Knee cartilage defects are commonly found by magnetic resonance imaging (MRI) in healthy subjects (1) and by arthroscopy in symptomatic subjects (2). The defects are thought to occur through sports injury, trauma, osteoarthritis (OA), and osteochondritis (3). Multiple treatments have been used to repair cartilage defects (3–6), based on the assumption that such defects will increase cartilage loss and will progress to OA (3). However, there is limited evidence to support this contention.
The prevalence and severity of chondral defects increase with increasing age (7), body mass index (BMI) (8), and genetic factors (9). In our recent cross-sectional study, we found that the severity and prevalence of knee cartilage defects were negatively associated with knee cartilage volume and were positively associated with urinary levels of the C-terminal crosslinking telopeptide of type II collagen, suggesting that knee cartilage defects may play a key role in cartilage loss (1). A smaller longitudinal study of healthy middle-age adults living in Melbourne, which was recently conducted by our group, suggested that baseline cartilage defects were associated with greater loss of cartilage from the medial tibial compartment, but not the lateral tibial compartment (10). This inconsistency may reflect the small sample size in the study, or it may reflect compartment-specific effects. An association between patellar cartilage defects at baseline and patellar cartilage loss has not been reported. Furthermore, it is unknown whether increases or decreases in knee cartilage defects lead to changes in cartilage volume. These uncertainties indicated the need to validate our findings in a larger independent sample.
MRI techniques can be used to visualize joint structures directly and noninvasively, and MRI is recognized as a valid, accurate, and reproducible tool with which to measure articular cartilage defects (1, 7–11) and cartilage volume (12–14). The aim of this longitudinal study, therefore, was to describe the association between prevalent and incident knee cartilage defects and knee cartilage loss in a convenience sample of male and female adults.
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- SUBJECTS AND METHODS
A total of 325 subjects (135 men and 190 women) completed the study (87% of those originally evaluated). This was a young sample, with an average age of 45 years at baseline (age range 26–61 years). Characteristics of the study subjects are presented in Table 1. Knee cartilage defects were common, varying from grade 1 to grade 4, but the mean defect score at each site was low. After an average of 2.3 years, the patellar cartilage defect score increased significantly (P < 0.01), whereas there were no significant changes in cartilage defect scores at the other 2 sites (P >0.05). However, 12%, 13%, and 22% of subjects had an increase in cartilage defect scores, whereas 13%, 12%, and 13% of subjects had a decrease in cartilage defect scores at the medial, lateral, and patellar sites, respectively. Knee cartilage volume decreased significantly from baseline (P < 0.001 for each site), with the annual rate of loss varying from 1.5% to 4.2%. There were 50%, 49%, and 71% of subjects who had significant cartilage loss at the medial tibial, lateral tibial, and patellar sites, respectively. There were 22%, 35%, and 10% of subjects who had an absolute increase in knee cartilage volume at the medial tibial, lateral tibial, and patellar sites, respectively.
