Independent association of joint space narrowing and osteophyte formation at the knee with health-related quality of life in Japan: A cross-sectional study†
Patents for the Knee Osteoarthritis Computer-Aided Diagnosis (KOACAD) system are held by the University of Tokyo.
To clarify the individual associations of joint space narrowing (JSN) and osteophytosis at the knee with quality of life (QOL) in Japanese men and women using a large-scale population-based cohort from the Research on Osteoarthritis Against Disability (ROAD) study.
The associations of minimum joint space width (JSW) and osteophyte area in the medial compartment of the knee with QOL parameters, such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), were examined. Minimum JSW and osteophyte area in the medial compartment of the knee were measured using a computer-aided system for the diagnosis of knee osteoarthritis.
Of the 3,040 participants in the ROAD study, the present study included 2,039 participants age 40 years or older who completed the questionnaires (741 men and 1,298 women with a mean ± SD age of 68.6 ± 10.9 years). Multiple regression analysis after adjustment for age and body mass index showed that minimum JSW was significantly associated with scores on the pain domains of the WOMAC in men and women, while osteophyte area was significantly associated with scores on the physical function domains of the WOMAC in men and women.
The findings of this cross-sectional study using a large-scale population from the ROAD study indicate that JSN and osteophytosis are independently associated with QOL.
Knee osteoarthritis (OA) is a major public health issue that causes chronic pain and disability (1–3). The prevalence of radiographic knee OA is high in Japan (4), with 25,300,000 persons age 40 years and older estimated to have radiographic knee OA (5). According to the recent National Livelihood Survey of the Ministry of Health, Labor, and Welfare of Japan, OA is ranked fourth among diseases that cause disabilities that subsequently require support with activities of daily living (6).
Knee OA is characterized by the pathologic features of joint space narrowing (JSN) and osteophytosis, but there is some controversy regarding whether osteophytosis affects knee symptoms or quality of life (QOL). Nevertheless, researchers examining the hand and hip have argued that the separate radiographic features should be recorded and may be more meaningful than overall composite scores such as the Kellgren/Lawrence (K/L) scale (7). Furthermore, a previous study showed that osteophytes were well correlated with knee symptoms and performed better as a primary diagnostic feature than JSN in cross-sectional epidemiologic studies of knee OA (8). However, most conventional systems for grading radiographic severity have consisted of categorical grades, such as the K/L scale (9), which is unable to individually assess JSN and osteophytosis. Several studies have shown that knee OA had a strong effect on QOL (10–13), but in those studies, knee OA was defined by categorical grades such as the K/L grade or the American College of Rheumatology grade (14), total knee arthroplasty, and self-questionnaire.
A radiographic atlas of individual features published by the OA Research Society International in 1995 (15) and revised in 2007 (16) allows JSN and osteophyte formation to be evaluated separately. However, the grading is still limited in reproducibility and sensitivity due to the subjective judgment of individual observers and the categorical classification into 4 grades (0–3). To overcome this problem, joint space width (JSW) and osteophyte area should be evaluated using a fully automatic system. To the best of our knowledge, no population-based studies have been conducted to separately measure JSW or osteophyte area in order to clarify the associations of JSN with QOL and of osteophytosis with QOL, despite the fact that the associations between these major features of knee OA and QOL are likely to be different.
Differences between the sexes have also been observed in knee OA. The prevalence of knee OA is higher in women than in men (4), and the association of knee pain with knee OA also differs by sex (4). Thus, the impact of JSN on QOL and of osteophytosis on QOL may also differ between the sexes. However, to the best of our knowledge, no population-based studies have been conducted to assess the associations of JSN and osteophytosis with QOL in men and women separately.
The objective of this study was therefore to separately clarify the association between JSN and QOL and the association between osteophytosis and QOL in Japanese men and women in a large-scale, population-based cohort from the Research on Osteoarthritis Against Disability (ROAD) study. A fully automatic system was used to measure JSW and osteophyte area. QOL was measured using disease-specific scales for knee OA, such as the Western Ontario and McMaster Universities OA Index (WOMAC).
