Osteoarthritis (OA) is a progressive chronic disease that results in pain and disability1. It has recently been suggested that OA is a syndrome comprising multiple distinct subgroups rather than a single disease2. The identification of clinically relevant subgroups of OA of the knee and their relevance to clinical outcomes have recently gained attention3. Patients who have less severe disease as seen on radiographs respond better to therapeutic interventions than those with severe disease; therefore, identifying subgroups of OA that are less severe, as was previously done by Felson et al.4, can have a therapeutic advantage.
The utilization of radiographic evaluation to determine the potential subgroup is useful because of its simplicity and wide use in the clinical setting. A recent cross-sectional study of 100 subjects who had Kellgren and Lawrence (KL) grade-2 OA5 in the medial compartment of the knee identified a subgroup6: individuals who had coexisting lateral osteophytes and mild medial OA had more severe pain in the knee than those who had medial OA alone6. The 2 groups of patients may have had different clinical profiles. Although the pathogenesis of bicompartmental tibiofemoral joint disease has not been elucidated, impaired muscle function in the lower limb is a potential factor associated with this subgroup, and the reverse may also be true. Quadriceps weakness7 and inactivation during gait8 result in decreased shock absorption and thereby increase the load transmitted through the entire tibiofemoral joint, which may be responsible for OA changes in the medial and lateral compartments9. Conversely, bicompartmental disease may induce more severe pain that then impairs quadriceps muscle contractions10. A plausible hypothesis is that individuals who have coexisting lateral and medial OA have less muscle strength. This hypothesis is supported by evidence demonstrating that cells from the knees of subjects who had bicompartmental disease (medial and lateral OA) showed a greater inflammatory response than cells from the knees of subjects who had unicompartmental disease11; inflammation is a significant factor associated with decreased strength of the quadriceps in individuals who have knee OA12,13.
This study tested the hypothesis that individuals who have lateral OA have less muscle strength than those without lateral OA. This knowledge should provide us with new insight into understanding subgroups of OA of the knee and their relevance to clinical outcomes.
Materials and Methods
Community-dwelling elderly individuals who had pain in the knee were identified through a mailed survey and were invited to attend a research meeting at Kyoto University in September 2017. The ethics committee of Kyoto University approved the study, and written informed consent was obtained from all participants before their enrollment. All recruited participants had a history of pain in 1 or both knees in the last month. Eligibility criteria included (1) age more than 45 years; (2) mild medial tibiofemoral OA (KL grade 2) in 1 or both knees, evaluated using weight-bearing anteroposterior radiographs; and (3) the ability to walk without assistive devices. Individuals who had a history of knee surgery, rheumatoid arthritis, current neurological problems, or lateral OA of the knee were excluded from this study. Lateral OA was defined as a KL grade of ≥1 with joint-space narrowing graded >0 in the lateral compartment and 0 in the medial compartment14. Medial and lateral OA of the knee have distinct characteristics15, and the medial type is the most common in Japan16,17, so individuals in whom the severity of lateral OA exceeded the severity of medial OA were excluded from this study. We previously reported excellent interrater reliability scores for the severity of radiographic changes in the medial compartment18,19.
Radiographic assessment of the knee was performed and the lower-limb muscle strength of the participants was measured. Demographic characteristics, a self-reported measure of pain related to the OA of the knee, and range of motion of the knee were also assessed as covariates.
Anteroposterior radiographs of both knees, fully extended and weight-bearing, were made at the time of enrollment in the study. The radiographic severity of OA in the lateral compartment was assessed by a trained examiner (H.I.) in accordance with the previous study6. In brief, the Osteoarthritis Research Society International (OARSI) atlas14 and KL grading system5 were used for radiographic evaluation in a compartment-specific manner20 because these systems provide a different prevalence rate of radiographic evidence of OA21. Radiographic evidence of OA in the lateral compartment, determined with use of the OARSI atlas, was considered to be present if 1 or more of the following criteria were present: (1) joint-space narrowing was grade 2, (2) the sum of the 2 marginal osteophyte grades was 2, or (3) grade-1 joint-space narrowing was combined with a grade of 1 for marginal osteophytes22. Radiographic evidence of lateral OA according to the KL grading system was considered to be present if the presence of marginal osteophytes in either the femur or the tibia was definitely confirmed23. We previously reported fair to good interrater reliability for osteophyte grade, joint-space narrowing, and KL grade in the lateral compartment6.
The maximum isometric strengths (Nm/kg) of the quadriceps, hip extensors, and hip abductors of both legs were measured using a hand-held dynamometer (μTas F-1; Anima) in accordance with a method previously validated for community-dwelling elderly fallers24. Details about the measurement procedure for each muscle are provided in the Appendix and shown in Appendix Figure E-1. The minimum detectable change (MDC95) was calculated using 100 randomly selected participants (200 knees) to indicate the smallest degree of change that is outside the error of the strength testing. The MDC95 was 0.227, 0.211, and 0.132 Nm/kg for quadriceps, hip extensor, and hip abductor strengths, respectively. The intrarater reliability was excellent for quadriceps strength (intraclass correlation [ICC1,1]: 0.939, 95% confidence interval [CI]: 0.921 to 0.954), hip extensor strength (ICC1,1: 0.942, 95% CI: 0.925 to 0.956), and hip abductor strength (ICC1,1: 0.936, 95% CI: 0.916 to 0.951).
