Varus Thrust and Incident and Progressive Knee Osteoarthritis.
ABSTRACT: OBJECTIVE:To determine if varus thrust, a bowing out of the knee during gait (i.e., the first appearance or worsening of varus alignment during stance), is associated with incident and progressive knee osteoarthritis (OA), we undertook an Osteoarthritis Initiative ancillary study. We further considered hypothesized associations adjusted for static alignment, anticipating some attenuation. METHODS:Gait was observed for the presence of thrust by 1 of 2-3 examiners per study site at 4 sites. In eligible knees, incident OA was defined as subsequent incident Kellgren/Lawrence grade ?2, whole- and partial-grade medial joint space narrowing (JSN), and annualized loss of joint space width (JSW); progression was defined as medial JSN and JSW loss. Outcome measures were assessed for up to 7 years of follow-up. Analyses were knee-level, using multivariable logistic and linear regression with generalized estimating equations to account for between-limb correlation. RESULTS:The incident OA sample included 4,187 knees (2,610 persons); the progression sample included 3,421 knees (2,284 persons). In knees with OA, thrust was associated with progression as assessed by each outcome measure, with adjustment for age, sex, body mass index, and pain on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale. In knees without OA, varus thrust was not associated with incident OA or other outcomes. After adjustment for alignment, the thrust-progression association was attenuated, but an independent association persisted for partial-grade JSN and JSW loss outcome models. WOMAC pain and alignment were consistently associated with all outcome measures. Within the stratum of varus knees, thrust was associated with an increased risk of progression. CONCLUSION:Varus thrust visualized during gait is associated with knee OA progression and should be a target of intervention development.
Project description:<h4>Background</h4>Cartilage morphometry based on magnetic resonance images (MRIs) is an emerging outcome measure for clinical trials among patients with knee osteoarthritis (KOA). However, current methods for cartilage morphometry take many hours per knee and require extensive training on the use of the associated software. In this study we tested the feasibility, reliability, and construct validity of a novel osteoarthritis cartilage damage quantification method (Cartilage Damage Index [CDI]) that utilizes informative locations on knee MRIs.<h4>Methods</h4>We selected 102 knee MRIs from the Osteoarthritis Initiative that represented a range of KOA structural severity (Kellgren Lawrence [KL] Grade 0 - 4). We tested the intra- and inter-tester reliability of the CDI and compared the CDI scores against different measures of severity (radiographic joint space narrowing [JSN] grade, KL score, joint space width [JSW]) and static knee alignment, both cross-sectionally and longitudinally.<h4>Results</h4>Determination of the CDI took on average14.4 minutes (s.d. 2.1) per knee pair (baseline and follow-up of one knee). Repeatability was good (intra- and inter-tester reliability: intraclass correlation coefficient >0.86). The mean CDI scores related to all four measures of osteoarthritis severity (JSN grade, KL score, JSW, and knee alignment; all p values < 0.05). Baseline JSN grade and knee alignment also predicted subsequent 24-month longitudinal change in the CDI (p trends <0.05). During 24 months, knees with worsening in JSN or KL grade (i.e. progressors) had greater change in CDI score.<h4>Conclusions</h4>The CDI is a novel knee cartilage quantification method that is rapid, reliable, and has construct validity for assessment of medial tibiofemoral osteoarthritis structural severity and its progression. It has the potential to addresses the barriers inherent to studies requiring assessment of cartilage damage on large numbers of knees, and as a biomarker for knee osteoarthritis progression.
Project description:To explore the association of baseline trabecular bone structure with incident tibiofemoral (TF) osteoarthritis (OA) and with increase in joint space narrowing (JSN) score.The Multicenter Osteoarthritis Study (MOST) includes subjects with or at risk for knee OA. Knee radiographs were scored for Kellgren-Lawrence (KL) grade and JSN at baseline, 30, 60 and 84 months. Knees (KL ? 1) at baseline were assessed for incident OA (KL ? 2) and increases in JSN score. For each knee image at baseline, a variance orientation transform method (VOT) was applied to subchondral tibial bone regions of medial and lateral compartments. Seventeen fractal parameters were calculated per region. Associations of each parameter with OA incidence and with medial and lateral JSN increases were explored using logistic regression. Analyses were stratified by digitized film (DF) vs computer radiography (CR) and adjusted for confounders.Of 894 knees with CR and 1158 knees with DF, 195 (22%) and 303 (26%) developed incident OA. Higher medial bone roughness was associated with increased odds of OA incidence at 60 and 84 months and also, medial and lateral JSN increases (primarily vertical). Lower medial and lateral anisotropy was associated with increased odds of medial and lateral JSN increase. Compared to DF, CR had more associations and also, similar results at overlapping scales.Baseline trabecular bone texture was associated with incident radiographic OA and increase of JSN scores independently of risk factors for knee OA. Higher roughness and lower anisotropy were associated with increased odds for radiographic OA change.