SUBJECTS AND METHODS
The ROAD study is a nationwide prospective study designed to establish epidemiologic indexes for the evaluation of clinical evidence for the development of a disease-modifying treatment for bone and joint diseases (with OA and osteoporosis as the representative bone and joint diseases). It consists of population-based cohorts in several communities in Japan. The ROAD study has been described in detail previously (4, 5, 17). To date, we have completed the creation of a baseline database including clinical and genetic information for 3,040 participants (1,061 men and 1,979 women) ranging in age from 23 to 95 years (mean 70.6 years), who were recruited from resident registration listings in 3 communities: an urban region in Itabashi, Tokyo; a mountainous region in Hidakagawa, Wakayama; and a seacoast region in Taiji, Wakayama. All participants provided written informed consent, and the study was conducted with the approval of the ethics committees of the University of Tokyo and the Tokyo Metropolitan Institute of Gerontology. Height, weight, and body mass index (BMI) (weight [kg]/height [m2]) were measured. Among the 2,995 participants in the ROAD study who were age 40 years or older, 2,222 (74.2%) completed the WOMAC. The 2,222 participants who completed the WOMAC were younger than those who did not (mean age 68.9 years for those who completed the WOMAC versus 75.9 years for those who did not; P < 0.0001). These 2,222 participants were also less likely to be women (63.8% of those who completed the WOMAC versus 68.3% of those who did not; P < 0.05), and were less likely to have knee OA than the subjects who did not complete the WOMAC (54.1% versus 60.4%; P < 0.01). Of the 2,222 subjects, 183 subjects with lateral knee OA or total knee arthroplasty were excluded. Therefore, a total of 2,039 participants (741 men and 1,298 women) age 40 years or older (mean ± SD 68.6 ± 10.9 years) who had completed the WOMAC were included in the present study.
Radiographic examinations of both knees of all participants, using an anteroposterior view with weight-bearing and foot map positioning, were performed by experienced radiologic technicians. The beam was positioned parallel to the floor with no angle and aimed at the joint space. To visualize the joint space properly and to center the patella over the lower end of the femur, we used fluoroscopic guidance with an anteroposterior x-ray beam, and the images were downloaded into Digital Imaging and Communication in Medicine (DICOM) format files. Knee radiographs were read by a single experienced orthopedist (SM), who was blinded with regard to participant clinical status, using the K/L radiographic atlas for overall knee radiographic grades (9), and knee OA was defined as a K/L grade of 2 or severe. Minimum JSW in the medial compartment and osteophyte area at the medial tibia were measured by the Knee Osteoarthritis Computer-Aided Diagnosis (KOACAD) system, and for each subject the knee with the lower minimum JSW was defined as the designated knee. The KOACAD system is a fully automatic system that can quantify the major features of knee OA on standard radiographs and allows for objective, accurate, and simple assessment of the structural severity of knee OA in general clinical practice. This system was programmed to measure minimum JSW in the medial and lateral compartments and osteophyte area at the medial tibia using digitized knee radiographs. The KOACAD system has been described in detail previously (18). The KOACAD system was applied to the DICOM data by the experienced orthopedist who developed this system (HO), and the reliability of measurement is good (18). Lateral knee OA was defined as a K/L grade of ≥2 with lower lateral minimum JSW than medial minimum JSW.
To carry out the QOL assessment, we used the WOMAC. The WOMAC, a 24-item OA-specific index, consists of 3 domains: pain, stiffness, and physical function. Each of these 24 items is graded on either a 5-point Likert scale (scores of 0–4) or a 100-mm visual analog scale (19, 20). In the present study, we used the Likert scale (version LK 3.0). The domain score ranges from 0 to 20 for pain, 0 to 8 for stiffness, and 0 to 68 for physical function. Japanese versions of the WOMAC have been validated (21).