Data on age, sex, and height were self-reported by the participants. Weight was measured with a weighing scale, with the participants clothed but not wearing shoes. The severity of knee pain and self-reported physical function were evaluated using the Japanese Knee Osteoarthritis Measure (JKOM)25. The anatomical axis angle (AAA) with sex-specific correction26 was assessed on the anteroposterior short view made with the individual bearing weight (see Appendix, Method 2). The range of passive flexion and extension of the knee was also evaluated (see Appendix, Method 3).
To minimize any bias generated by similarities between the right and left knees of the same person, only 1 knee per individual (the index knee) was analyzed. The index knee was defined as the knee that was considered more painful in either the past or the present. If an individual perceived that the 2 knees were equally painful, the index knee was selected randomly with use of a computer-generated permuted block randomization scheme27. A sample-size calculation based on the pilot data of quadriceps strength was performed. In this manner, it was determined that a minimum of 141 participants were required for the present study (see Appendix, Method 4).
To check the reproducibility of the previous study, which had been conducted to determine whether individuals who have bicompartmental tibiofemoral joint disease are more symptomatic than those who have OA in the medial compartment only6, the JKOM scores were compared using an analysis of covariance (ANCOVA) adjusted for age, female sex, and body mass index. Subsequently, the muscle strength of individuals who did and did not have OA in the lateral compartment was compared with use of the ANCOVA adjusted for age and sex.
To test the hypothesis that decreased muscle strength is significantly associated with the presence of lateral OA, logistic regression analysis was performed with muscle strength as an independent variable (continuous; per −1 Nm/kg) and the presence of lateral OA as a dependent variable (0: no, 1: yes). Age, female sex, the corrected AAA of the index knee, the range of motion of the index knee, and the JKOM pain score were included as covariates. These covariates were determined a priori based on clinical judgment and on potential association with muscle strength and the presence of OA in the lateral compartment6. Muscle strength was normalized to body mass, so body mass index was not included as a covariate, although it may be a potential confounder6. Data analyses were performed using JMP Pro 13.0 (SAS Institute). A p value of <0.05 was considered significant.
Of the 296 participants evaluated, 143 (48%) were excluded for the following reasons: (1) missing data, 6 individuals; (2) no definitive radiographic evidence of OA (KL grade 1), 106 individuals; or (3) radiographic evidence of moderate to severe OA (KL grade 3 or 4), 31 individuals. Thus, the final analysis included 153 participants. The mean age was 69.3 years (range, 48 to 88 years), and 84% of the participants were women. Radiographic evidence of OA in the lateral compartment was present in 45 individuals (29%) according to the criteria of the OARSI atlas compared with 58 individuals (38%) according to the KL criteria. Table I shows the comparison of characteristics between individuals with and without lateral OA. Of the 153 individuals, 99 (65%) had a history of knee pain within the past month; of these, 56 (57%) felt the pain ≥3 days per week. The mean duration of the pain was 41.0 months (range, 0.5 to 360 months), and individuals who had OA in the lateral compartment had a significantly longer duration of complaints (means, 60.8 and 58.6 months when the OA was graded with the OARSI and KL systems, respectively) than those without lateral OA (means, 30.8 and 28.1 months when graded with the OARSI and KL systems). The JKOM pain score in individuals who had lateral OA was more severe than it was in individuals without lateral OA, regardless of radiographic criteria, after adjusting for the covariates; the mean difference in JKOM pain score was 2.495 (95% CI, 0.950 to 4.040) points and 2.099 points for OA graded with the OARSI and KL systems, respectively.
TABLE I -
Comparison of Characteristics of Individuals Who Had Mild Medial OA with and without Lateral OA (N = 153)
|With Lateral OA (N = 45)
||Without Lateral OA (N = 108)
||With Lateral OA (N = 58)
||Without Lateral OA (N = 95)
||70.0 ± 9.60
||69.0 ± 9.30
||70.1 ± 9.75
||68.8 ± 9.15
|Women (no. [%])
||1.54 ± 0.07
||1.57 ± 0.08
||1.54 ± 0.08
||1.57 ± 0.07
||56.5 ± 12.5
||54.0 ± 9.90
||55.7 ± 12.0
||54.2 ± 9.90
|Body mass index (kg/m
||23.7 ± 4.12
||21.9 ± 2.93
||23.3 ± 3.78
||21.8 ± 3.06
|Index knee corrected AAA (°)
||178.3 ± 3.37
||177.2 ± 3.55
||178.3 ± 3.58
||177.0 ± 3.40
|Alignment [no. (%)]
| Neutral (corrected AAA ≥179° but <182°)
| Valgus (corrected AAA ≥182°)
| Varus (corrected AAA <179°)
|Lateral joint-space narrowing in index knee (no. [%])
| Grade 0
| Grade 1
| Grade 2
| Grade 3
|JKOM pain subscale (points)
||6.87 ± 5.04
||4.33 ± 3.95
||6.45 ± 5.08
||4.28 ± 3.81
|JKOM ADL subscale (points)
||4.59 ± 4.15
||2.08 ± 2.55
||3.88 ± 3.93
||2.19 ± 2.69
|JKOM total score (points)
||16.5 ± 10.5
||10.3 ± 7.60
||15.4 ± 10.4
||10.2 ± 7.52
|Flexion ROM of index knee (°)
||144.5 ± 8.44
||149.2 ± 8.40
||145.1 ± 7.76
||149.4 ± 8.80
|Extension ROM of index knee#(°)
||–2.67 ± 5.42
||–0.37 ± 4.17
||–2.16 ± 5.32
||–0.37 ± 4.11
*Values are given as the mean and the standard deviation, except where otherwise noted.