Project description:The pathogenesis of osteoarthritis (OA) includes both mechanical and inflammatory features. Studies have implicated synovial fluid uric acid (UA) as a potential OA biomarker, possibly reflecting chondrocyte damage. Whether serum UA levels reflect/contribute to OA is unknown. We investigated whether serum UA levels predict OA progression in a non-gout knee OA population.Eighty-eight patients with medial knee OA (body mass index [BMI] <33 kg/m2 ) but without gout were studied. Baseline serum UA levels were measured in previously banked serum samples. At 0 and 24 months, patients underwent standardized weight-bearing fixed-flexion posteroanterior knee radiography to determine joint space width (JSW) and Kellgren/Lawrence grades. Joint space narrowing (JSN) was calculated as the change in JSW from 0 to 24 months. Twenty-seven patients underwent baseline contrast-enhanced 3T knee magnetic resonance imaging for assessment of synovial volume.Serum UA levels correlated with JSN values in both univariate (r?=?0.40, P?<?0.01) and multivariate (r?=?0.28, P?=?0.01) analyses. There was a significant difference in mean JSN after dichotomization at a serum UA cut point of 6.8 mg/dl, the solubility point for serum urate, even after adjustment (JSN of 0.90 mm for a serum UA ?6.8 mg/dl and 0.31 mm for a serum UA <6.8 mg/dl; P?<?0.01). Baseline serum UA levels distinguished progressors (JSN >0.2 mm) and fast progressors (JSN >0.5 mm) from nonprogressors (JSN ?0.0 mm) in multivariate analyses (area under the receiver operating characteristic curve 0.63 [P?=?0.03] and 0.62 [P?=?0.05], respectively). Serum UA levels correlated with the synovial volume (r?=?0.44, P?<?0.01), a possible marker of JSN, although this correlation did not persist after controlling for age, sex, and BMI (r?=?0.13, P?=?0.56).In non-gout patients with knee OA, the serum UA level predicted future JSN and may serve as a biomarker for OA progression.
Project description:Diabetes has been proposed as a factor involved in the pathogenesis of osteoarthritis (OA). Currently, there is a lack of research evaluating the prospective impact of diabetes on OA structural outcomes. In this study, we assessed the effects of medication-treated diabetes on incidence and progression of knee OA. We analysed longitudinal data from the multi-center, longitudinal, prospective observational Osteoarthritis Initiative (OAI) study. The main outcomes were radiographic OA incidence (development of Kellgren-Lawrence grade 2 with joint space narrowing, JSN) and progression (increase in semiquantitative JSN or a new knee replacement). For the study of incidence, we selected participants with KL <2 or /KL?=?2 without JSN at baseline (incidence sample). To evaluate progression, we selected participants with baseline JSN <3 (progression sample). We used generalized estimating equations (GEE) logistic regression with adjustment for potential confounders to evaluate the effects of medication-treated diabetes on knee OA incidence and progression. We studied 3725 knees (3498 non-diabetic and 228 diabetic) in the incidence sample and 3594 knees (3335 non-diabetic and 259 diabetic) in the progression sample. Medication-treated diabetes did not have an effect on knee OA incidence (odds ratio, OR 0.53, 95% confidence interval, CI 0.23-1.5). There was an independent association between medication-treated diabetes and reduced progression of knee OA [OR 0.66, 95% CI (0.44-0.98)]. Medication-treated diabetes has no effect on knee OA incidence but reduces knee OA progression. The role of diabetes and anti-diabetic drugs in knee OA progression needs further exploration.
