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Objective: To explore whether the risk of incident tibiofemoral (TF) osteoarthritis (OA) in the radiographically normal contralateral knee of overweight/obese women with unilateral knee OA is mediated by malalignment and/or preceded by increased turnover of subchondral bone., Methods: We used data of post hoc analyses from a randomized controlled trial. Cross-sectional analyses evaluated the baseline association between frontal plane alignment and bone turnover in the medial TF compartment in 78 radiographically normal contralateral knees. Longitudinal analyses ascertained whether incident radiographic OA (TF osteophyte formation within 30 months) was associated with malalignment and/or increased bone turnover at baseline. Alignment subcategories (varus/neutral/valgus) were based on the anatomic axis angle. (99m)Tc-methylene diphosphonate uptake in a late-phase bone scan was quantified in regions of interest in the medial tibia (MT) and medial femur (MF) and adjusted for uptake in a reference segment of the ipsilateral tibial shaft (TS)., Results: MF and MT uptake in varus contralateral knees was 50-55% greater than in the TS. Adjusted MT uptake in varus contralateral knees was significantly greater than that in neutral and valgus contralateral knees (mean 1.55 versus 1.38 and 1.43, respectively; P < 0.05). Among 69 contralateral knees followed longitudinally, 22 (32%) developed TF OA. Varus angulation was associated with a marginally significant increase in the odds of incident OA (adjusted odds ratio 3.98, P = 0.067)., Conclusion: While the small sample size limited our ability to detect statistically significant risk factors, these data suggest that the risk of developing bilateral TF OA in overweight/obese women may be mediated by varus malalignment., (Copyright © 2011 by the American College of Rheumatology.)

Objective: To estimate the extent to which varus malalignment, a source of abnormal intra-articular stresses in the medial tibiofemoral compartment and risk factor for progression of knee osteoarthritis (OA), may have diminished the structure-modifying benefit of doxycycline in knee OA., Methods: Post hoc treatment group comparisons from a randomized, placebo-controlled trial of the effect of doxycycline (100mg, twice daily) on medial joint space narrowing (JSN) in subgroups of varus and non-varus OA knees. Subjects (N=379 with X-ray follow-up) were obese 45-64-year-old women with unilateral knee OA at baseline. JSN was measured manually in semiflexed anteroposterior (AP) radiographs acquired with standardized fluoroscopic positioning. The anatomic-axis angle (AAA) was measured in each baseline radiograph and transformed to an estimate of the mechanical-axis angle (MAA(est)) using a validated regression equation. Knees with MAA(est)<178 degrees were classified as varus., Results: In our original comparison with placebo, doxycycline slowed the rate of medial JSN in OA knees by 38% at 16 months and by 33% at 30 months. Among non-varus OA knees, 16-month JSN in the doxycycline group was 44% slower than in the placebo group (0.09 vs 0.16 mm/year, P=0.080), and 39% slower at month 30 (0.10 vs 0.17 mm/year, P=0.026). JSN in varus knees (0.20-0.27 mm/year) was more rapid than in non-varus knees (P=0.083) and unaffected by doxycycline., Conclusion: Varus malalignment negated the slowing of structural progression of medial-compartment OA by doxycycline. To our knowledge, this is the first report documenting that static varus angulation can negate a pharmacologic structure-modifying effect., (Copyright 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To examine whether urine concentrations of type II collagen neoepitope (uTIINE) distinguish subjects with progressive radiographic and/or symptomatic knee osteoarthritis (OA) from those with stable disease., Methods: Subjects were 120 obese middle-aged women with unilateral knee OA who participated in a 30-month randomized-controlled trial of structure modification with doxycycline, in which a standardized semiflexed anteroposterior view of the knee was obtained at baseline, 16 months and 30 months. Subjects were selected from a larger sample to permit a priori comparisons between 60 OA progressors and 60 nonprogressors, as defined by joint space narrowing (JSN) in the medial tibiofemoral compartment. Each group contained 30 subjects who exhibited clinically significant increases in knee pain over 30 months and 30 who did not. Urine samples were obtained every 6 months for determination of the creatinine (Cr)-adjusted uTIINE concentration., Results: Baseline uTIINE levels were unrelated to JSN in the placebo group. However, among subjects in the active treatment group, a 1-standard deviation increment in baseline uTIINE (68 ng/mM Cr) was associated with a marginally significant, two-fold increase in the odds of progression of JSN (odds ratio 2.04, 95% confidence interval 0.98-4.28). The within-subject mean of uTIINE values at baseline, 6 months and 12 months was associated with concurrent JSN measured at 16 months (0.10mm of JSN per 69 ng/mM Cr, P=0.008). Similar results were seen in the interval between months 16 and 30 and in analyses using the maximum of intercurrent uTIINE levels., Conclusion: Baseline uTIINE was not a consistent predictor of JSN in subjects with knee OA. However, serial measurements of uTIINE reflect concurrent JSN.