†ADL = activities of daily living, and ROM = range of motion.
‡P values are calculated using the Student t test (height, index corrected AAA), Mann-Whitney U test (age, weight, body mass index, JKOM scores, ROM of the knee), and chi-square test (female, alignment, and lateral joint-space narrowing).
#A negative value indicates flexion of the knee joint.
Table II shows the comparison of strength in the muscles of the lower limb of the index and non-index knees for individuals with and without lateral OA. The quadriceps, hip extensor, and hip abductor muscles of both lower limbs were weaker in individuals who had lateral OA than in those without lateral OA after adjusting for age and sex. Significant differences in hip muscles were determined only when the OARSI atlas were used.
TABLE II -
Muscle Strengths of Individuals Who Had Mild Medial OA with and without Lateral OA—Comparison Using ANCOVA (N = 153)
|With Lateral OA (N = 45)
||Without Lateral OA (N = 108)
||Adjusted Difference in Mean* (95% CI)
||With Lateral OA (N = 58)
||Without Lateral OA (N = 95)
||Adjusted Difference in Mean* (95% CI)
| Quadriceps strength (Nm/kg)
||0.998 ± 0.296
||1.298 ± 0.412
||0.272 (0.143, 0.401)†
||1.084 ± 0.388
||1.287 ± 0.397
||0.185 (0.061, 0.309)†
| Hip extensor strength (Nm/kg)
||1.184 ± 0.381
||1.476 ± 0.562
||0.249 (0.073, 0.424)†
||1.286 ± 0.464
||1.454 ± 0.561
||0.138 (−0.028, 0.305)
| Hip abductor strength (Nm/kg)
||0.716 ± 0.212
||0.829 ± 0.325
||0.120 (0.017, 0.224)‡
||0.743 ± 0.240
||0.828 ± 0.328
||0.093 (−0.005, 0.191)
| Quadriceps strength (Nm/kg)
||1.063 ± 0.303
||1.355 ± 0.442
||0.250 (0.114, 0.386)†
||1.148 ± 0.393
||1.343 ± 0.431
||0.166 (0.035, 0.296)‡
| Hip extensor strength (Nm/kg)
||1.221 ± 0.378
||1.535 ± 0.507
||0.275 (0.113, 0.437)†
||1.345 ± 0.487
||1.502 ± 0.489
||0.128 (−0.028, 0.284)
| Hip abductor strength (Nm/kg)
||0.721 ± 0.249
||0.835 ± 0.358
||0.122 (0.005, 0.238)‡
||0.744 ± 0.262
||0.837 ± 0.367
||0.100 (−0.009, 0.210)
*Adjusted for age and sex.
†P < 0.01.
‡P < 0.05.
We performed logistic regression analyses to determine whether muscle weakness was significantly associated with the presence of lateral OA (Table III). A weaker quadriceps was associated with 6.5-fold and 7.1-fold increases in the odds of the presence of lateral OA in the index and non-index knees, respectively. However, these differences were statistically significant only when the OARSI classification was used.
TABLE III -
Association Between Weaker Muscle Strength and the Presence of Lateral OA in Individuals with Mild Medial OA—Binary Logistic Regression Analyses (N = 153)
|OR (95% CI) of the Presence of Lateral OA*
||OR (95% CI) of the Presence of Lateral OA*
| Quadriceps strength, per –1 Nm/kg
||11.3 (3.69, 39.9)†
||6.53 (1.81, 27.1)†
||4.13 (1.66, 11.3)†
||2.00 (0.71, 6.03)
| Hip extensor strength, per –1 Nm/kg
||3.25 (1.56, 7.31)†
||2.02 (0.85, 5.06)
||1.87 (0.99, 3.68)
||1.08 (0.49, 2.37)
| Hip abductor strength, per –1 Nm/kg
||4.83 (1.24, 22.2)‡
||2.23 (0.42, 14.2)
||2.95 (0.90, 11.1)
||0.90 (0.21, 3.82)
| Quadriceps strength, per –1 Nm/kg
||8.23 (2.87, 27.2)†
||7.12 (2.07, 28.6)†
||3.37 (1.43, 8.65)†
||2.70 (0.99, 8.01)
| Hip extensor strength, per –1 Nm/kg
||4.63 (2.03, 11.6)†
||2.82 (1.11, 7.68)‡
||1.97 (0.99, 4.09)
||0.99 (0.43, 2.28)
| Hip abductor strength, per –1 Nm/kg
||3.85 (1.10, 15.9)‡
||1.84 (0.41, 10.1)
||2.71 (0.90, 9.45)
||1.22 (0.35, 5.16)
*OR (odds ratio) was calculated per –1 Nm/kg to indicate predictive ability of weaker muscle strength. Adjustments were made for age and sex and for corrected AAA, extension range of motion, flexion range of motion, and JKOM scores for pain and stiffness of the index knee.
