Introduction
Osteoarthritis (OA) is the most common form of arthritis, especially of the knee, and is a leading cause of musculoskeletal disability in most developed countries [
1]. Although the exact pathogenesis remains unknown, OA of the knee is believed to be multifactorial and involves the whole joint. Felson and colleagues [
2] first demonstrated that bone marrow lesions observed by MRI were associated with the presence of pain in OA of the knee, indicating its clinical significance. However, there are limited data on their pathology and causes. Altered biomechanical stress can cause similar bone marrow lesions in the feet, knee and hip of healthy subjects [
3], whereas running can cause similar lesions in the foot and ankle [
4], implying that altered loading across bones might be a possible cause of bone marrow lesions. Indeed, knee alignment is one of the key determinants of load distribution [
5], and knee medial bone marrow lesions are more likely in OA patients with varus knee alignment, whereas lateral bone marrow lesions are more common in those with valgus alignment [
6]. Chondral defects and bone marrow lesions commonly coexist in patients with either OA or chondral injuries, and bone marrow lesions are mostly located beneath chondral defects [
7‐
9]. However, we recently found in a large sample that chondral defects and bone marrow lesions were independently associated with knee pain [
10], suggesting other pathways between bone marrow lesions and pain.
In a previous study, we reported that knee cartilage volume, bone size and chondral defects all have high heritability, suggesting their potential for association and linkage studies [
11,
12]. With the use of the same sibpair cohort measured at follow-up, the aim of the present study was to estimate the heritability of bone marrow lesions and to assess whether the heritability is independent of other factors including chondral defects and knee alignment. Further, we describe the correlates of bone marrow lesions with both structural and environmental factors measured in the study.
Results
A total of 115 subjects (55 males and 60 females) representing 95 sib pairs with an average age of 47 years took part in this study. Thirty-five families had two children, nine had three, three had four, and one had six. Table
1 presents the characteristics of the subjects. The prevalence of bone marrow lesions was 14% and 24% for lateral and medial compartments, respectively, but most were mild as indicated by a mean total score of 0.27 to 0.48 (SD 0.78 to 1.09). The prevalence of grade 1 bone marrow lesions was 6% and 10% for lateral and medial compartments, respectively, and accounted for 40% of the total prevalence. Medial bone marrow lesions were more common in males (
p = 0.04). Chondral defects and knee pain were also mild, and ROA was relatively uncommon at baseline. Knee alignment was 180.4°, with a low SD of ± 2.6°.
Table 1
Characteristics of the subjects
Age (years) | 47 ± 6.9 |
Female sex (%) | 52 |
Height (cm) | 168.9 ± 8.9 |
Weight (kg) | 80 ± 16.4 |
Lateral BML total score (possible range 0–6) | 0.27 ± 0.78 |
Medial BML total score (possible range 0–6) | 0.48 ± 1.09 |
Any lateral BML (%) | 14 |
Any medial BML (%) | 24 |
Lateral chondral defects score (possible range 0–8) | 2.20 ± 0.91 |
Medial chondral defects score (possible range 0–8) | 2.39 ± 1.09 |
Any lateral chondral defects (%) | 44 |
Any medial chondral defects (%) | 47 |
Any ROA of the knee at baseline (%) | 16 |
Total ROA score at baseline (possible range 0–12) | 0.3 ± 0.8 |
Knee alignment (degrees) | 180.4 ± 2.6 |
Muscle strength (kg) | 118.3 ± 48 |
WOMAC pain score (possible range 0–45) | 3.7 ± 5.7 |
Both lateral and medial bone marrow lesions were significantly correlated with age (Spearman's rho = 0.26 and 0.27, respectively; p < 0.01 for both), chondral defects (Spearman's rho = 0.26 for both; p < 0.01) and knee ROA (Spearman's rho = 0.20 and 0.23; p = 0.04 and 0.02, respectively). Medial bone marrow lesions were also correlated with body mass index (BMI; Spearman's rho = 0.19; p = 0.04). No association was observed for previous knee injury, knee alignment and muscle strength.
Table
2 presents the heritability estimates for bone marrow lesions. The heritability estimates were significant for both severity and prevalence of bone marrow lesions at both lateral and medial compartments after adjustment for age, sex, height, weight, muscle strength, knee pain and knee alignment. There was an 8 to 9% reduction in the estimate for the severity but only a 1% reduction for prevalence after adjustment for chondral defects and ROA, and the estimates remained significant or borderline significant. The heritability estimate for knee alignment was zero.
Table 2
Heritability estimates for the prevalence and severity of bone marrow lesions
Lateral compartment | | | | | | | | |
Severity of BML | 60 ± 26 | 0.01 | 53 ± 28 | 0.03 | 45 ± 28 | 0.06 | 45 ± 28 | 0.06 |
Prevalent BML | 100 | <0.01 | 100 | 0.02 | 99 | 0.04 | 99 | 0.05 |
Medial compartment | | | | | | | | |
Severity of BML | 20 ± 25 | 0.21 | 65 ± 32 | 0.03 | 46 ± 31 | 0.07 | 56 ± 31 | 0.04 |
Prevalent BML | 100 | 0.01 | 100 | <0.01 | 99 | 0.02 | 99 | 0.01 |
Discussion
This is, to our knowledge, the first study that reports on causes of bone marrow lesions and documents a genetic contribution to both the prevalence and severity of bone marrow lesions in subchondral knee bone. The heritability estimates were reduced by a small amount after adjustment for chondral defects and ROA, suggesting that they share common genetic mechanisms to only a limited degree. The heritability estimate for knee alignment was zero, suggesting that it is not a heritable trait. Bone marrow lesions were also associated with some structural change within the knee and have some risk factors in common with osteoarthritis.
