Rates of change and sensitivity to change in cartilage morphology in healthy knees and in knees with mild, moderate, and end-stage radiographic osteoarthritis: results from 831 participants from the Osteoarthritis Initiative

Objective

To study the longitudinal rate of (and sensitivity to) change of knee cartilage thickness across defined stages of radiographic osteoarthritis (OA), specifically healthy knees and knees with end‐stage radiographic OA.

Methods

One knee of 831 Osteoarthritis Initiative participants was examined: 112 healthy knees, without radiographic OA or risk factors for knee OA, and 719 radiographic OA knees (310 calculated Kellgren/Lawrence [K/L] grade 2, 300 calculated K/L grade 3, and 109 calculated K/L grade 4). Subregional change in thickness was assessed after segmentation of weight‐bearing femorotibial cartilage at baseline and 1 year from coronal magnetic resonance imaging (MRI). Regional and ordered values (OVs) of change were compared by baseline radiographic OA status.

Results

Healthy knees displayed small changes in plates and subregions (±0.7%; standardized response mean [SRM] ±0.15), with OVs being symmetrically distributed close to zero. In calculated K/L grade 2 knees, changes in cartilage thickness were small (<1%; minimal SRM ?0.22) and not significantly different from healthy knees. Knees with calculated K/L grade 3 showed substantial loss of cartilage thickness (up to ?2.5%; minimal SRM ?0.35), with OV1 changes being significantly (P < 0.05) greater than those in healthy knees. Calculated K/L grade 4 knees displayed the largest rate of loss across radiographic OA grades (up to ?3.9%; minimal SRM ?0.51), with OV1 changes also significantly (P < 0.05) greater than in healthy knees.

Conclusion

MRI‐based cartilage thickness showed high rates of loss in knees with moderate and end‐stage radiographic OA, and small rates (indistinguishable from healthy knees) in mild radiographic OA. From the perspective of sensitivity to change, end‐stage radiographic OA knees need not be excluded from longitudinal studies using MRI cartilage morphology as an end point.

     

Greater rates of cartilage loss in painful knees than in pain‐free knees after adjustment for radiographic disease stage: Data from the Osteoarthritis Initiative

Objective

To investigate whether rates of cartilage loss differ in knees with frequent baseline pain versus those without pain, after adjustment for radiographic osteoarthritis (OA) stage.

Methods

One knee in each of 718 Osteoarthritis Initiative participants was examined: 310 with calculated Kellgren/Lawrence (K/L) grade 2, 299 with calculated K/L grade 3, and 109 with calculated K/L grade 4. Twelve‐month change in (subregional) cartilage thickness was assessed by magnetic resonance imaging. Change in cartilage thickness in the central subregion of the weight‐bearing medial femoral condyle and ordered value 1 (OV1) were selected as primary end points. Frequent knee symptoms were defined as pain, aching, or stiffness on most days of at least 1 month during the previous year.

Results

The mean 12‐month rate of change in cartilage thickness in the central subregion of the medial femoral condyle was −12 μm (standardized response mean [SRM] −0.15) in knees without pain (n = 146), −27 μm (SRM −0.25) in those with infrequent pain (n = 255), and −54 μm (SRM −0.32) in those with frequent pain (n = 317). Rates differed significantly between frequently painful knees and pain‐free knees after adjustment for age, sex, body mass index, and calculated K/L grade (P = 0.011, R² = 2.6%, partial R² for frequent pain = 1.4%). Similar results were found in stratified samples of calculated K/L grade 2/calculated K/L grade 3 knees, and in analyses restricted to knees with consistent pain frequency between baseline and followup. OV1 results showed similar trends but were not significant.

Conclusion

Knees with frequent pain display greater rates of medial cartilage loss longitudinally than knees without pain, with or without adjustment or stratification for radiographic disease stage. Enrollment of participants with frequent knee pain in clinical trials can increase the observed rate of structural progression (i.e., cartilage loss) and sensitivity to change.

     

Effect of alignment of the medial tibial plateau and X‐ray beam on apparent progression of osteoarthritis in the standing anteroposterior knee radiograph

Objective

Previous studies of knee osteoarthritis (OA) have yielded variable estimates of the rate of joint space narrowing (JSN) in the standing anteroposterior (AP) radiograph, due largely to longitudinal changes in the alignment of the medial tibial plateau (MTP) and x‐ray beam. To characterize this bias, we examined serial radiographs of subjects with knee OA in population‐based and clinical OA cohorts from 3 locations in the United States and the United Kingdom.