†P < 0.01.
‡P < 0.05.
A significant finding of the current study is that individuals who had coexisting lateral OA had weaker muscles, particularly the quadriceps muscle, after adjusting for the covariates. Consistent with the previous study6, individuals who had coexisting medial and lateral OA had greater pain in the knee, indicating that these patients had a more symptomatic disease than those with medial OA alone. Our findings indicate that if closer attention is given to the weaker quadriceps, this information may provide a key in clarifying the pathogenesis of bicompartmental disease in the tibiofemoral joint.
The prevalence of lateral OA in this study was similar to or slightly less than has been reported in previous studies6,28,29. We considered lateral OA to be present if osteophytes were detected in either the tibia or the femur, which is different from the original version of KL grading. Thus, the prevalence according to KL grading was less than that determined when the OARSI atlas was used for grading. Racial differences might also contribute the lower prevalence of lateral OA in this study29,30. The magnitude of between-group difference in knee pain was approximately equal to the minimal clinically important difference (MCID)31, indicating that these 2 groups may have different pain profiles. The complaints of individuals with lateral OA were of longer duration, a finding that supports the above-mentioned interpretation. A prospective cohort study is warranted to address the causal relationship between greater pain in the knee and bicompartmental disease in the tibiofemoral joint.
Muscle strength was evaluated using a handheld dynamometer, with which the test-retest reliability was similar to that reported in a previous study32. The group difference in quadriceps strength might be affected by knee pain during testing33,34. The impact of pain during testing would be expected to be small; however, the data should be interpreted with caution. Because individuals who had lateral OA also had greater pain, the precise difference in the strength of the quadriceps between those who did and did not have lateral OA may be less than the values provided in the present study. On a related note, the mean difference of muscle strength in the quadriceps and hip extensors, when OA was determined by the OARSI atlas criteria, exceeded the MDC95 value, indicating that in individuals who had coexisting lateral OA, muscle strength was diminished by more than the measurement error of muscle-strength testing. However, the mean differences in quadriceps and hip extensor strength when OA was determined by the KL classification were lower than the MDC95; thus, close attention is needed when translating our research findings into clinical practice. Furthermore, the mean difference in hip abductor strength was lower than the MDC95 regardless of the radiographic OA classification used, although the MDC95 of hip abductor muscle strength was lower than that reported in a previous study35.
The mechanism responsible for lesser muscle strength in individuals who have lateral OA has not yet been clarified; however, it has been suggested that individuals who have bicompartmental OA have a more inflammatory disease than those with unicompartmental OA11. The elevated inflammatory response may contribute to weakness of the quadriceps12,13,36, and this should be considered in future studies. These systemic effects may explain why the muscles in the non-index knee of the participants in this study who had lateral OA were also significantly weaker than they were in the individuals who did not have lateral OA.
An important implication of this study is that a weak quadriceps may be a factor associated with bicompartmental disease in the tibiofemoral joint, although the cross-sectional nature of the present study limits our interpretation of any causal relationship. Race is known to be associated with bicompartmental disease29,30; however, previous studies did not consider the effects of strength of the muscles of the lower limb. It should be highlighted that the difference in quadriceps strength between the 2 groups in the present study exceeded the MCID value (6% reduction in muscle strength) for self-reported functional decline37. Quadriceps weakness or inactivity during gait could result in large loads at the tibiofemoral joint7,8 and might be responsible for OA changes in the lateral compartment. A previous meta-analysis revealed moderate to high-quality evidence that a rehabilitation program targeting the quadriceps increased muscle strength, with a small to moderate effect38. Therefore, the difference in quadriceps strength between individuals with and without lateral OA might be treatable through a non-pharmacological method. However, bicompartmental OA could contribute to weakness of the quadriceps because severe pain in the knee impairs quadriceps contractions10. A longitudinal cohort study is warranted to clarify whether weakness of the quadriceps is a modifiable risk factor associated with bicompartmental disease.