Differences in age, height, weight, BMI, minimum JSW, osteophyte area, and QOL measurements between men and women were examined using Student's unpaired t-test. Associations of minimum JSW and osteophyte area with scores on the pain and physical function domains of the WOMAC were determined using multiple regression analysis without adjustment. To assess independent associations of minimum JSW and osteophyte area with QOL, multiple regression analysis was used with age, BMI, minimum JSW, and osteophyte area as independent variables. Data analysis was performed using SAS, version 9.0.
The characteristics of the 2,039 participants in the present study are shown in Table 1. The minimum JSW was significantly lower and osteophyte area was significantly higher in women than in men. Scores on all domains of the WOMAC were significantly lower (indicating better status) in men than in women. Osteophyte area was only moderately associated with minimum JSW on linear regression analysis (R2 = 0.173, P < 0.05).
Table 1. Characteristics of the subjects*
|Age, years||68.6 ± 10.9||69.7 ± 10.5||67.9 ± 11.2†|
|Height, cm||154.7 ± 8.9||162.8 ± 6.5||150.1 ± 6.5†|
|Weight, kg||55.1 ± 10.4||61.4 ± 10.2||51.5 ± 8.6†|
|BMI, kg/m2||22.9 ± 3.3||23.1 ± 3.1||22.8 ± 3.4†|
|Minimum JSW, mm||2.61 ± 0.98||2.97 ± 0.92||2.40 ± 0.96†|
|Osteophyte area, mm2||2.99 ± 8.68||1.28 ± 4.46||3.98 ± 10.25†|
|Radiographic knee OA, %||50.2||39.0||56.8|
|WOMAC|| || || |
| Pain||1.35 ± 2.42||1.10 ± 2.12||1.50 ± 2.57†|
| Stiffness||0.72 ± 1.25||0.63 ± 1.10||0.77 ± 1.33†|
| Function||3.99 ± 7.84||3.24 ± 6.69||4.42 ± 8.41†|
Linear regression analysis without adjustment showed that minimum JSW and osteophyte area were significantly associated with scores on the pain and physical function domains of the WOMAC in the overall population as well as in men and women analyzed separately (Table 2). To determine the independent associations of minimum JSW and osteophyte area with scores on the pain and physical function domains of the WOMAC, we used multiple regression analysis with age, sex, BMI, minimum JSW, and osteophyte area as independent variables in the overall population (Table 2). Minimum JSW and osteophyte area were independently associated with scores on the pain and physical function domains of the WOMAC (β coefficients −0.16 and 0.11 for the association of pain domain score with minimum JSW and osteophyte area, respectively, and β coefficients −0.13 and 0.16 for the association of physical function domain score with minimum JSW and osteophyte area, respectively).