Methods

Radiographic features of knee OA (e.g., osteophytosis, JSN) and MTP alignment in 428 OA knees were evaluated by consensus of 2 readers. Alignment was considered satisfactory if the anterior and posterior margins of the MTP were superimposed within 1 mm. Readers were blinded to subject identity, and films were read in random order. The minimum medial joint space width was also measured manually (standard error of repeated measurements 0.20 mm) in serial knee images.

Results

Only 14% of serial radiographs exhibited alignment of the MTP in both images. In OA knees with satisfactory alignment in both images, the mean rate of JSN over 2–3 years (0.26 mm/year) was significantly larger (P = 0.004) than that in OA knees with misalignment in 1 or both radiographs and was 86% more rapid than the mean JSN in all OA knees. Moreover, the within‐group standard deviation of JSN was significantly smaller among knees with reproduced alignment of the MTP than in knees in which misalignment occurred in 1 or both images (P = 0.006).

Conclusion

Poor standardization of knee positioning in serial standing AP radiographs in previous studies of OA progression has obscured the rate and variability of articular cartilage loss in subjects with knee OA. True JSN (i.e., JSN that is not attributable to longitudinal changes in the alignment of the MTP with the x‐ray beam in serial radiographic examinations) may occur more rapidly, and with less between‐subject variability, than that previously thought to be characteristic of knee OA.

     

Individual magnetic resonance imaging and radiographic features of knee osteoarthritis in subjects with unilateral knee pain: The Health,Aging, and Body Composition Study

Objective

Strong associations between radiographic features of knee osteoarthritis (OA) and pain have been demonstrated in persons with unilateral knee symptoms. This study was undertaken to compare radiographic and magnetic resonance imaging (MRI) features of knee OA and assess their ability to discriminate between painful and nonpainful knees in persons with unilateral symptoms.

Methods

The study population included 283 individuals ages 70–79 years with unilateral knee pain who were enrolled in the Health, Aging, and Body Composition Study, a study of weight‐related diseases and mobility. Radiographs of both knees were read for Kellgren/Lawrence (K/L) grade and individual radiographic features, and 1.5T MRIs were assessed using the Whole‐Organ Magnetic Resonance Imaging Score. The association between structural features and pain was assessed using a within‐person case–control design and conditional logistic regression. Receiver operating characteristic (ROC) analysis was then used to test the discriminatory performance of structural features.

Results

In conditional logistic analyses, knee pain was significantly associated with both radiographic features (any joint space narrowing grade ≥1) (odds ratio 3.20 [95% confidence interval 1.79–5.71]) and MRI features (any cartilage defect scored ≥2) (odds ratio 3.67 [95% confidence interval 1.49–9.04]). However, in most subjects, MRI revealed osteophytes and cartilage and bone marrow lesions in both knees, and using ROC analysis, no individual structural feature discriminated well between painful and nonpainful knees. The best‐performing MRI feature (synovitis/effusion) was not significantly more informative than K/L grade ≥2 (P = 0.42).

Conclusion

In persons with unilateral knee pain, MRI and radiographic features were associated with knee pain, confirming that structural abnormalities in the knee have an important role in the etiology of pain. However, no single MRI or radiographic finding performed well in discriminating between painful and nonpainful knees. Further work is needed to examine how structural and nonstructural factors influence knee pain.

     

Prevalence of magnetic resonance imaging–defined atrophic and hypertrophic phenotypes of knee osteoarthritis in a population‐based cohort

Objective

To describe the association of osteophytes with concomitant cartilage damage, assessed using semiquantitative magnetic resonance imaging (MRI), and to describe the prevalence of atrophic and hypertrophic phenotypes of tibiofemoral knee osteoarthritis (OA) in a population‐based cohort.

Methods

Participants of the Framingham Knee Osteoarthritis Study were examined with a 1.5T MRI system using triplanar intermediate‐weighted fat‐suppressed sequences. Cartilage and osteophytes were assessed using the Whole‐Organ Magnetic Resonance Imaging Score (WORMS). Overall prevalence of knees with severe cartilage damage and concomitant osteophyte status were described. Odds ratios for the likelihood of having severe cartilage damage according to osteophyte size were estimated using a logistic regression model. An additional analysis assessed knees according to phenotype in relation to radiographic OA status, with the atrophic phenotype being defined as knees with absent or only tiny osteophytes (WORMS grade ≤2 on a 0–7 scale) in all 10 tibiofemoral subregions but exhibiting severe cartilage damage, and the hypertrophic phenotype being defined as knees with large osteophytes (WORMS grade ≥5 on a 0–7 scale) but lacking substantial cartilage damage.

Results

In this study, 1,597 knees of 1,248 subjects were included. Of the 67 knees with large osteophytes, 54 (80.6%) exhibited severe cartilage damage. The risk of severe cartilage damage increased markedly with increasing osteophyte size. Twenty‐one knees (1.3%) showed an atrophic phenotype. Only 3 knees (0.2%) exhibited a hypertrophic phenotype.