The present study has some limitations. A lack of information about patellofemoral OA restricted our analysis. Patellofemoral OA contributes to quadriceps weakness39. Thus, the decreased strength of the quadriceps in individuals who have lateral OA may be attributable to the greater prevalence of disease in the patellofemoral joint. Additionally, we lacked information about the patients’ history of injury. A previous injury such as a rupture of the anterior cruciate ligament, which is a risk factor for progression of radiographic evidence of lateral OA40, might explain the weaker quadriceps in individuals who have lateral OA. We had no data on forms of muscle contraction other than isometric strength, and this restricted our analysis of the relationship between muscle strength and the presence of coexisting medial and lateral OA. Individuals who have OA of the knee have impaired eccentric quadriceps contraction compared with concentric and isometric contractions41; this should be a subject of future studies.
In conclusion, in this study, individuals who had coexisting medial and lateral OA had decreased muscle strength, particularly of the quadriceps, in conjunction with more severe knee pain compared with individuals who did not have lateral OA. Weakness of the quadriceps may be an important manifestation of bicompartmental OA and has demonstrated associations with important clinical outcomes, including knee pain. Close attention to quadriceps weakness might provide the key to clarification of the pathogenesis of bicompartmental disease in the tibiofemoral joint.
Additional details regarding the methods used in the present study (including references42-46, which are cited only in the Appendix) and a figure demonstrating measurement of lower-limb muscle strength are available with the online version of this article as a data supplement at jbjs.org (http://links.lww.com/JBJSOA/A83).
Note: The authors thank the members of Aoyama laboratory (Kyoto University, Kyoto) for their assistance in data collection. Editage (www.editage.jp) assisted with English-language editing.
1. Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V, Abraham J, Ackerman I, Aggarwal R, Ahn SY, Ali MK, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Bahalim AN, Barker-Collo S, Barrero LH, Bartels DH, Basáñez MG, Baxter A, Bell ML, Benjamin EJ, Bennett D, Bernabé E, Bhalla K, Bhandari B, Bikbov B, Bin Abdulhak A, Birbeck G, Black JA, Blencowe H, Blore JD, Blyth F, Bolliger I, Bonaventure A, Boufous S, Bourne R, Boussinesq M, Braithwaite T, Brayne C, Bridgett L, Brooker S, Brooks P, Brugha TS, Bryan-Hancock C, Bucello C, Buchbinder R, Buckle G, Budke CM, Burch M, Burney P, Burstein R, Calabria B, Campbell B, Canter CE, Carabin H, Carapetis J, Carmona L, Cella C, Charlson F, Chen H, Cheng AT, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahiya M, Dahodwala N, Damsere-Derry J, Danaei G, Davis A, De Leo D, Degenhardt L, Dellavalle R, Delossantos A, Denenberg J, Derrett S, Des Jarlais DC, Dharmaratne SD, Dherani M, Diaz-Torne C, Dolk H, Dorsey ER, Driscoll T, Duber H, Ebel B, Edmond K, Elbaz A, Ali SE, Erskine H, Erwin PJ, Espindola P, Ewoigbokhan SE, Farzadfar F, Feigin V, Felson DT, Ferrari A, Ferri CP, Fèvre EM, Finucane MM, Flaxman S, Flood L, Foreman K, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabbe BJ, Gabriel SE, Gakidou E, Ganatra HA, Garcia B, Gaspari F, Gillum RF, Gmel G, Gosselin R, Grainger R, Groeger J, Guillemin F, Gunnell D, Gupta R, Haagsma J, Hagan H, Halasa YA, Hall W, Haring D, Haro JM, Harrison JE, Havmoeller R, Hay RJ, Higashi H, Hill C, Hoen B, Hoffman H, Hotez PJ, Hoy D, Huang JJ, Ibeanusi SE, Jacobsen KH, James SL, Jarvis D, Jasrasaria R, Jayaraman S, Johns N, Jonas JB, Karthikeyan G, Kassebaum N, Kawakami N, Keren A, Khoo JP, King CH, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lalloo R, Laslett LL, Lathlean T, Leasher JL, Lee YY, Leigh J, Lim SS, Limb E, Lin JK, Lipnick M, Lipshultz SE, Liu W, Loane M, Ohno SL, Lyons R, Ma J, Mabweijano J, MacIntyre MF, Malekzadeh R, Mallinger L, Manivannan S, Marcenes W, March L, Margolis DJ, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGill N, McGrath J, Medina-Mora