Table 1. Characteristics of the study participants*
| ||Total (n = 325)||Men (n = 135)||Women (n = 190)|
|Age, years||45.2 ± 6.5||45.0 ± 6.5||45.3 ± 6.4|
|Height, cm||169.0 ± 8.4||176.0 ± 6.5||164.1 ± 5.6|
|Weight, kg||77.4 ± 15.3||84.6 ± 12.6||72.3 ± 15.1|
|BMI, kg/m2||27.0 ± 4.8||27.3 ± 3.7||26.9 ± 5.4|
|Past knee injury, %||19||31||11|
|Radiographic osteoarthritis, %||18||16||19|
|Medial tibial bone area, cm2||17.3 ± 2.7||19.8 ± 2.2||15.8 ± 1.7|
|Lateral tibial bone area, cm2||12.0 ± 2.0||13.6 ± 1.8||10.8 ± 1.3|
|Patellar bone volume, ml||13.7 ± 3.3||16.5 ± 2.8||11.8 ± 2.1|
|Cartilage volume, ml|| || || |
| Medial tibia||2.2 ± 0.5||2.6 ± 0.5||1.9 ± 0.4|
| Lateral tibia||2.6 ± 0.7||3.1 ± 0.6||2.2 ± 0.4|
| Patella||3.4 ± 1.0||4.2 ± 0.9||2.9 ± 0.7|
|Annual loss of cartilage volume, ml|| || || |
| Medial tibia||0.06 ± 0.10||0.06 ± 0.11||0.06 ± 0.09|
| Lateral tibia||0.04 ± 0.09||0.05 ± 0.10||0.04 ± 0.09|
| Patella||0.15 ± 0.15||0.20 ± 0.17||0.12 ± 0.12|
|Annual loss of cartilage, %|| || || |
| Medial tibia||2.5 ± 4.1||2.1 ± 4.2||2.8 ± 4.0|
| Lateral tibia||1.5 ± 3.4||1.4 ± 3.3||1.6 ± 3.5|
| Patella||4.2 ± 3.8||4.6 ± 4.0||4.0 ± 3.7|
|Cartilage defect score at baseline|| || || |
| Medial tibia||1.2 ± 0.4||1.2 ± 0.5||1.2 ± 0.4|
| Lateral tibia||1.2 ± 0.4||1.2 ± 0.5||1.1 ± 0.4|
| Patella||1.2 ± 1.0||1.0 ± 0.9||1.4 ± 1.1|
|Change in cartilage defect score at followup|| || || |
| Medial tibia||−0.06 ± 0.86||0.13 ± 0.87||−0.20 ± 0.83|
| Lateral tibia||−0.04 ± 0.87||0.05 ± 0.86||−0.11 ± 0.87|
| Patella||0.12 ± 0.73||0.10 ± 0.74||0.12 ± 0.71|
In individual compartments, baseline cartilage defect scores were significantly associated with the rate of annual cartilage volume loss at the medial tibial, lateral tibial, and patellar sites after adjustment for confounders (Table 2). In women, baseline cartilage defect scores were significantly associated with the rate of annual cartilage volume loss at all sites, but only the patellar baseline cartilage defect scores were significantly associated with the rate of annual patellar cartilage volume loss in men (Figure 2). Changes in cartilage defect scores were also strongly associated with the rate of annual cartilage volume loss before and after adjustment for confounders in the total sample (Table 2), as well as in men and women separately (Figure 3).
Table 2. Association between knee cartilage defects and annual rate of change in cartilage volume (%), by site
| ||Univariable analysis β (95% CI)||Multivariable analysis β (95% CI)*||P|
|Change in medial tibial cartilage|| || || |
| Baseline defects, per grade||−0.17 (−1.19, +0.85)||−1.15 (−2.21, −0.09)†||0.034†|
| Change in defects, per grade||−1.49 (−1.99, −0.99)†||−1.15 (−1.67, −0.63)†||<0.001†|
| Increase in defects, yes versus no||−2.80 (−3.86, −1.75)†||−1.75 (−2.77, −0.72)†||0.001†|
| Decrease in defects, yes versus no||+2.18 (+1.18, +3.17)†||+1.59 (+0.62, +2.56)†||0.001†|
|Change in lateral tibial cartilage|| || || |
| Baseline defects, per grade||−0.88 (−1.77, +0.01)||−1.20 (−2.09, −0.31)†||0.009†|
| Change in defects, per grade||−0.99 (−1.41, −0.56)†||−0.96 (−1.34, −0.54)†||<0.001†|
| Increase in defects, yes versus no||−2.08 (−2.99, −1.16)†||−1.65 (−2.55, −0.75)†||<0.001†|
| Decrease in defects, yes versus no||+1.07 (+0.20, +1.94)†||+0.99 (+0.13, +1.85)†||0.024†|
|Change in patellar cartilage|| || || |
| Baseline defects, per grade||−0.47 (−0.89, −0.06)†||−1.32 (−1.78, −0.85)†||<0.001†|
| Change in defects, per grade||−1.66 (−2.21, −1.11)†||−1.79 (−2.31, −1.27)†||<0.001†|
| Increase in defects, yes versus no||−2.04 (−3.03, −1.05)†||−1.92 (−2.84, −1.00)†||<0.001†|
| Decrease in defects, yes versus no||+2.45 (+1.24, +3.67)†||+2.65 (+1.50, +3.80)†||<0.001†|
Figure 2. Box plots of the annual change in cartilage volume (%) at the medial tibia, the lateral tibia, and the patella versus the corresponding cartilage defect score at baseline in A, men and B, women. Each box represents the 25th to 75th percentiles (interquartile range [IQR]). Lines inside the boxes represent the median. Vertical bars represent 1.5 times the IQR. Circles represent outliers. Data were adjusted for age, body mass index, offspring/control status, baseline cartilage volume, baseline bone size, and/or radiographic osteoarthritis, using residuals from the regression models and adding these to the mean cartilage volume change or change in defect scores. P values were determined after adjustment for the covariates.