Conclusion

The majority of knees with severe tibiofemoral cartilage damage exhibited moderate to large osteophytes. The larger the osteophyte, the more likely was the presence of severe cartilage damage. A minority of knees exhibited the atrophic phenotype, which also included knees without radiographic OA. The hypertrophic phenotype was extremely rare.

     

Comparison of radiographic joint space width with magnetic resonance imaging cartilage morphometry: Analysis of longitudinal data from the osteoarthritis initiative

Objective

Magnetic resonance imaging (MRI) and radiography are established imaging modalities for the assessment of knee osteoarthritis (OA). The objective of our study was to compare the responsiveness of radiographic joint space width (JSW) with MRI‐derived measures of cartilage morphometry for OA progression in participants from the Osteoarthritis Initiative (OAI).

Methods

This study examined the baseline and 12‐month visits of a subset of 150 subjects from the OAI. Measurement of radiographic JSW was facilitated by the use of automated software that delineated the femoral and tibial margins of the joint. Measures of medial compartment minimum JSW and JSW at fixed locations were compared with cartilage morphometry measures derived from MRI. The results were stratified by Kellgren/Lawrence (K/L) scale grade and by tibiofemoral anatomic axis angle. In order to examine the relative responsiveness of various techniques, we calculated the standardized response mean (SRM) between the 2 visits.

Results

The SRM for radiographic JSW measured at the optimal location was ?0.32 compared with ?0.39 for the most responsive MRI measure. For the subgroup with a K/L scale grade of 2 or 3, the most responsive SRM values were ?0.34 for radiographic JSW and ?0.42 for MRI.

Conclusion

Our study demonstrates that new measures using a software analysis of digital knee radiographic images are comparable with MRI in detecting OA progression, and potentially superior when considering the cost‐effectiveness of the 2 imaging modalities.

     

Magnetic resonance imaging‐based cartilage loss in painful contralateral knees with and without radiographic joint space narrowing: Data from the osteoarthritis initiative

Objective

To determine by magnetic resonance imaging (MRI), whether knees with advanced radiographic disease (medial joint space narrowing [mJSN]) encounter greater longitudinal cartilage loss than contralateral knees with earlier disease (no or less mJSN).

Methods

Participants were selected from 2,678 cases in the Osteoarthritis Initiative, based on exhibition of bilateral pain, body mass index >25 (kg/m²), mJSN in 1 knee, no or less mJSN in the contralateral knee, and no lateral JSN in both knees. Eighty participants (mean ± SD age 60.6 ± 9.1 years) fulfilled these criteria. Medial tibial and femoral cartilage morphology was analyzed from the baseline and the 1‐year followup MRI (sagittal double echo at steady state by 3.0T) of both knees by experienced readers blinded to the time point and mJSN status.

Results

Knees with more radiographic mJSN displayed greater medial cartilage loss (?80 μm) assessed by MRI than contralateral knees with less mJSN (?57 μm). The difference reached statistical significance in participants with an mJSN grade of 2 or 3 (P = 0.005–0.08), but not in participants with an mJSN grade of 1 (P = 0.28–0.98). In knees with more mJSN, cartilage loss increased with higher grades of mJSN (P = 0.003 in the medial femur). Knees with an mJSN grade of 2 or 3 displayed greater cartilage loss in the weight‐bearing medial femur than in the posterior femur or in the medial tibia (P = 0.048).

Conclusion

Knees with advanced mJSN displayed greater cartilage loss than contralateral knees with less mJSN. These data suggest that radiography can be used to stratify fast structural progressors, and that MRI cartilage thickness loss is more pronounced at advanced radiographic disease stage.

     

Risk factors for symptomatic knee osteoarthritis fifteen to twenty‐two years after meniscectomy

Objective

To evaluate the influence of age, sex, body mass index (BMI), extent of meniscal resection, cartilage status, and knee load on the development of radiographically evident osteoarthritis (OA) of the knee and knee symptoms after meniscal resection.

Methods

We evaluated 317 patients with no cruciate ligament injury (mean ± SD age 54 ± 11 years) who had undergone meniscal resection 15–22 years earlier (followup rate 70%), with radiographic and clinical examination. The Knee injury and Osteoarthritis Outcome Score was used to quantify knee‐related symptoms. Sixty‐eight unoperated subjects identified from national population records were included as a reference group.