ME, Meltzer M, Mensah GA, Merriman TR, Meyer AC, Miglioli V, Miller M, Miller TR, Mitchell PB, Mocumbi AO, Moffitt TE, Mokdad AA, Monasta L, Montico M, Moradi-Lakeh M, Moran A, Morawska L, Mori R, Murdoch ME, Mwaniki MK, Naidoo K, Nair MN, Naldi L, Narayan KM, Nelson PK, Nelson RG, Nevitt MC, Newton CR, Nolte S, Norman P, Norman R, O’Donnell M, O’Hanlon S, Olives C, Omer SB, Ortblad K, Osborne R, Ozgediz D, Page A, Pahari B, Pandian JD, Rivero AP, Patten SB, Pearce N, Padilla RP, Perez-Ruiz F, Perico N, Pesudovs K, Phillips D, Phillips MR, Pierce K, Pion S, Polanczyk GV, Polinder S, Pope CA 3rd, Popova S, Porrini E, Pourmalek F, Prince M, Pullan RL, Ramaiah KD, Ranganathan D, Razavi H, Regan M, Rehm JT, Rein DB, Remuzzi G, Richardson K, Rivara FP, Roberts T, Robinson C, De Leòn FR, Ronfani L, Room R, Rosenfeld LC, Rushton L, Sacco RL, Saha S, Sampson U, Sanchez-Riera L, Sanman E, Schwebel DC, Scott JG, Segui-Gomez M, Shahraz S, Shepard DS, Shin H, Shivakoti R, Singh D, Singh GM, Singh JA, Singleton J, Sleet DA, Sliwa K, Smith E, Smith JL, Stapelberg NJ, Steer A, Steiner T, Stolk WA, Stovner LJ, Sudfeld C, Syed S, Tamburlini G, Tavakkoli M, Taylor HR, Taylor JA, Taylor WJ, Thomas B, Thomson WM, Thurston GD, Tleyjeh IM, Tonelli M, Towbin JA, Truelsen T, Tsilimbaris MK, Ubeda C, Undurraga EA, van der Werf MJ, van Os J, Vavilala MS, Venketasubramanian N, Wang M, Wang W, Watt K, Weatherall DJ, Weinstock MA, Weintraub R, Weisskopf MG, Weissman MM, White RA, Whiteford H, Wiersma ST, Wilkinson JD, Williams HC, Williams SR, Witt E, Wolfe F, Woolf AD, Wulf S, Yeh PH, Zaidi AK, Zheng ZJ, Zonies D, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012 Dec 15;380(9859):2163-96.
2. Bruyère O, Cooper C, Arden N, Branco J, Brandi ML, Herrero-Beaumont G, Berenbaum F, Dennison E, Devogelaer JP, Hochberg M, Kanis J, Laslop A, McAlindon T, Reiter S, Richette P, Rizzoli R, Reginster JY. Can we identify patients with high risk of osteoarthritis progression who will respond to treatment? A focus on epidemiology and phenotype of osteoarthritis. Drugs Aging. 2015 Mar;32(3):179-87.
3. Deveza LA, Melo L, Yamato TP, Mills K, Ravi V, Hunter DJ. Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review. Osteoarthritis Cartilage. 2017 Dec;25(12):1926-41. Epub 2017 Aug 25.
4. Felson DT, Niu J, Guermazi A, Sack B, Aliabadi P. Defining radiographic incidence and progression of knee osteoarthritis: suggested modifications of the Kellgren and Lawrence scale. Ann Rheum Dis. 2011 Nov;70(11):1884-6. Epub 2011 Sep 8.
5. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957 Dec;16(4):494-502.
6. Iijima H, Aoyama T, Nishitani K, Ito H, Fukutani N, Isho T, Kaneda E, Kuroki H, Matsuda S. Coexisting lateral tibiofemoral osteoarthritis is associated with worse knee pain in patients with mild medial osteoarthritis. Osteoarthritis Cartilage. 2017 Aug;25(8):1274-81. Epub 2017 Mar 3.
7. Mikesky AE, Meyer A, Thompson KL. Relationship between quadriceps strength and rate of loading during gait in women. J Orthop Res. 2000 Mar;18(2):171-5.
8. Jefferson RJ, Collins JJ, Whittle MW, Radin EL, O’Connor JJ. The role of the quadriceps in controlling impulsive forces around heel strike. Proc Inst Mech Eng H. 1990;204(1):21-8.
9. Radin EL, Yang KH, Riegger C, Kish VL, O’Connor JJ. Relationship between lower limb dynamics and knee joint pain. J Orthop Res. 1991 May;9(3):398-405.
10. Rice DA, McNair PJ, Lewis GN, Mannion J. Experimental knee pain impairs submaximal force steadiness in isometric, eccentric, and concentric muscle actions. Arthritis Res Ther. 2015 Sep 12;17:259.
11. Moradi B, Rosshirt N, Tripel E, Kirsch J, Barié A, Zeifang F, Gotterbarm T, Hagmann S. Unicompartmental and bicompartmental knee osteoarthritis show different patterns of mononuclear cell infiltration and cytokine release in the affected joints. Clin Exp Immunol. 2015 Apr;180(1):143-54.
12. Sanchez-Ramirez DC, van der Leeden M, van der Esch M, Gerritsen M, Roorda LD, Verschueren S, van Dieën J, Dekker J, Lems WF. Association of serum C-reactive protein and erythrocyte sedimentation rate with muscle strength in patients with knee osteoarthritis. Rheumatology (Oxford). 2013 Apr;52(4):727-32. Epub 2012 Dec 28.