Table 2. Associations of minimum JSW and osteophyte area with WOMAC domain scores*
|Overall population|| || || || || || || || |
| Minimum JSW||−0.71 (−0.81, −0.60)||<0.0001||−0.37 (−0.48, −0.25)||<0.0001||−2.33 (−2.66, −1.99)||<0.0001||−0.97 (−1.34, −0.59)||<0.0001|
| Osteophyte area||0.07 (0.05, 0.08)||<0.0001||0.03 (0.02, 0.04)||<0.0001||0.25 (0.21, 0.29)||<0.0001||0.14 (0.10, 0.18)||<0.0001|
|Men|| || || || || || || || |
| Minimum JSW||−0.47 (−0.64, −0.31)||<0.0001||−0.29 (−0.47, −0.11)||0.002||−1.34 (−1.86, −0.82)||<0.0001||−0.48 (−1.04, 0.08)||0.10|
| Osteophyte area||0.07 (0.04, 0.11)||<0.0001||0.03 (−0.005, 0.07)||0.09||0.30 (0.19, 0.41)||<0.0001||0.20 (0.09, 0.32)||0.0005|
|Women|| || || || || || || || |
| Minimum JSW||−0.83 (−0.97, −0.69)||<0.0001||−0.41 (−0.57, −0.25)||<0.0001||−2.89 (−3.35, −2.43)||<0.0001||−1.22 (−1.72, −0.72)||<0.0001|
| Osteophyte area||0.06 (0.05, 0.08)||<0.0001||0.03 (0.01, 0.04)||0.0001||0.24 (0.20, 0.29)||<0.0001||0.12 (0.08, 0.17)||<0.0001|
When men and women were analyzed separately (Table 2), in men, minimum JSW was independently associated with the pain domain scores (β coefficient −0.13), but not with the physical function domain scores (β coefficient 0.07) of the WOMAC, while osteophyte area was independently associated with the physical function domain scores (β coefficient 0.14), but not with the pain domain scores (β coefficient −0.07) of the WOMAC. In women, both minimum JSW and osteophyte area were independently associated with scores on the pain and physical function domains of the WOMAC, and the absolute values of the beta values for minimum JSW for scores on the pain domains of the WOMAC were larger than those for osteophyte area (−0.15 and 0.11, respectively), while the absolute values of the beta values for minimum JSW for scores on the physical function domains of the WOMAC were smaller than those for osteophyte area (−0.14 and 0.15, respectively).
When the analysis was restricted to the participants with knee OA, the results were almost the same (Table 3). In men with knee OA, minimum JSW was independently associated with pain domain scores (β coefficient −0.17), but not with physical function domain scores (β coefficient 0.05). In women with knee OA, both minimum JSW and osteophyte area were independently associated with physical function domain scores, but the beta value for minimum JSW for physical function domain scores was smaller than that for osteophyte area (−0.12 and 0.20, respectively).
Table 3. Associations of minimum JSW and osteophyte area with WOMAC domain scores in the subjects with knee OA*
|Overall population|| || || || || || || || |
| Minimum JSW||−0.81 (−0.97, −0.65)||<0.0001||−0.51 (−0.69, −0.33)||<0.0001||−2.77 (−3.32, −2.22)||<0.0001||−1.46 (−2.05, −0.87)||<0.0001|
| Osteophyte area||0.06 (0.04, 0.07)||<0.0001||0.03 (0.01, 0.04)||0.0007||0.22 (0.18, 0.27)||<0.0001||0.12 (0.07, 0.17)||<0.0001|
|Men|| || || || || || || || |
| Minimum JSW||−0.59 (−0.86, −0.31)||<0.0001||−0.42 (−0.72, −0.11)||0.009||−1.95 (−2.81, −1.08)||<0.0001||−0.97 (−1.97, −0.01)||0.05|
| Osteophyte area||0.07 (0.02, 0.11)||0.003||0.02 (−0.02, 0.07)||0.40||0.34 (0.21, 0.48)||<0.0001||0.24 (0.10, 0.39)||0.001|
|Women|| || || || || || || || |
| Minimum JSW||−0.89 (−1.09, −0.68)||<0.0001||−0.56 (−0.78, −0.34)||<0.0001||−3.00 (−3.71, −2.29)||<0.0001||−1.61 (−2.35, −0.88)||<0.0001|
| Osteophyte area||0.05 (0.04, 0.07)||<0.0001||0.03 (0.01, 0.04)||0.002||0.20 (0.15, 0.26)||<0.0001||0.11 (0.05, 0.16)||0.0001|
This is the first study to separately examine the associations of JSN and osteophytosis with QOL, measured by a disease-specific scale such as WOMAC, using a large-scale population-based Japanese cohort. In addition, JSN and osteophytosis were estimated not by categorical grade but by continuous values such as minimum JSW and osteophyte area at the knee. In the present study, JSN as well as osteophytosis was independently associated with QOL.