Results

Symptomatic radiographic OA (corresponding to Kellgren/Lawrence grade ≥2) was present in 83 of 305 operated knees (27%) and 7 of 68 control knees (10%) (relative risk 2.6, 95% confidence interval [95% CI] 1.3–6.1). Patients who had undergone total meniscectomy and subjects with obesity (BMI ≥30) had a greater likelihood of tibiofemoral radiographic OA than those who had undergone partial meniscal resection and those with a BMI <25, respectively. Furthermore, degenerative meniscal tear, intraoperative cartilage changes, and lateral meniscectomy were associated with radiographic OA more frequently than were longitudinal tear, absence of cartilage changes, and medial meniscectomy, respectively. Symptomatic tibiofemoral or patellofemoral radiographic OA was associated with obesity, female sex, and degenerative meniscal tear.

Conclusion

Contributing risk factors for OA development after meniscal resection are similar to risk factors for common knee OA. Systemic factors and local biomechanical factors interact. Obesity, female sex, and preexisting early‐stage OA are features associated with poor self‐reported and radiographic outcome. Partial meniscal resection is associated with less radiographic OA over time than is total meniscectomy.

     

Delayed gadolinium‐enhanced magnetic resonance imaging of cartilage in knee osteoarthritis: Findings at different radiographic stages of disease and relationship to malalignment

Objective

Delayed gadolinium‐enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) is used to examine the distribution of glycosaminoglycan in cartilage. This study sought to characterize dGEMRIC in the evaluation of knee osteoarthritis (OA) according to various radiographically determined disease parameters, and to examine the relationship between alignment of the knee joint and the lateral:medial dGEMRIC ratio.

Methods

Thirty‐one patients with knee OA underwent MRI with a dGEMRIC protocol at 1.5T. Semiflexed knee radiographs and full‐limb radiographs were also obtained for assessment of alignment.

Results

Compartments of the knee joint without joint space narrowing had a higher dGEMRIC index than those with any level of narrowing (mean 408 msec versus 365 msec; P = 0.001). In knees with 1 unnarrowed (spared) and 1 narrowed (diseased) compartment, the dGEMRIC index was greater in the spared versus the diseased compartment (mean 395 msec versus 369 msec; P = 0.001). In spared compartments, there was a trend toward a lower dGEMRIC index with increasing Kellgren/Lawrence (K/L) radiographic severity grade; the spared compartments of knees with a K/L grade 2 had a higher dGEMRIC index than those of knees with a K/L grade 4 (mean 425 msec versus 371 msec; P < 0.05). There was a range of dGEMRIC values in the spared compartments within a given K/L grade, demonstrating biochemical differentiation of disease in radiographically comparable compartments. Almost all compartments with narrowing had dGEMRIC indices of <400 msec. Valgus‐aligned knees tended to have lower dGEMRIC values laterally, and varus‐aligned knees tended to have lower dGEMRIC values medially; as a continuous variable, alignment correlated with the lateral:medial dGEMRIC ratio (Pearson's R = 0.43, P = 0.02).

Conclusion

The biochemical information provided by dGEMRIC scans may augment radiography by improving the differentiation of disease status within a given radiographic grade, especially in early OA.

     

Type I collagen α1 Sp1 transcription factor binding site polymorphism is associated with reduced risk of hip osteoarthritis defined by severe joint space narrowing in elderly women

Objective

A common G/T substitution at an Sp1 binding site in intron 1 of the COL1A1 gene has been reported to be associated with reduced bone mineral density and increased risk of osteoporotic fracture. The purpose of this study was to examine whether there is an association between COL1A1 Sp1 polymorphism and radiographic osteoarthritis (OA) of the hip in elderly women in the Study of Osteoporotic Fractures.

Methods

Radiographic hip OA status of subjects was defined by the presence of 1 of the following criteria in either hip: a joint space narrowing (JSN) score of ≥3, a Croft summary grade of ≥3, or both definite (score ≥2) osteophytes and JSN in the same hip. Cases of radiographic OA of the hip were further subdivided into those with JSN score ≥3 and those with a femoral osteophyte score ≥2 and JSN score ≤2. The COL1A1 Sp1 polymorphism was genotyped using allele‐specific kinetic polymerase chain reaction in 4,746 women. Multivariate logistic regression was performed to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results

Radiographic OA of the hip was present in 571 women (12%). Of these patients, 325 (57%) had severe JSN (score ≥3), and 131 (23%) had moderate or moderate‐to‐severe femoral osteophytosis (score ≥2). There was no association of the T/T genotype with either radiographic hip OA or radiographic hip OA characterized by osteophytosis. For radiographic OA of the hip characterized by moderate‐to‐severe JSN, the odds of disease were significantly reduced among subjects with the T/T compared with the G/G genotype (OR 0.30, 95% CI 0.11–0.81, P = 0.02) and did not change after adjustment for potential confounders (OR 0.36, 95% CI 0.13–0.99, P = 0.048).