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Figure 3. Box plots of the annual change in cartilage volume (%) at the medial tibia, the lateral tibia, and the patella versus the corresponding change in cartilage defect score at followup in A, men and B, women. Each box represents the 25th to 75th percentiles (interquartile range [IQR]). Lines inside the boxes represent the median. Vertical bars represent 1.5 times the IQR. Circles represent outliers. Data were adjusted for age, body mass index, offspring/control status, baseline cartilage volume, baseline bone size, and/or radiographic osteoarthritis, using residuals from the regression models and adding these to the mean cartilage volume change or change in defect scores. P values were determined after adjustment for the covariates.
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When groups were split according to an increase or a decrease in cartilage defects, we found that increases in cartilage defects were positively associated, and decreases in cartilage defects were negatively associated, with the rate of annual cartilage loss before and after adjustment for confounders (Table 2). Increases in knee cartilage defect scores were all significantly associated with the rate of annual cartilage volume loss in women (medial tibia β = –1.51 [P = 0.03], lateral tibia β = –1.66 [P = 0.009], and patella β = –2.23 [P < 0.001]), with similar trends but borderline significant results in men (medial tibia β = –1.59 [P = 0.053], lateral tibia β = –1.68 [P = 0.014], and patella β = –1.40 [P = 0.079]). Furthermore, a decrease in knee cartilage defect scores was significantly associated with an increase in cartilage volume at all sites in men (medial tibia β = +2.98 [P = 0.001], lateral tibia β = +1.53 [P = 0.036], and patella β = +3.99 [P < 0.001]), but with inconsistent results in women (medial tibia β = +1.11 [P = 0.055], lateral tibia β = +0.55 [P = 0.33], and patella β = +1.71 [P = 0.018]).
Consistent associations were observed between prevalent and incident knee cartilage defects and significant cartilage loss in the whole sample (Table 3), with similar trends in men and women. When offspring and controls were analyzed separately or when subjects with tibiofemoral radiographic OA were excluded from the analyses, similar results were obtained (data not shown). Results remained unchanged after adjustment for past knee injury (data not shown).
