (P ⫽ 0.61, 0.30, and 0.07, respectively). The ratio of medial to lateral cartilage loss was 3.7:1. In the medial tibia, the reduction in cartilage area made a stronger contribution than the loss in thickness (P ⫽ 0.012), but in the medial femur (P ⫽ 0.42) and the lateral tibia (P ⫽ 0.11), a trend toward the opposite was observed (Table 2). In the medial tibia, there was a highly significant difference in the rate of change between the subregions (P ⬍ 0.001), with the central subregion (⫺3.1%, SRM ⫺0.50) and external subregion (⫺5.1%, SRM ⫺0.43) showing the highest rates of change (Figure 3). In the medial femur, the changes in the 3 subregions did not differ significantly from one another (P ⫽ 0.47) (Table 2 and Figure 3). In the lateral tibia, the internal (⫺2.3%, SRM ⫺0.72), central (⫺1.5%, SRM ⫺0.44), and posterior subregions (⫺0.9%, SRM ⫺0.23) displayed significant change, but the anterior and external subregions did not. None of the subregions of the lateral femur showed significant differences between baseline and followup (Table 2).

Varus knees. The reduction in cartilage thickness in the medial tibia (⫺2.6%, SRM ⫺0.52; P ⫽ 0.0001) was significantly greater (P ⫽ 0.04) than that in neutral knees. The medial femur also showed a greater reduction in cartilage thickness (⫺2.6%, SRM ⫺0.49; P ⫽ 0.002) than in the

Valgus knees. The reduction in cartilage thickness of the medial tibia (⫺0.1%, SRM ⫺0.06; P ⫽ 0.63) was not significant and was significantly less than for neutral knees (P ⫽ 0.04). The medial femur also showed only little cartilage thinning (⫺0.7%, SRM ⫺0.22; P ⫽ 0.08), with

Femorotibial Cartilage Loss Patterns in Malaligned Knees

1567 external regions did not (Figure 3). In the lateral femur, the difference in the rate of change between the subregions was also significant (P ⬍ 0.01), with the greatest change in the external subregion (⫺2.9%, SRM ⫺0.50; P ⫽ 0.002) (Table 3).

DISCUSSION

Figure 3. The subregional changes of thickness of the cartilage over the entire subchondral bone area (including denuded areas with 0-mm cartilage thickness) (ThCtAB) of the medial femorotibial compartment in neutral and varus knees, and of the lateral compartment in neutral and valgus knees. Whereas the rate of change was higher in the medial compartment in varus knees and higher in the lateral compartment in valgus knees, the regional pattern of cartilage loss was very similar to that in neutral knees. MT ⫽ medial tibia; cMF ⫽ medial weight-bearing femur; LT ⫽ lateral tibia; cLF ⫽ lateral weight-bearing femur; c ⫽ central; e ⫽ external; i ⫽ internal; a ⫽ anterior; p ⫽ posterior. The dotted lines display the average change in cartilage thickness (ThCtAB) throughout the entire cartilage plate, in order to visualize which subregions show greater and which ones smaller changes than the average.

values not significantly different (P ⫽ 0.26) from neutral knees (Table 3). In the lateral tibia, the change in cartilage thickness (⫺3.0%, SRM ⫺0.71; P ⫽ 0.0001) was significantly higher (P ⫽ 0.018) than in neutral knees. In the lateral femur, changes in cartilage thickness were significant (⫺1.9%, SRM ⫺0.42; P ⫽ 0.0079), but did not differ significantly (P ⫽ 0.30) from neutral knees (Table 3). The medial-to-lateral ratio of cartilage loss was 1:6.0. In both the lateral tibia and the lateral femur, the reduction in cartilage area tended to make a stronger contribution than the loss in thickness (Table 3), but the difference did not reach statistical significance (P ⫽ 0.22 and 0.51, respectively). In the medial tibia and medial femur, none of the subregions showed significant change with time. In the lateral tibia, the changes in the subregions differed significantly among each other (P ⬍ 0.05). The central (⫺4.7%, SRM ⫺0.81), internal (⫺4.2%, SRM ⫺0.76), and posterior subregions (⫺2.0%, SRM ⫺0.42) displayed significant differences between baseline and followup, but the anterior and