Conclusion

The T/T genotype of the COL1A1 Sp1 polymorphism was associated with a reduced risk of radiographic OA of the hip characterized by JSN. This association should be confirmed in other populations to determine if mechanistic studies are warranted.

     

Change in joint space width: Hyaline articular cartilage loss or alteration in meniscus?

Objective

To explore the relative contribution of hyaline cartilage morphologic features and the meniscus to the radiographic joint space.

Methods

The Boston Osteoarthritis of the Knee Study is a natural history study of symptomatic knee osteoarthritis (OA). Baseline and 30‐month followup assessments included knee magnetic resonance imaging (MRI) and fluoroscopically positioned weight‐bearing knee radiographs. Cartilage and meniscal degeneration were scored on MRI in the medial and lateral tibiofemoral joints using a semiquantitative grading system. Meniscal position was measured to the nearest millimeter. The dependent variable was joint space narrowing (JSN) on the plain radiograph (possible range 0–3). The predictor variables were MRI cartilage score, meniscal degeneration, and meniscal position measures. We first conducted a cross‐sectional analysis using multivariate regression to determine the relative contribution of meniscal factors and cartilage morphologic features to JSN, adjusting for body mass index (BMI), age, and sex. The same approach was used for change in JSN and change in predictor variables.

Results

We evaluated 264 study participants with knee OA (mean age 66.7 years, 59% men, mean BMI 31.4 kg/m²). The results from the models demonstrated that meniscal position and meniscal degeneration each contributed to prediction of JSN, in addition to the contribution by cartilage morphologic features. For change in medial joint space, both change in meniscal position and change in articular cartilage score contributed substantially to narrowing of the joint space.

Conclusion

The meniscus (both its position and degeneration) accounts for a substantial proportion of the variance explained in JSN, and the change in meniscal position accounts for a substantial proportion of change in JSN.

     

Selection of knee radiographs for trials of structure‐modifying drugs in patients with knee osteoarthritis: A prospective,longitudinal study of lyon schuss knee radiographs with the definition of adequate alignment of the medial tibial plateau

Objective

The quality of medial tibial plateau (MTP) alignment, which is assessed by measuring the distance between the anterior and posterior margins (intermargin distance [IMD]) of the tibial plateau, and the reproducibility of alignment in serial radiographs are suggested to be key elements in determining the accuracy and sensitivity to change in knee radiographs in patients with tibiofemoral osteoarthritis (OA). We evaluated the influence of both MTP alignment and radiograph superimposition on the sensitivity to change in radiographic joint space narrowing (JSN) in knee OA.

Methods

The study group comprised 106 patients with knee pain (73 with OA). Lyon schuss radiographic images of the knee were obtained twice (at baseline [month 0] and 12 months later), using a standardized radiographic procedure. Computerized measurement of the IMD for the assessment of MTP alignment was compared with the grading of MTP alignment by 2 observers using a 5‐point scale (excellent, good, fair, poor, bad). To obtain the rate of JSN, computerized measurement of the joint space width was performed at month 0 and month 12. The sensitivity of the joint space width to change over 1 year was evaluated by the standardized response mean (SRM).

Results

The mean (±SD) IMD was 1.2 ± 0.9 mm. The correlation between scoring and computer measurement of MTP alignment was highly significant. The cutoff value for satisfactory alignment (excellent or good) was an IMD of ≤1.2 mm. In OA knees, the mean (±SD) annual rate of JSN and the SRM were statistically higher in knees with an IMD of ≤1.2 mm at both month 0 and month 12 (0.34 ± 0.50 mm and 0.68, respectively) than in knees with an IMD of >1.2 mm at month 0 and/or month 12.

Conclusion

The quality of MTP alignment at both baseline and the end point highly influences the sensitivity to change in radiographic JSN in knee OA. To obtain relevant data, only radiographs showing an IMD of ≤1.2 mm at both baseline and the end point would have to be analyzed in studies of structure‐modifying OA drugs.

     

Valgus malalignment is a risk factor for lateral knee osteoarthritis incidence and progression: Findings from the multicenter osteoarthritis study and the osteoarthritis initiative

Objective

To study the effect of valgus malalignment on knee osteoarthritis (OA) incidence and progression.