13. Sanchez-Ramirez DC, van der Leeden M, van der Esch M, Roorda LD, Verschueren S, van Dieën JH, Dekker J, Lems WF. Elevated C-reactive protein is associated with lower increase in knee muscle strength in patients with knee osteoarthritis: a 2-year follow-up study in the Amsterdam Osteoarthritis (AMS-OA) cohort. Arthritis Res Ther. 2014 Jun 13;16(3):R123.
14. Altman RD, Gold GE. Atlas of individual radiographic features in osteoarthritis, revised. Osteoarthritis Cartilage. 2007;15(Suppl A):A1-56.
15. Butler RJ, Barrios JA, Royer T, Davis IS. Frontal-plane gait mechanics in people with medial knee osteoarthritis are different from those in people with lateral knee osteoarthritis. Phys Ther. 2011 Aug;91(8):1235-43. Epub 2011 Jun 16.
16. Muraki S, Oka H, Akune T, Mabuchi A, En-yo Y, Yoshida M, Saika A, Suzuki T, Yoshida H, Ishibashi H, Yamamoto S, Nakamura K, Kawaguchi H, Yoshimura N. Prevalence of radiographic knee osteoarthritis and its association with knee pain in the elderly of Japanese population-based cohorts: the ROAD study. Osteoarthritis Cartilage. 2009 Sep;17(9):1137-43. Epub 2009 Apr 17.
17. Muraki S, Akune T, En-Yo Y, Yoshida M, Suzuki T, Yoshida H, Ishibashi H, Tokimura F, Yamamoto S, Tanaka S, Nakamura K, Kawaguchi H, Oka H, Yoshimura N. Joint space narrowing, body mass index, and knee pain: the ROAD study (OAC1839R1). Osteoarthritis Cartilage. 2015 Jun;23(6):874-81. Epub 2015 Jan 30.
18. Ohi H, Iijima H, Aoyama T, Kaneda E, Ohi K, Abe K. Association of frontal plane knee alignment with foot posture in patients with medial knee osteoarthritis. BMC Musculoskelet Disord. 2017 Jun 7;18(1):246.
19. Iijima H, Ohi H, Isho T, Aoyama T, Fukutani N, Kaneda E, Ohi K, Abe K, Kuroki H, Matsuda S. Association of bilateral flat feet with knee pain and disability in patients with knee osteoarthritis: A cross-sectional study. J Orthop Res. 2017 Nov;35(11):2490-8. Epub 2017 Apr 24.
20. Gudbergsen H, Lohmander LS, Jones G, Christensen R, Bartels EM, Danneskiold-Samsøe B, Bliddal H, Boesen M. Correlations between radiographic assessments and MRI features of knee osteoarthritis—a cross-sectional study. Osteoarthritis Cartilage. 2013 Apr;21(4):535-43. Epub 2012 Dec 26.
21. Culvenor AG, Engen CN, Øiestad BE, Engebretsen L, Risberg MA. Defining the presence of radiographic knee osteoarthritis: a comparison between the Kellgren and Lawrence system and OARSI atlas criteria. Knee Surg Sports Traumatol Arthrosc. 2015 Dec;23(12):3532-9. Epub 2014 Jul 31.
22. Lohmander LS, Ostenberg A, Englund M, Roos H. High prevalence of knee osteoarthritis, pain, and functional limitations in female soccer players twelve years after anterior cruciate ligament injury. Arthritis Rheum. 2004 Oct;50(10):3145-52.
23. Guccione AA, Felson DT, Anderson JJ. Defining arthritis and measuring functional status in elders: methodological issues in the study of disease and physical disability. Am J Public Health. 1990 Aug;80(8):945-9.
24. Wang CY, Olson SL, Protas EJ. Test-retest strength reliability: hand-held dynamometry in community-dwelling elderly fallers. Arch Phys Med Rehabil. 2002 Jun;83(6):811-5.
25. Akai M, Doi T, Fujino K, Iwaya T, Kurosawa H, Nasu T. An outcome measure for Japanese people with knee osteoarthritis. J Rheumatol. 2005 Aug;32(8):1524-32.
26. Kraus VB, Vail TP, Worrell T, McDaniel G. A comparative assessment of alignment angle of the knee by radiographic and physical examination methods. Arthritis Rheum. 2005 Jun;52(6):1730-5.
27. Vickers AJ. How to randomize. J Soc Integr Oncol. 2006 Fall;4(4):194-8.
28. Faschingbauer M, Renner L, Waldstein W, Boettner F. Are lateral compartment osteophytes a predictor for lateral cartilage damage in varus osteoarthritic knees?: Data from the Osteoarthritis Initiative. Bone Joint J. 2015 Dec;97-B(12):1634-9.
29. Braga L, Renner JB, Schwartz TA, Woodard J, Helmick CG, Hochberg MC, Jordan JM. Differences in radiographic features of knee osteoarthritis in African-Americans and Caucasians: the Johnston county osteoarthritis project. Osteoarthritis Cartilage. 2009 Dec;17(12):1554-61. Epub 2009 Sep 1.