Table 3. Association between knee cartilage defects and significant loss of cartilage, by site
| ||Univariable analysis OR (95% CI)||Multivariable analysis OR (95% CI)*||P|
|Significant loss of medial tibial cartilage|| || || |
| Baseline defects, per grade||1.26 (0.76, 2.09)||2.48 (1.20, 5.14)†||0.015†|
| Change in defects, per grade||1.88 (1.42, 2.49)†||1.59 (1.13, 2.23)†||0.008†|
| Increase in defects, yes versus no||3.31 (1.84, 5.94)†||1.89 (1.00, 3.62)†||0.05|
| Decrease in defects, yes versus no||0.43 (0.25, 0.72)†||0.51 (0.27, 0.96)†||0.036†|
|Significant loss of lateral tibial cartilage|| || || |
| Baseline defects, per grade||1.94 (1.12, 3.36)†||2.35 (1.17, 4.71)†||0.017†|
| Change in defects, per grade||1.59 (1.21, 2.09)†||1.61 (1.18, 2.20)†||0.002†|
| Increase in defects, yes versus no||2.54 (1.44, 4.50)†||2.27 (1.21, 4.24)†||0.01†|
| Decrease in defects, yes versus no||0.60 (0.36, 1.00)†||0.56 (0.31, 1.00)†||0.05|
|Significant loss of patellar cartilage|| || || |
| Baseline defects, per grade||0.87 (0.68, 1.10)||1.93 (1.31, 2.84)†||0.001†|
| Change in defects, per grade||2.33 (1.60, 3.38)†||2.78 (1.76, 4.42)†||<0.001†|
| Increase in defects, yes versus no||3.33 (1.58, 7.03)†||3.22 (1.40, 7.45)†||0.006†|
| Decrease in defects, yes versus no||0.38 (0.20, 0.74)†||0.34 (0.15, 0.75)†||0.008†|
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- SUBJECTS AND METHODS
In this study, we demonstrated consistent and significant associations between knee cartilage defects and knee cartilage loss in a relatively young population. Baseline cartilage defect scores were associated with higher cartilage loss at the medial tibial site, which is consistent with the findings of our previous study (10). However, this study is the first to demonstrate that baseline cartilage defect scores are associated with higher cartilage loss in the lateral tibial and patellar sites. These findings suggest that knee cartilage defects are predictive of knee cartilage loss over 2 years. Furthermore, this study is also the first to demonstrate that both increases and decreases in knee cartilage defect scores are associated with changes in cartilage volume.
Knee cartilage defects assessed by MRI are highly comparable to findings of arthroscopic (22–24) and histologic (25) assessments and have been significantly associated with radiographic evidence of knee OA (11, 26) as well as with knee pain (27). In our previous cross-sectional study (1), we found that knee cartilage defects are common, with 44% of our subjects having cartilage defects of grade 2 or more at any site of the knee. The prevalence and severity of knee cartilage defects increase with increasing risk factors for OA, such as increasing age (7) and BMI (8), and are significantly associated with tibiofemoral osteophytes, increased tibial bone area, decreased knee cartilage volume, and increased urine levels of a type II collagen biomarker that may reflect hyaline cartilage breakdown (1). This suggests an important role for knee cartilage defects in early knee OA.
We recently reported an association between knee cartilage defects and medial tibial cartilage loss in healthy middle-age adults, but the sample size in that study was small, and the association in the lateral compartment was not significant (10). However, this may represent a compartment-specific effect, since OA is much more common in the medial compartment. There have been no previous reports of an association between baseline cartilage defects and patellar cartilage loss. In this longitudinal study, we found that the rate of cartilage loss increased by 1.2–1.3% per year per grade of baseline cartilage defects in a dose-response manner, suggesting that knee cartilage defects are precursors of knee cartilage loss and are relevant in all knee compartments. The results were independent of baseline cartilage volume, bone size, risk factors for OA (sex, age, and BMI), past knee injury, and tibiofemoral radiographic OA itself, suggesting a direct link. When our analyses were repeated excluding those with tibiofemoral radiographic OA, the magnitude or direction of our findings did not change, suggesting that the findings are unlikely to be due to significant tibiofemoral radiographic OA, but it remains possible that they reflect early pathophysiologic changes of OA.
The relationship between change in knee cartilage defects and knee cartilage loss has not previously been reported, although an increase in knee cartilage defect score is often defined as cartilage loss (28, 29). However, a change in cartilage defects, as measured in our study, does not account for the much larger change in cartilage volume we observed. These are not necessarily the same process, and therefore, they do not have to directly correspond. Indeed, in the current study, there was no significant change in cartilage defect score overall, whereas there was an overall decrease in cartilage volume. Furthermore, the scoring of volume is fully quantitative, while the scoring of defects is semiquantitative and, thus, cannot be as accurate. Knee cartilage defects are not static (28). A recent report suggested that increases in knee cartilage defects were associated with a loss of joint space over a period of 30 months in subjects with symptomatic OA (29); however, joint space measurements on radiographs do not measure cartilage alone, since the radiographic joint space includes the menisci and is dependent on positioning of the knee.