Methods

We measured the mechanical axis from long limb radiographs from the Multicenter Osteoarthritis Study (MOST) and the Osteoarthritis Initiative (OAI) to define limbs with valgus malalignment (mechanical axis of ≥1.1° valgus) and examined the effect of valgus alignment versus neutral alignment (neither varus nor valgus) on OA structural outcomes. Posteroanterior radiographs and knee magnetic resonance (MR) images were obtained at the time of the long limb radiograph and at followup examinations. Lateral progression was defined as an increase in joint space narrowing (on a semiquantitative scale) in knees with OA, and incidence was defined as new lateral narrowing in knees without radiographic OA. We defined lateral cartilage damage and progressive meniscal damage as increases in cartilage or meniscus scores at followup on the Whole‐Organ Magnetic Resonance Imaging Score scale (for the MOST) or the Boston Leeds Osteoarthritis Knee Score scale (for the OAI). We used logistic regression with adjustment for age, sex, body mass index, and Kellgren/Lawrence grade, as well as generalized estimating equations, to evaluate the effect of valgus alignment versus neutral alignment on disease outcomes. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results

We studied 5,053 knees (881 valgus) of subjects in the MOST cohort and 5,953 knees (1,358 valgus) of subjects in the OAI cohort. In both studies, all strata of valgus malalignment, including 1.1° to 3° valgus, were associated with an increased risk of lateral disease progression. In knees without radiographic OA, valgus alignment >3° was associated with incidence (e.g., in the MOST, adjusted OR 2.5 [95% CI 1.0–5.9]). Valgus alignment >3° was also associated with cartilage damage on MR imaging in knees without OA (e.g., in the OAI, adjusted OR 5.9 [95% CI 1.1–30.3]).We found a strong relationship of valgus malalignment with progressive lateral meniscal damage.

Conclusion

Valgus malalignment increases the risk of knee OA radiographic progression and incidence as well as the risk of lateral cartilage damage. It may cause these effects, in part, by increasing the risk of meniscal damage.

     

Frizzled‐related protein variants are risk factors for hip osteoarthritis

Objective

To examine the association of the Arg200Trp and Arg324Gly variants of FRZB with the risk and phenotype of radiographic osteoarthritis (OA) of the hip and serum levels of Frizzled‐related protein (FRP) in a prospective cohort of elderly Caucasian women.

Methods

Radiographic hip OA status of patients was defined by the presence of severe joint space narrowing (JSN) (feature grade ≥3), a summary grade ≥3, or definite osteophytes (grade ≥2) and JSN (grade ≥2) in the same hip. Genotypes were obtained in 569 patients with radiographic OA of the hip and in 1,317 and 4,136 controls for the Arg200Trp and Arg324Gly variants, respectively. Serum FRP levels were measured by enzyme‐linked immunosorbent assay. Multivariate logistic regression was performed.

Results

The minor allele frequency for the Arg200Trp polymorphism was 0.12 in the control group compared with 0.14 in the group with radiographic OA of the hip (P = 0.12), and the minor allele frequency for the Arg324Gly variant was 0.083 in the control group compared with 0.088 in the group with radiographic OA of the hip (P = 0.63). The multilocus genotypes available in 1,886 subjects suggested that inheritance of both minor alleles was a risk factor for developing OA characterized by JSN (P < 0.01). Patients with radiographic OA of the hip who were homozygous for the Arg200Trp minor allele had higher serum FRP levels than controls who were homozygous for the major allele.

Conclusion

Our data confirm findings of another study, that a rare haplotype with both Arg200Trp and Arg324Gly FRZB variants contributes to the genetic susceptibility to hip OA among Caucasian women, and that these polymorphisms may contribute to increased serum levels of proteins as biomarkers of OA.

     

One‐year change in radiographic joint space width in patients with unilateral joint space narrowing: Data from the osteoarthritis initiative

Objective

To examine the rate of joint space width (JSW) loss in both knees of patients with unilateral medial joint space narrowing (JSN) at baseline.

Methods

Cases were selected from a pool of 2,678 subjects enrolled in the Osteoarthritis Initiative cohort. Inclusion criteria for the present study were unilateral medial JSN, bilateral frequent knee pain, and body mass index (BMI) ≥25 kg/m². Baseline and 1‐year fixed flexion radiographs of both knees were read (blinded to time point) using an automated algorithm for minimum JSW and JSW at 4 fixed locations in the medial compartment.

Results

Sixty‐seven participants met the inclusion criteria: 43 women and 24 men, with mean ± SD age 60 ± 9 years and mean ± SD BMI 31 ± 4 kg/m². Thirty‐seven subjects (55%) had ≥1 definite tibiofemoral osteophyte. The average progression in no‐JSN knees was comparable with that in JSN knees (approximately ?0.2 mm/year). However, JSW change was more variable in no‐JSN knees, resulting in standardized response means (SRMs; the mean/SD) of approximately ?0.24 in no‐JSN knees versus approximately ?0.41 in JSN knees on average at the 4 fixed locations, and SRMs of ?0.24 and ?0.35, respectively, for minimum JSW. Young age and high BMI were associated with increased progression, especially in JSN knees.

Conclusion

JSN and no‐JSN knees progressed at a comparable rate, but a wider distribution of JSW change in no‐JSN knees resulted in a poorer sensitivity to change in these knees.