Project description:OBJECTIVE:To evaluate systemic inflammatory biomarkers in symptomatic knee osteoarthritis (OA) and their association with radiographic and biochemical OA progression. METHODS:Lipopolysaccharide (LPS) binding protein (LBP), soluble Toll-like receptor 4 (sTLR4) and interleukin 6 (IL-6) were measured in plasma of 431 knee OA patients from the doxycycline (DOXY) trial at baseline and 18 months. Plasma lipopolysaccharide and lipopolysaccharide binding protein (LBP) were also measured at 12 months. As a biochemical indicator of disease activity and OA progression, urinary (u) C-telopeptide of Type II collagen (uCTX-II) was measured in samples collected at baseline and 18 months. Change over 16 months in radiographic tibiofemoral joint space width (JSW in mm) and joint space narrowing (JSN?0.5 mm) were used to indicate radiographic OA progression. Change over 18 months for uCTX-II was used as a secondary outcome. Both univariate and multivariable regression analyses were performed to test the association between Z-score transformed biomarkers and outcomes. RESULTS:Baseline LBP and time-integrated concentration (TIC) of LBP over 12 and 18 months were associated with worsening joint space width (JSW) (parameter estimates: -0.1 to -0.07) and JSN (OR: 1.32 to 1.42) adjusting for treatment group, age, body mass index (BMI) and corresponding baseline radiographic measures. Baseline sTLR4 and TIC over 18 months were associated with change in uCTX-II over 18 months (adjusted parameter estimates: 0.0017 to 0.0020). Results were not modified by treatment with doxycycline. CONCLUSION:Plasma LBP and sTLR4 were associated with knee OA progression over 16-18 months. These results lend further support for a role of systemic low-grade inflammation in the pathogenesis of knee OA progression.
Project description:OBJECTIVE:Static alignment influences knee loading and predicts osteoarthritis (OA) progression. Periarticular bone is important in dispersing forces across the knee, and there is substantial evidence for molecular crosstalk between cartilage and subchondral bone. The aim of this study was to evaluate the relationship between periarticular trabecular bone morphology and bone mineral density (BMD) and knee alignment in OA. METHODS:This was a cross-sectional analysis of participants in the Osteoarthritis Initiative Bone Ancillary Study. Dual x-ray absorptiometry (DXA) was performed to measure tibial periarticular bone mineral density (paBMD). Magnetic resonance imaging of knee trabecular bone was performed to calculate the apparent bone volume fraction (aBVF), apparent trabecular number (aTbN), apparent trabecular spacing (aTbSp), and apparent trabecular thickness (aTbTh). Static alignment was assessed by measuring the hip-knee-ankle (HKA) angle on long-limb films. RESULTS:The study group comprised 436 participants (mean ± SD age 65.4 ± 9.2 years, 46% female, mean ± SD body mass index 29.6 ± 4.6 kg/m2 ), 71% of whom had OA. Correlations between the HKA angle and medial:lateral paBMD, medial paBMD, aBVF, aTbN, aTbTh, and aTbSp were -0.63, -0.34, -0.29, -0.32, -0.22, and 0.30, respectively. More varus alignment was associated with higher medial:lateral paBMD, medial paBMD, aBVF, aTbN, aTbTh, and lower aTbSp. In OA knees, the results were more pronounced. In non-OA knees, the most consistent association was with medial:lateral paBMD. CONCLUSION:Static alignment was associated with medial:lateral paBMD in all knees and with medial paBMD and trabecular morphometry in OA knees only. Aberrant knee loading may lead to increased relative subchondral bone density, which is partly related to a higher aBVF and a greater number of thicker trabeculae with smaller intertrabecular spacing. Knee DXA may be a useful early biomarker of knee OA.
Project description:OBJECTIVES:Knee osteoarthritis (OA) onset and progression has been defined with transitions in Kellgren-Lawrence (KL) grade or Osteoarthritis Research Society International (OARSI) Joint Space Narrowing (JSN) grade. We quantitatively describe one-year transitions in KL grade and JSN, using fixed joint space width (fJSW), among knees with or at risk of OA. METHODS:Radiographic assessments from the Osteoarthritis Initiative (OAI) were used to identify transitions in KLG and JSN grade between consecutive annual visits. The fJSW was measured in the medial and lateral compartments. The distribution of change in fJSW for KLG and JSN transitions were described, and mean change in fJSW was estimated using mixed models. RESULTS:KL grade and JSN scores were available for about 20,000 annual transitions from 6047 knees contributed by 3389 participants. Knees that remained stable in KL or OARSI-JSN over 1 year had mean medial fJSW loss between -0.06 and -0.19 mm/year. Transition from KL grade 0 to 1, 0 to 2, and KL 1 to 2 were similar with respect to mean medial fJSW loss (0.18-0.28 mm). Greatest annual changes in medial fJSW corresponded to KL 0 to 3 (1.62 mm), KL 2 to 4 (1.23 mm) and JSN 0 to 2 (1.85 mm). CONCLUSIONS:Anchoring quantitatively measured loss of joint space width to transitions in KL grade and JSN provides reference values based on traditional definitions of knee OA onset and progression.