MRI-defined bone marrow lesions were first described by Wilson and colleagues [
20] in patients with debilitating knee and hip pain. Felson and colleagues [
2] documented its clinical relevance to pain in OA of the knee. Sower and colleagues [
8] reported that women with bone marrow lesions and full-thickness chondral defects accompanied by adjacent subchondral cortical bone defects were significantly more likely than others to have painful OA of the knee. In a recent study of an older population [
10], we demonstrated that ROA was not independently associated with knee pain but MRI-defined bone marrow lesions were associated with knee pain independently of ROA and chondral defects, suggesting an independent effect and wider clinical relevance. However, both the pathology and causes of MRI-defined bone marrow lesions are unknown. Felson and colleagues [
6] reported that medial bone marrow lesions were more likely in OA patients with varus limbs, whereas lateral lesions were seen mostly in those with valgus limbs. Malalignment mediated 37 to 53% of the association between bone marrow lesions and progression of OA of the knee, suggesting that knee alignment may have a role in the occurrence of bone marrow lesions.
The current study is the first to document a significant genetic contribution, suggesting that further studies to identify specific gene(s) responsible for the development of bone marrow lesions might shed light on the prevention and management of knee pain. The heritability estimate was high for prevalent bone marrow lesions and independent of other factors including knee pain, knee alignment, chondral defects, and ROA, suggesting that they are under independent genetic control, with at most a small shared genetic component. However, the inability to estimate the standard error for the prevalence heritability estimates indicates that the results are not robust, possibly reflecting relative limitations of the program we used for dichotomous traits in comparison with continuous traits [
21]. It is likely that the true heritability is substantially lower.
In comparison with prevalent bone marrow lesions, the heritability estimate for severity of bone marrow lesions was lower, but with a smaller standard error. The estimate again remained significant after adjustment for other factors including knee pain, muscle strength and knee alignment, suggesting that they are not under common genetic control. However, the estimate was reduced by 8 to 9% after adjustment for chondral defects and ROA, suggesting that they share common genetic mechanisms to a limited degree.
In contrast to this, but consistent with previous reports [
7‐
9], was our observation that bone marrow lesions coexist with chondral defects and ROA of the knee, suggesting that they have environmental factors in common. Significant correlations between bone marrow lesions, age and BMI in the current study support this, although the increased prevalence in males suggests a possible role for trauma. However, in contrast to other reports [
6,
22], we did not find a significant association between knee alignment and bone marrow lesions, possibly because of a low prevalence of ROA in this sample. Further studies with independent samples are needed to confirm these results and confirm whether bone marrow lesions independently predict cartilage loss as chondral defects do [
23].
The current study has several potential limitations. First, there is controversy about the ideal study design for estimating the heritability of disease. The twin model is often used but has been criticized as overestimating heritability because of the assumption of similar shared environments between monozygotic and dizygotic twins. This has been documented for bone mineral density [
24] but not for osteoarthritis. Family studies such as the present one may be more likely to represent true heritability but make it more difficult to assess the contribution of shared environment. However, before this study, little was known about environmental effects on bone marrow lesions and we adjusted for all significant covariates in the analysis, so the results do not support a strong shared environmental contribution.
Second, the choice of subjects who are at all at higher risk of disease may bias the heritability estimates and limit the generalizability of the results to the general population. However, it is most likely that this bias will act to decrease estimates by decreasing genetic heterogeneity in comparison with an unselected sample.
Third, the bone marrow lesions were assessed in only one plane and the scoring system may not differentiate between various sizes of lesions in sagittal plane. However, most lesions are spherical, which suggests that they will have the same anteroposterior and lateral dimensions and would be strongly correlated with a volumetric scoring system based on mathematical principles [
22]. Measurement error in the assessment of bone marrow lesions may have reduced the estimates. However, the method had high intra-observer reproducibility and we used a single observer for all readings, suggesting that this is not of major concern.
Fourth, using baseline X-ray measurements may not be appropriate because there was a two-year gap between the X-ray and MRI measurements. However, there is little radiographic change over this time frame and within-subject correlation for X-ray changes is very high, suggesting that this is not a big concern.
Fifth, bone marrow lesions in this sample were generally mild with grade 1 lesions accounting for 40% of the total prevalence, raising a concern of clinical relevance. However, these lesions have been associated with knee pain [
2,
10], suggesting that they are still clinically relevant.
Last, a clear elucidation of the nature of MRI-defined bone marrow lesions is uncertain. In a histological study of specimens taken from end-stage knees undergoing total joint replacement, Zanetti and colleagues [
25] reported histological evidence of fibrosis, marrow necrosis and abnormal trabeculae for MRI-defined bone marrow lesions.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
GJ, GZ and FC were responsible for the study design and interpretation of the results. CD and GZ performed data collection. GZ, JS and GJ conducted the statistical analysis. GZ and GJ prepared the manuscript, with critical suggestions and comments from FC, CD and JS. All authors read and approved the final manuscript.