Our study is the first to investigate patterns of cartilage loss in knees with neutral, varus, and valgus alignment. We found the medial-to-lateral ratio of femorotibial cartilage loss to be strongly affected by alignment. Correlations between thickness changes and the hip-knee-ankle angle were stronger for the tibia than for the femur in the medial, but stronger for the femur than for the tibia in the lateral femorotibial compartment. The relative contribution of cartilage thickness change tended to be greater in mild cartilage loss, whereas the increase of denuded area was greater in accelerated cartilage loss in the mechanically stressed compartments. In varus and neutral knees, the greatest changes were observed in the same subregions of the medial femorotibial compartment (central and external medial tibia, central medial femur). Greater-than-average changes were also observed in similar subregions of the lateral femorotibial compartment in valgus and neutral knees (internal and central lateral tibia, external lateral femur), albeit the similarity in the subregional pattern of cartilage loss was less obvious than in the medial compartment. Limitations of this study include the modest sample size compared with some of the radiographic studies (10), the fact that, given the larger number of regions, cartilage plates, and parameters that were compared, it was not feasible to fully correct for multiple statistical testing, and the fact that the observation period varied between 14 and 50 months. To account for differences in time between baseline and followup measurements, the changes were normalized to 1 year, although it is more likely that cartilage thinning is not linear, but that periods of flares alternate with periods of relative stability. Another limitation is the lack of measurement of the dynamic loads (33), because static measurements of malalignment can only predict approximately 50% of the variability in knee adduction moments (34). However, Thorp et al (35) reported that static (knee alignment angle) and dynamic markers of knee loads (knee adduction angular momentum) each explained the same proportion (18%) of the variability of proximal tibial bone mineral density in subjects with knee OA. A strength of the present study is that it is the first to report correlations and rates of MRI-based cartilage loss with alignment measurements taken from full-limb radiographs. Although knee radiographs can capture approximately 50% of the variability, they only provide an estimate of the hip-knee-ankle angle (36). It is well known that the medial-to-lateral femorotibial load and stress distribution depend on alignment: in neutral knees, the medial compartment is more highly loaded than the lateral compartment because of the stance phase knee adduction moment (1,6,37). This fits in well with the 1.4:1 ratio of medial-to-lateral cartilage loss observed in neutral knees

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Table 2. Changes in cartilage morphology parameters from baseline to followup in varus knees* Medial femorotibial compartment



Lateral femorotibial compartment

Parameter

MC%

SRM

P†

Parameter

MC%

SRM

P†


⫺2.6 ⫺2.1 ⫺2.4 ⫺2.6 ⫺2.6 ⫺2.6 ⫺0.9 ⫺1.6 ⫺2.1 ⫺0.6 ⫺3.1 ⫺5.1 ⫺1.5 ⫺2.5 ⫺1.8 ⫺3.3 ⫺2.9 ⫺1.9

⫺0.46 ⫺0.38 ⫺0.51 ⫺0.52 ⫺0.49 ⫺0.62 ⫺0.31 ⫺0.37 ⫺0.49 ⫺0.14 ⫺0.50 ⫺0.43 ⫺0.31 ⫺0.37 ⫺0.34 ⫺0.37 ⫺0.32 ⫺0.55

⬍ 0.001 ⬍ 0.01 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.05 ⬍ 0.01 ⬍ 0.01


⫺1.0 ⫺0.1 ⫺0.7 ⫺1.2 ⫺0.2 ⫺0.7 ⫺1.0 0.0 0.1 0.0 ⫺1.5 ⫺0.5 ⫺2.3 ⫺0.5 ⫺0.8 ⫺0.1 ⫺0.1 ⫺0.3

⫺0.42 ⫺0.02 ⫺0.27 ⫺0.54 ⫺0.06 ⫺0.34 ⫺0.47 0.00 0.08 ⫺0.01 ⫺0.44 ⫺0.20 ⫺0.72 ⫺0.14 ⫺0.23 ⫺0.02 ⫺0.04 ⫺0.09

⬍ 0.001

⬍ 0.001 ⬍ 0.001 ⬍ 0.05 ⬍ 0.01 ⬍ 0.01 ⬍ 0.01 ⬍ 0.05 ⬍ 0.001

⬍ 0.05 ⬍ 0.001 ⬍ 0.01 ⬍ 0.001

⬍ 0.001 ⬍ 0.001 ⬍ 0.05

* See Table 1 for definitions. † Level of significance of change between baseline and followup.

in this study. Varus alignment is known to increase and valgus alignment to decrease medial load (2– 4,38). The correlations of the hip-knee-ankle angle with medial versus lateral cartilage loss did therefore show the expected relationships, and they were somewhat stronger for cartilage thickness than for cartilage volume. However, in contrast with a previous study (22), in the medial femorotibial compartment the correlation was significant for the tibial but not for the femoral cartilage, whereas in the lateral femorotibial compartment it was significant for the femo-

ral but not for the tibial cartilage. The 3.7:1 medial-tolateral ratio of cartilage loss in varus knees reinforces the notion that increased mechanical stress, caused by malalignment, is an important risk factor of femorotibial OA progression. The ratio of 1:6.0 in valgus knees is somewhat surprising, because a previous study reported that greater load was observed in the lateral femorotibial compartment only in knees with severe valgus malalignment (3). Previous longitudinal MRI studies have mainly focused on the relationship between cartilage volume loss and

Table 3. Changes in cartilage morphology parameters from baseline to followup in valgus knees* Medial femorotibial compartment



Parameter

MC%

SRM


⫺0.2 ⫺0.8 ⫺0.4 ⫺0.1 ⫺0.7 ⫺0.4 ⫺0.2 ⫺0.7 0.0 0.0 0.0 0.5 ⫺0.6 ⫺0.2 ⫺0.4 ⫺1.0 ⫺0.6 ⫺0.5

⫺0.08 ⫺0.25 ⫺0.17 ⫺0.06 ⫺0.22 ⫺0.19 ⫺0.06 ⫺0.23 0.01 0.03 0.01 0.15 ⫺0.29 ⫺0.04 ⫺0.10 ⫺0.27 ⫺0.18 ⫺0.11

* See Table 1 for definitions. † Level of significance of change between baseline and followup.