Project description:To compare the prevalence of medial and lateral patellofemoral (PF) cartilage damage in three large osteoarthritis (OA) studies and determine the relationship of this damage to varus, neutral and valgus knee alignment.In the Boston OA of the Knee, Framingham OA and Multicenter OA studies, MRIs were read for cartilage morphology at the medial and lateral patella and trochlea femoris using Whole-Organ MRI Scores (WORMS). WORMS scores ?2 (any cartilage defect), ?3 (areas of partial thickness loss), ?4 (diffuse partial thickness loss) and ?5 (extensive full thickness loss) were all variously considered as thresholds to identify damage that may indicate OA. Full-limb radiographs were measured for mechanical alignment, and varus (<-2°), neutral (-2° to 2°) and valgus (>2°) knees were identified.The prevalence of medial PF cartilage damage exceeded that of lateral damage in all three studies and according to nearly every threshold. Only among severely involved knees (WORMS ?4 or ?5) did the prevalence of lateral PF cartilage damage approximate that of medial damage. The high prevalence of medial PF damage persisted in all strata of knee alignment. Even among knees with valgus alignment, the prevalence of lateral PF cartilage damage equalled or surpassed that of medial PF damage only when the threshold was specific to severely involved knees.Medial PF cartilage damage is at least as prevalent within these older adult populations as lateral PF cartilage damage.
Project description:OBJECTIVE:Osteoarthritis (OA) of the knee causes significant morbidity and current medical treatment is limited to symptom relief, while therapies able to slow structural damage remain elusive. This study was undertaken to evaluate the effect of glucosamine and chondroitin sulfate (CS), alone or in combination, as well as celecoxib and placebo on progressive loss of joint space width (JSW) in patients with knee OA. METHODS:A 24-month, double-blind, placebo-controlled study, conducted at 9 sites in the United States as part of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), enrolled 572 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence [K/L] grade 2 or grade 3 changes and JSW of at least 2 mm at baseline). Patients with primarily lateral compartment narrowing at any time point were excluded. Patients who had been randomized to 1 of the 5 groups in the GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The minimum medial tibiofemoral JSW was measured at baseline, 12 months, and 24 months. The primary outcome measure was the mean change in JSW from baseline. RESULTS:The mean JSW loss at 2 years in knees with OA in the placebo group, adjusted for design and clinical factors, was 0.166 mm. No statistically significant difference in mean JSW loss was observed in any treatment group compared with the placebo group. Treatment effects on K/L grade 2 knees, but not on K/L grade 3 knees, showed a trend toward improvement relative to the placebo group. The power of the study was diminished by the limited sample size, variance of JSW measurement, and a smaller than expected loss in JSW. CONCLUSION:At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW loss as compared with placebo. However, knees with K/L grade 2 radiographic OA appeared to have the greatest potential for modification by these treatments.
Project description:OBJECTIVE:To test whether radiographically normal knees with contralateral radiographic knee osteoarthritis (OA), but without contralateral trauma history, display greater cartilage thickness loss than knees from subjects with bilaterally radiographically normal knees. METHODS:828 radiographically normal knees (Kellgren Lawrence grade [KLG] 0) from the Osteoarthritis Initiative [OAI] were studied; 150 case knees displayed definite radiographic knee OA (KLG ? 2) contralaterally, and had MRI double echo steady state (DESS) images available at 12 and 48 month follow-up. 678 reference knees displayed KLG0 at the contralateral side. Cartilage thickness change was determined in femorotibial subregions and location-independent cartilage thinning scores were computed. Case and reference knees were compared using ANCOVA. RESULTS:Of the 150 KLG0 case knees, 108 had a contralateral KLG2 knee (50 without, and 58 with joint space narrowing [JSN]), 31 a KLG3 and 11 a KLG4 knee. The cartilage thinning score tended to be greater in case than reference knees; the cartilage thinning score in KLG0 case knees with contralateral radiographic JSN (-858 ?m; [95% confidence interval -1016, -701 ?m]) was significantly greater (P = 0.0012) than that in bilaterally KLG0 reference knees (-634 ?m; [-673, -596 ?m]), whereas KLG0 knees with contralateral KLG2 without JSN only showed relatively small thinning scores (-530 ?m, [-631, -428 ?m]). Region-specific analysis suggested greater rates of cartilage loss in case than in reference knees in the lateral, rather than medial, femorotibial compartment. CONCLUSIONS:Radiographically normal knees with contralateral JSN may serve as a human model of early OA, for testing disease modifying drugs in clinical trials designed to prevent cartilage loss before the onset of radiographic change. CLINICALTRIALS. GOV IDENTIFICATION:NCT00080171.