The present study showed that both JSN and osteophytosis reduce QOL. Osteophytosis appears to begin with the activation of periosteal layers, with initial generation of chondrophytes and subsequent calcification to real osteophytes. The process is probably an adaptive reaction of the joint in order to cope with joint instability, and thus osteophyte area may indicate the severity of joint instability (22), which might lead to loss of QOL. When men and women were analyzed separately, minimum JSW was significantly associated with scores on the WOMAC pain domain but not the WOMAC physical function domain in men, while osteophyte area was associated with scores on the physical function domain but not the pain domain. According to the methodology of the WOMAC, pain domains estimate the severity of pain, indicating that JSN may be strongly associated with pain. In contrast, physical function domains assess difficulties in activities of daily living, indicating that osteophytosis may be mainly associated with activities of daily living, particularly in men.
Our findings also indicated differences between the sexes in the associations of JSN and osteophytosis with QOL. Minimum JSW was significantly associated with scores on the physical function domains of the WOMAC in women, but not in men. Similarly, osteophyte area was associated with scores on the pain domains of the WOMAC in women, but not in men. These differences may indicate that JSN and osteophytosis were more strongly associated with loss of QOL in women than in men. Our previous study also showed that the odds ratio of knee pain for K/L grade 3 or 4 knee OA was approximately twice as high in women as in men (4). This may be partly explained by the lower muscle mass in women than in men. Previous reports have shown that muscle mass is also associated with QOL (23, 24). In men, muscular strength may obscure the associations of JSN and osteophytosis with QOL loss; thus, these were not associated with some QOL parameters in men.
The present study has several limitations. First, this is a large-scale, population-based study, with a cross-sectional study of baseline data. Thus, causal relationships could not be determined. The ROAD study is a longitudinal survey, so further progress may help elucidate any causal relationships. Second, we did not include other weight-bearing forms of OA, such as hip OA, in the analysis, although this disorder may also affect QOL. However, the prevalence of K/L grade 3 or 4 hip OA is 1.4% and 3.5% in Japanese men and women (25), respectively, which is lower than the prevalence of K/L grade 3 or 4 knee OA (13.5% and 24.6% in Japanese men and women, respectively) (4). Thus, it is possible that including hip OA would not strongly affect the results of the present study. Third, the QOL questionnaire was completed by 74.2% of all participants age 40 years or older in the ROAD study. Participants who completed the questionnaire were younger and more likely to have knee OA than the participants who did not complete the questionnaire, and thus the participants included in this study may have had better QOL than those who did not complete the questionnaire, and our results may have overestimated QOL. Fourth, although osteophytes may be even more pronounced in the contralateral tibiofemoral compartment (26), at present the KOACAD system can only measure medial osteophytes at the tibia. We are now developing the KOACAD system to measure osteophytes at other sites; thus, we may be able to clarify the association between osteophytes at other sites and QOL in the near future.
In conclusion, the present cross-sectional study using a large-scale population from the ROAD study revealed that JSN and osteophytosis are independently associated with QOL. Further studies, along with continued longitudinal surveys in the ROAD study, will help clarify the mechanisms of JSN and osteophytosis at the knee, and their relationship with QOL.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Muraki 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 conception and design. Muraki, Oka, Akune, En-yo, M. Yoshida, Suzuki, H. Yoshida, Ishibashi, Tokimura, Yamamoto, Nakamura, Kawaguchi, Yoshimura.
Acquisition of data. Muraki, Oka, Akune, En-yo, Yoshimura.
Analysis and interpretation of data. Muraki, Oka, Akune, Yoshimura.
The authors wish to thank Dr. Anamizu and members of the Department of Orthopedics, Tokyo Metropolitan Geriatric Medical Center and Mr. Kutsuma and other members of the Department of Radiology, Tokyo Metropolitan Geriatric Medical Center. The authors thank Mrs. Tomoko Takijiri and other members of the Public Office in Hidakagawa Town and Mrs. Tamako Tsutsumi, Mrs. Kanami Maeda, and other members of the Public Office in Taiji Town for their assistance in locating and scheduling participants for examinations.