In the present study, we found that changes in knee cartilage defects were significantly and strongly associated with changes in knee cartilage volume in all 3 compartments. For every increase in the grade of change in cartilage defect scores, the annual loss of cartilage increased by 1.0–1.8% and the significant cartilage loss increased 1.6–2.8-fold. Moreover, increases in knee cartilage defects over 2.3 years were associated with 1.7–1.9% per year higher cartilage loss and 1.9–3.2-fold higher significant cartilage loss in all 3 knee compartments. This most likely reflects a real change in cartilage volume, since volume averaging or the presence of focal and non–full-thickness cartilage defects itself has little effect on the overall volume measurement. The magnitude of this loss is substantial. For example, it can be estimated from the data in Table 2 that subjects with a stable grade 3 medial tibial defect will lose 60% of their cartilage, which represents end-stage OA (30, 31), in 17 years.
In this sample, 12–13% of the subjects had a decrease in knee cartilage defects in each of the individual compartments. Although this may be due to partial volume averaging, it seems unlikely, since to minimize this possibility, we required that defects had to be present on 2 consecutive slices. The decrease in cartilage defects may therefore represent cartilage repair and healing, since it was greater than what would be expected due to measurement error alone. We further found that decreases in knee cartilage defects were associated with increases in knee cartilage volume. While interventions such as weight loss (Ding C, et al: unpublished observations), surgical treatment (3, 4), and gene therapy (5, 6) can improve knee cartilage defects, the results of our study suggest that knee cartilage defects are potential targets for reversing the loss of knee cartilage.
The association between baseline cartilage defects and annual cartilage loss was more consistent in women, which may suggest that women with knee cartilage defects are more susceptible to cartilage loss. In contrast, the association between a decrease in knee cartilage defects and an increase in knee cartilage volume was more consistent in men, which suggests that men who have a decrease in knee cartilage defects are more likely to gain cartilage volume. This variability may reflect actual sex differences due to differences in sex hormones, joint loading, or size, or, more likely, it reflects random statistical variation due to sample size issues. Overall, the results are more consistent than inconsistent across the sexes, but even larger studies will be required to resolve these inconsistencies.
There are several potential limitations of this study. First, the study was primarily designed to examine genetic mechanisms of knee OA and used a matched design. The matching was broken for the current study, but adjustment for family history did not alter the results. Indeed, while there was a reduction in power, the results otherwise did not differ when examined separately in offspring and controls, showing similar associations in these two groups. While the study population is a convenience sample, Miettinen (32) states that for associations to be generalizable to other populations, 3 key criteria need to be met: selection (inclusion/exclusion criteria for both offspring and controls are explicitly defined), sample size, and adequate distribution of study factors. All of them were met by our study.
Second, measurement error may have influenced the results. However, scoring of knee cartilage defects and measurements of volume, bone size, and tibiofemoral radiographic OA were highly reproducible, suggesting that measurement error is unlikely.
Third, we used tibial cartilage, rather than femoral cartilage, as the measure of joint cartilage at the tibiofemoral joint. However, we have previously shown both in cross-sectional (33) and longitudinal (20) studies a strong correlation between the tibial and femoral cartilage in the medial and lateral tibiofemoral compartments. Since the femoral cartilage articulates with 3 joints (the medial and lateral tibiofemoral and the patellofemoral joints), it is more difficult to clearly identify the relevant component of the femoral joint when assessing the medial and lateral tibiofemoral joints, since this requires arbitrary definitions. In contrast, each of the tibial cartilage plates examined in this study forms only part of 1 joint (either the medial or the lateral tibiofemoral joint).
Fourth, knee alignment is associated with the rate of knee cartilage loss (34); thus, the absence of leg alignment data (varus/valgus) in this study represents a potential limitation for the interpretation of these data. Last, we did not have patellofemoral radiographic views in this study, so we cannot comment on the influence of patellofemoral radiographic OA.
In conclusion, the findings of this longitudinal study suggest that prevalent knee cartilage defects are predictive of compartment-specific cartilage loss over 2 years at all sites in women and at the patellar site in men, whereas both increases and decreases in knee cartilage defects are associated with changes in knee cartilage volume, which implies a potential for the reversal of knee cartilage loss.