Lateral femorotibial compartment P†

Parameter

MC%

SRM

P†


⫺2.8 ⫺1.6 ⫺2.3 ⫺3.0 ⫺1.9 ⫺2.4 ⫺1.2 ⫺0.6 ⫺2.2 ⫺1.4 ⫺4.7 ⫺2.4 ⫺4.2 ⫺1.2 ⫺2.0 ⫺1.7 ⫺2.9 ⫺1.3

⫺0.64 ⫺0.33 ⫺0.57 ⫺0.71 ⫺0.42 ⫺0.61 ⫺0.46 ⫺0.16 ⫺0.51 ⫺0.34 ⫺0.81 ⫺0.28 ⫺0.76 ⫺0.19 ⫺0.42 ⫺0.31 ⫺0.50 ⫺0.30

⬍ 0.001 ⬍ 0.05 ⬍ 0.01 ⬍ 0.001 ⬍ 0.01 ⬍ 0.001 ⬍ 0.01 ⬍ 0.01 ⬍ 0.001 ⬍ 0.001 ⬍ 0.05 ⬍ 0.05 ⬍ 0.01

Femorotibial Cartilage Loss Patterns in Malaligned Knees malalignment (22,39). Measurement of cartilage volume, however, does not exploit the full capacity of MRI, as it does not reveal the spatial pattern of cartilage loss (18 –21). In our study, we found somewhat higher correlations and greater changes for cartilage thickness than for cartilage volume because, as observed in previous studies (32,40,41), there was some increase in the subchondral bone area between baseline and followup. The finding of a greater reduction of cartilage thickness without denuded areas than cartilage area in cases of mild cartilage loss, and that of a greater reduction in cartilage area (⫽ greater increase in denuded area) than reduction in cartilage thickness in cases of accelerated cartilage loss is intriguing. This should be examined in other cohorts (i.e., OA Initiative: www.oai.ucsf.edu) (42) to identify whether this relationship is specific to varus and valgus malalignment or a more general phenomenon. Of particular interest is that the magnitude, but not the (relative) regional pattern of cartilage loss within the stressed compartment differed between neutral, varus, and valgus knees. Regions of maximal cartilage loss in the medial femorotibial compartment were similar in varus and in neutral knees, and those in the lateral femorotibial compartment were similar (albeit to a lesser extent) between valgus and neutral knees. The only inconsistencies were that in the lateral tibia, the internal subregion displayed the greatest changes in neutral knees and the central subregions, the greatest changes in valgus knees, but both regions showed greater changes than the other subregions in both neutral and valgus knees. In addition, in the lateral femur, the pattern was relatively diffuse in neutral knees, with all subregions showing similar changes. Finally, the posterior region of the lateral tibia showed significant changes in valgus and varus (but not in neutral) knees, whereas the anterior subregions displayed significant changes in neutral (but not in varus and valgus) knees. Although it is speculative to draw conclusions from patterns of cartilage loss about the regional patterns of mechanical stress, these data may indicate that the stress magnitude but not the relative stress distribution within cartilage plates differs substantially between malaligned knees. Therefore, it may be sufficient for treatment strategies to improve the medial-to-lateral load–stress balance in the femorotibial joint of malaligned knees, to prevent or slow down OA progression. In conclusion, we found that alignment direction predicted the medial-to-lateral ratio of femorotibial cartilage loss. Medially, there was a significant correlation of tibial (but not femoral) cartilage loss with the hip-knee-ankle angle, and laterally, a significant correlation of femoral (but not tibial) cartilage loss. When cartilage loss was mild (i.e., neutral knees), it was dominated by a loss in cartilage thickness (without including denuded areas), whereas when it was more accelerated (i.e., stressed compartment in varus and valgus knees), it was dominated by a decrease in cartilage area (increase in denuded area). The subregional pattern of cartilage loss in the mechanically stressed compartment was similar between neutral, varus, and valgus knees. This indicates that, whereas medial-to-lateral load distribution is strongly affected by alignment, the (sub)regional loading pattern of femorotibial cartilage may

1569 not differ substantially between varus, valgus, and neutral knees.

ACKNOWLEDGMENTS We would like to thank the following readers: Gudrun Goldmann, Linda Jakobi, Manuela Kunz, Dr. Susanne Maschek, Sabine Mu¨hlsimer, Franz Romeder, Annette Thebis, and Dr. Barbara Wehr for dedicated data segmentation. AUTHOR CONTRIBUTIONS Dr. Eckstein had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design. Eckstein, Cahue, Marshall, Prasad, Sharma. Acquisition of data. Cahue, Marshall, Prasad, Sharma. Analysis and interpretation of data. Eckstein, Wirth, Hudelmaier, Stein, Lengfelder, Sharma. Manuscript preparation. Eckstein, Wirth, Hudelmaier, Stein, Lengfelder, Cahue, Marshall, Prasad, Sharma. Statistical analysis. Eckstein.

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