     

Association of biomarkers with pre–radiographically defined and radiographically defined knee osteoarthritis in a population‐based study

Objective

To evaluate 10 biomarkers in magnetic resonance imaging (MRI)–determined, pre–radiographically defined osteoarthritis (pre‐ROA) and radiographically defined OA (ROA) in a population‐based cohort of subjects with symptomatic knee pain.

Methods

Two hundred one white subjects with knee pain, ages 40–79 years, were classified into OA subgroups according to MRI‐based cartilage (MRC) scores (range 0–4) and Kellgren/Lawrence (K/L) grades of radiographic severity (range 0–4): no OA (MRC score 0, K/L grade <2), pre‐ROA (MRC score ≥1, K/L grade <2), or ROA (MRC score ≥1, K/L grade ≥2). Urine and serum samples were assessed for levels of the following biomarkers: urinary biomarkers C‐telopeptide of type II collagen (uCTX‐II), type II and types I and II collagen cleavage neoepitopes (uC2C and uC1,2C, respectively), and N‐telopeptide of type I collagen, and serum biomarkers sC1,2C, sC2C, C‐propeptide of type II procollagen (sCPII), chondroitin sulfate 846 epitope, cartilage oligomeric matrix protein, and hyaluronic acid. Multicategory logistic regression was performed to evaluate the association of OA subgroup with individual biomarker levels and biomarker ratios, adjusted for age, sex, and body mass index.

Results

The risk of ROA versus no OA increased with increasing levels of uCTX‐II (odds ratio [OR] 3.12, 95% confidence interval [95% CI] 1.35–7.21), uC2C (OR 2.13, 95% CI 1.04–4.37), and uC1,2C (OR 2.07, 95% CI 1.06–4.04), and was reduced in association with high levels of sCPII (OR 0.53, 95% CI 0.30–0.94). The risk of pre‐ROA versus no OA increased with increasing levels of uC2C (OR 2.06, 95% CI 1.05–4.01) and uC1,2C (OR 2.06, 95% CI 1.12–3.77). The ratios of type II collagen degradation markers to collagen synthesis markers were better than individual biomarkers at differentiating the OA subgroups, e.g., the ratio of [uCTX‐II][uC1,2C] to sCPII was associated with a risk of ROA versus no OA of 3.47 (95% CI 1.34–9.03) and a risk of pre‐ROA versus no OA of 2.56 (95% CI 1.03–6.40).

Conclusion

Different cartilage degradation markers are associated with pre‐ROA than are associated with ROA, indicating that their use as diagnostic markers depends on the stage of OA. Biomarker ratios contrasting cartilage degradation with cartilage synthesis are better able to differentiate OA stages compared with levels of the individual markers.

     

Meniscal tear in knees without surgery and the development of radiographic osteoarthritis among middle‐aged and elderly persons: The multicenter osteoarthritis study

Objective

Although partial meniscectomy is a risk factor for the development of knee osteoarthritis (OA), there is a lack of evidence that meniscal damage that is not treated with surgery would also lead to OA, suggesting that surgery itself may cause joint damage. Furthermore, meniscal damage is common. The aim of this study was to evaluate the association between meniscal damage in knees without surgery and the development of radiographic tibiofemoral OA.

Methods

We conducted a prospective case–control study nested within the observational Multicenter Osteoarthritis Study, which included a sample of men and women ages 50–79 years at high risk of knee OA who were recruited from the community. Patients who had no baseline radiographic knee OA but in whom tibiofemoral OA developed during the 30‐month followup period were cases (n = 121). Control subjects (n = 294) were drawn randomly from the same source population as cases but had no knee OA after 30 months of followup. Individuals whose knees had previously undergone surgery were excluded. Meniscal damage was defined as the presence of any medial or lateral meniscal tearing, maceration, or destruction.

Results

Meniscal damage at baseline was more common in case knees than in control knees (54% versus 18%; P < 0.001). The model comparing any meniscal damage with no meniscal damage (adjusted for baseline age, sex, body mass index, physical activity, and mechanical knee alignment) yielded an odds ratio of 5.7 (95% confidence interval 3.4–9.4).

Conclusion

In knees without surgery, meniscal damage is a potent risk factor for the development of radiographic OA. These results highlight the need for better understanding, prevention, and treatment of meniscal damage.

     

Varus–valgus alignment in the progression of patellofemoral osteoarthritis

Objective

To test the hypotheses that lateral patellofemoral (PF) osteoarthritis (OA) progression is more common than medial PF OA progression, that varus alignment increases the likelihood of medial PF OA progression, and that valgus alignment increases the likelihood of lateral PF OA progression.