Objective: To determine whether urinary concentrations of the cross linked C-telopeptide of type II collagen (CTx-II) distinguish subjects with progressive radiographic or symptomatic knee osteoarthritis from those with stable disease., Subjects: were 120 obese women with unilateral knee osteoarthritis who participated in a 30 month, randomised, placebo controlled trial of structure modification by doxycycline, in which a standardised semiflexed anteroposterior view of the knee was obtained at baseline and 30 months. Subjects were selected from a larger sample to permit comparisons of urinary CTx-II levels between 60 progressors and 60 non-progressors with respect to medial joint space narrowing. Each group contained 30 subjects who, across five semi-annual assessments, reported on at least two occasions an increase of > or =20% in 50 ft walk pain (minimum = 1 cm on a 10 cm visual analogue scale), relative to the previous visit. The remainder reported no increases in knee pain. Urine samples were obtained semi-annually for determination of the CTx-II and creatinine concentrations., Results: In an analysis of the placebo group only, the frequency of radiographic progressors in the upper and middle tertiles (48% and 60%, respectively) of the baseline CTx-II distribution was not significantly different than that in the lower tertile (64%). These results were unchanged after inclusion of data from subjects in the doxycycline group. Furthermore, serial CTx-II levels did not distinguish subjects with progressive radiographic or symptomatic knee osteoarthritis from those with stable disease., Conclusions: In this pilot study, urinary CTx-II concentration was not a useful biomarker of osteoarthritis progression.

Objective: We examined whether plasma concentrations of biomarkers of the collagenase cleavage of type II collagen (C2C), types I and II collagens (C1,2C), type II collagen synthesis (CPII), proteoglycan aggrecan turnover (CS846), and the ratio C2C:CPII would distinguish subjects with progressive radiographic osteoarthritis (OA) from those with stable disease., Methods: Subjects were 120 obese middle-aged women with unilateral knee OA who participated in a 30-month clinical trial of structure modification with doxycycline, in which a standardized semiflexed anteroposterior view of the knee was obtained at baseline, 16 months, and 30 months. Subjects were selected from a larger sample to permit a priori comparisons between 60 OA progressors and 60 nonprogressors, as defined by joint space narrowing (JSN) in the medial tibiofemoral compartment. Each group contained 30 subjects who exhibited clinically significant increases in knee pain over 30 months and 30 who did not. Plasma samples were obtained every 6 months for determination of C2C, CPII, CS846, and C1,2C., Results: None of the biomarkers was a significant predictor of progression of JSN. Over the interval from baseline to 16 months, the mean and the maximum of the intercurrent CS846 values were significantly associated with JSN (i.e., 0.12-0.14 mm of JSN per SD decrease in mean or maximum CS846; p < 0.01). The mean of serial CS846 levels was related to JSN also during the interval between months 16 and 30., Conclusion: Markers of type II collagen synthesis/degradation and of proteoglycan aggrecan turnover were not predictive of JSN in knee OA in this pilot study. However, serial concentrations of proteoglycan aggrecan epitope CS846 were associated with JSN during both the intervals studied.

Objective: To evaluate risk factors for progressive radiographic changes of knee osteoarthritis using a standardised fluoroscopically assisted protocol for knee radiography., Subjects: (n = 319) with unilateral or bilateral knee osteoarthritis underwent a fluoroscopically standardised x ray examination of the knees (semiflexed AP view) and assessment with the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index at baseline and at 30 months. Tibiofemoral joint space narrowing and osteophytosis were graded in randomly ordered serial radiographs by consensus of two readers using standard pictorial atlases., Results: Progression of joint space narrowing was inversely related to baseline joint space width (odds ratio (OR) = 0.67/1.4 mm (95% confidence interval (CI), 0.49 to 0.91)) and positively associated with patellofemoral osteoarthritis (OR = 3.36 (1.83 to 6.18)). Osteophyte growth was inversely related to overall severity (number and size) of osteophytosis at baseline (OR = 0.47/1.8 points on a 12 point osteophyte severity scale (95% CI, 0.33 to 0.66)), and directly related to baseline stiffness (OR = 1.39/2.1 WOMAC scale points (95% CI, 1.09 to 1.77)) and the presence of patellofemoral osteoarthritis at baseline (OR = 2.31 (1.37 to 3.88))., Conclusions: Progression of both joint space narrowing and osteophyte growth are predicted by the severity of the respective radiographic features of osteoarthritis at baseline and by the presence of patellofemoral osteoarthritis. In addition, knee stiffness is a risk factor for progressive osteophyte growth.