30. Wise BL, Niu J, Yang M, Lane NE, Harvey W, Felson DT, Hietpas J, Nevitt M, Sharma L, Torner J, Lewis CE, Zhang Y; Multicenter Osteoarthritis (MOST) Group. Patterns of compartment involvement in tibiofemoral osteoarthritis in men and women and in whites and African Americans. Arthritis Care Res (Hoboken). 2012 Jun;64(6):847-52. Epub 2012 Jan 11.
31. Pham T, van der Heijde D, Altman RD, Anderson JJ, Bellamy N, Hochberg M, Simon L, Strand V, Woodworth T, Dougados M. OMERACT-OARSI initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis Cartilage. 2004 May;12(5):389-99.
32. Carpenter MR, Carpenter RL, Peel J, Zukley LM, Angelopoulou KM, Fischer I, Angelopoulos TJ, Rippe JM. The reliability of isokinetic and isometric leg strength measures among individuals with symptoms of mild osteoarthritis. J Sports Med Phys Fitness. 2006 Dec;46(4):585-9.
33. Riddle DL, Stratford PW. Impact of pain reported during isometric quadriceps muscle strength testing in people with knee pain: data from the osteoarthritis initiative. Phys Ther. 2011 Oct;91(10):1478-89. Epub 2011 Aug 11.
34. Stevens JE, Mizner RL, Snyder-Mackler L. Quadriceps strength and volitional activation before and after total knee arthroplasty for osteoarthritis. J Orthop Res. 2003 Sep;21(5):775-9.
35. Tevald MA, Murray A, Luc BA, Lai K, Sohn D, Pietrosimone B. Hip abductor strength in people with knee osteoarthritis: A cross-sectional study of reliability and association with function. Knee. 2016 Jan;23(1):57-62. Epub 2015 Jun 30.
36. Toth MJ, Matthews DE, Tracy RP, Previs MJ. Age-related differences in skeletal muscle protein synthesis: relation to markers of immune activation. Am J Physiol Endocrinol Metab. 2005 May;288(5):E883-91. Epub 2004 Dec 21.
37. Ruhdorfer A, Wirth W, Eckstein F. Relationship between isometric thigh muscle strength and minimum clinically important differences in knee function in osteoarthritis: data from the osteoarthritis initiative. Arthritis Care Res (Hoboken). 2015 Apr;67(4):509-18.
38. Zacharias A, Green RA, Semciw AI, Kingsley MI, Pizzari T. Efficacy of rehabilitation programs for improving muscle strength in people with hip or knee osteoarthritis: a systematic review with meta-analysis. Osteoarthritis Cartilage. 2014 Nov;22(11):1752-73. Epub 2014 Jul 24.
39. Stefanik JJ, Guermazi A, Zhu Y, Zumwalt AC, Gross KD, Clancy M, Lynch JA, Segal NA, Lewis CE, Roemer FW, Powers CM, Felson DT. Quadriceps weakness, patella alta, and structural features of patellofemoral osteoarthritis. Arthritis Care Res (Hoboken). 2011 Oct;63(10):1391-7.
40. Swärd P, Kostogiannis I, Neuman P, Von Porat A, Boegård T, Roos H. Differences in the radiological characteristics between post-traumatic and non-traumatic knee osteoarthritis. Scand J Med Sci Sports. 2010 Oct;20(5):731-9.
41. Hortobágyi T, Garry J, Holbert D, Devita P. Aberrations in the control of quadriceps muscle force in patients with knee osteoarthritis. Arthritis Rheum. 2004 Aug 15;51(4):562-9.
42. Iijima H, Fukutani N, Aoyama T, Fukumoto T, Uritani D, Kaneda E, Ota K, Kuroki H, Matsuda S. Clinical impact of coexisting patellofemoral osteoarthritis in Japanese patients with medial knee osteoarthritis. Arthritis Care Res (Hoboken). 2016 Apr;68(4):493-501.
43. McDaniel G, Mitchell KL, Charles C, Kraus VB. A comparison of five approaches to measurement of anatomic knee alignment from radiographs. Osteoarthritis Cartilage. 2010 Feb;18(2):273-7. Epub 2009 Oct 24.
44. Sharma L, Song J, Dunlop D, Felson D, Lewis CE, Segal N, Torner J, Cooke TD, Hietpas J, Lynch J, Nevitt M. Varus and valgus alignment and incident and progressive knee osteoarthritis. Ann Rheum Dis. 2010 Nov;69(11):1940-5. Epub 2010 May 28.
45. Sharma L, Chmiel JS, Almagor O, Felson D, Guermazi A, Roemer F, Lewis CE, Segal N, Torner J, Cooke TD, Hietpas J, Lynch J, Nevitt M. The role of varus and valgus alignment in the initial development of knee cartilage damage by MRI: the MOST study. Ann Rheum Dis. 2013 Feb;72(2):235-40. Epub 2012 May 1.
46. Watkins MA, Riddle DL, Lamb RL, Personius WJ. Reliability of goniometric measurements and visual estimates of knee range of motion obtained in a clinical setting. Phys Ther. 1991 Feb;71(2):90-6, discussion :96-7.