Methods

Patients with knee OA were recruited from the community. Inclusion criteria were definite osteophyte presence (i.e., Kellgren/Lawrence radiographic grade ≥2) in 1 or both knees and at least some difficulty with knee‐requiring activity. Varus–valgus alignment (the angle formed by the intersection of the mechanical axes of the femur and tibia) was measured on a full‐limb radiograph at baseline. To assess PF OA progression, weight‐bearing skyline views of the PF compartment were obtained at baseline and at 18‐month followup. Knees with the highest grade of PF narrowing at baseline were excluded from analysis. Logistic regression and generalized estimating equations were used; odds ratios (ORs) were adjusted for age, sex, and body mass index.

Results

Lateral PF OA progression, which occurred in 120 (30%) of 397 knees, was more common than was medial PF OA progression, which occurred in 60 knees (15%). Varus (versus nonvarus) alignment increased the odds of PF OA progression isolated to the medial PF compartment (adjusted OR 1.85, 95% confidence interval [95% CI] 1.00–3.44). Valgus alignment increased the odds of PF OA progression isolated to the lateral compartment (adjusted OR 1.64, 95% CI 1.01–2.66).

Conclusion

Lateral PF OA progression was more common than medial progression, and varus–valgus alignment influenced the likelihood of PF OA progression in a compartment‐specific manner. Interventions that address the stress imposed by alignment on the PF compartments may delay PF OA progression and should be developed.

     

Biomarkers of incident radiographic knee osteoarthritis: Do they vary by chronic knee symptoms?

Objective

To explore the ability of osteoarthritis (OA)–related biomarkers to predict incident radiographic knee OA in a large sample of African American and Caucasian men and women.

Methods

Baseline levels of serum cartilage oligomeric matrix protein (COMP), hyaluronan (HA), high‐sensitivity C‐reactive protein (hsCRP), and keratan sulfate (KS) and baseline and followup radiographs were available for 353 knees without baseline osteophyte formation and for 446 knees without baseline joint space narrowing (JSN). Cox models estimated the hazard ratio (HR) and 95% confidence interval (95% CI) for incident knee OA for a 1‐unit increase in the ln of each biomarker, with adjustment for age, race, sex, body mass index, and knee OA of the contralateral limb. Report of chronic knee symptoms was explored as a modifier of the association.

Results

The hazard of incident knee osteophytes (HR 2.16 [95% CI 1.39–3.37]) and incident JSN (HR 1.82 [95% CI 1.15–2.89]) increased with higher baseline ln(COMP) levels. The hazard of incident knee JSN increased with higher ln(HA) levels (HR 1.46 [95% CI 1.14–1.87]). Baseline ln(hsCRP) and ln(KS) did not predict incident knee outcomes. HRs per unit increase in ln(COMP), ln(HA), and ln(KS) were higher among knees with chronic symptoms than among those without symptoms.

Conclusion

Higher baseline ln(COMP) and ln(HA) levels were associated with incident knee OA over an average followup period of 6.3 years. These results represent detection of a molecular stage of OA prior to radiographic manifestations. Further exploration is needed to determine how chronic knee symptoms modify the biomarker–incident knee OA association.

     

Estrogen receptor α gene haplotype is associated with radiographic osteoarthritis of the knee in elderly men and women

Objective

Genetic influences have been shown to play an important role in the etiology of osteoarthritis (OA), but the genes involved are ill‐defined. We studied the association between polymorphisms in the estrogen receptor α (ERα) gene and the prevalence of radiographic OA of the knee.

Methods

The study group comprised 1,483 men and women from the Rotterdam Study. Direct molecular haplotyping was used to determine the relationship between 2 polymorphisms in the ERα gene (the Pvu II and Xba I restriction fragment–length polymorphisms). Radiographs of the knee were evaluated according to the Kellgren/Lawrence (K/L) score, along with separate scores for osteophytosis and joint space narrowing.

Results

Three different haplotype alleles were identified: px (54%), PX (34%), and Px (12%). Allele PX was associated with an increased prevalence of radiographic knee OA (K/L score ≥2). The prevalence of radiographic OA was 22% among subjects without allele PX, 24% among those carrying 1 copy, and 35% among subjects carrying 2 copies. The corresponding odds ratios, after adjustment for confounding factors, were 1.3 (95% confidence interval [95% CI] 0.9–1.7) for heterozygotes and 2.2 (95% CI 1.5–3.4) for homozygotes. Separate analyses for men and women showed similar risk estimates. The association appeared to be driven by osteophytosis and is somewhat consistent with the association observed in previous studies of these polymorphisms in relation to OA.

Conclusion

This study shows that polymorphisms in the ERα gene are associated with radiographic OA of the knee, and in particular with osteophytosis, in both elderly men and elderly women.