Objective: To determine whether baseline or serial plasma concentrations of stromelysin (matrix metalloproteinase 3 [MMP-3]) protein might distinguish subjects with progressive radiographic knee osteoarthritis (OA) from those with stable disease., Methods: Subjects were 120 women with unilateral knee OA who participated in a 30-month randomized, placebo-controlled trial of structure modification with doxycycline. Anteroposterior views of both knees in a semiflexed position were obtained at baseline, 16 months, and 30 months. Subjects were selected to obtain comparisons of plasma MMP-3 levels between 60 progressors (21 taking doxycycline, 39 taking placebo) and 60 nonprogressors (30 taking doxycycline, 30 taking placebo) with respect to medial joint space narrowing (JSN) in the index knee. Each group consisted of 30 subjects who exhibited significant increases in knee pain. Blood samples were obtained semiannually for MMP-3 assay., Results: Subjects in the placebo group whose MMP-3 concentration was in the upper tertile of the baseline distribution showed a 4-fold increase in the odds of progression of JSN as compared with the lower tertile (odds ratio 4.12, P = 0.037). Baseline MMP-3 levels were unrelated to knee pain. The within-subject mean of serial MMP-3 concentrations was associated with concurrent JSN in the placebo group over the 0-16-month interval (b = 0.18 mm/SD increase in the mean MMP-3, P < 0.01) and over the 16-30-month interval (b = 0.15, P < 0.05). Similar evidence of concurrent validity was found in the placebo group for the maximum of intercurrent MMP-3 values., Conclusion: The baseline MMP-3 level was a significant predictor of JSN in this pilot study. Moreover, serial plasma MMP-3 levels reflected concurrent JSN in the placebo group over the 30-month period of observation.

Objective: To compare the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a baseline late-phase bone scan and assessments of the radiographic and symptomatic severity of knee osteoarthritis (OA) at baseline as predictors of loss of articular cartilage thickness, as reflected in joint space narrowing (JSN) in the medial tibiofemoral compartment., Methods: Subjects (174 obese women, 45-64 yrs of age, with unilateral knee OA) were a subset of a larger cohort who participated in a placebo controlled trial of a disease modifying OA drug. Uptake of technetium medronate (99mTc-MDP) in anteroposterior (AP) and lateral views of a late-phase bone scan was measured at baseline in a region of interest drawn around the medial tibia, and was adjusted for (i.e., expressed as a ratio to) uptake in a reference segment of the tibial shaft, which served as an internal standard. Each subject underwent a fluoroscopically standardized radiographic examination of the knees (semiflexed AP view) and a pain assessment with the WOMAC OA Index at baseline, 16 months, and 30 months., Results: Controlling for baseline joint space width and treatment group, multiple linear regression models showed that the adjusted 99mTc-MDP uptake at baseline was a significant predictor of joint space narrowing (JSN) in the index knee at 16 months (b = 0.180, p = 0.015) and 30 months (b = 0.221, p = 0.049). In the contralateral knee, uptake was only a marginally significant predictor of JSN at 30 months (b = 0.246, p = 0.083). Uptake in the upper and middle tertiles of the distribution predicted subjects who would exhibit JSN >/= 0.50 mm within 16 months with 65% sensitivity (PPV 23%) and 36% specificity (NPV 77%). In contrast, a prediction rule based solely on the presence of Kellgren-Lawrence grade 3 OA severity and greater than median WOMAC Pain score identified progressors with 65% sensitivity (PPV 48%) and 79% specificity (NPV 88%)., Conclusion: Although the level of adjusted 99mTc-MDP uptake was significantly associated with JSN in knees with established radiographic OA, baseline bone scintigraphy is inferior to the radiographic severity of OA and knee pain (alone or in combination) as a predictor of loss of articular cartilage in subjects with knee OA.

Objective: To ascertain the extent to which the "Chingford knee" (that is, contralateral knee of the middle aged, obese, female patient with unilateral knee osteoarthritis (OA)) is a high risk radiographically normal joint as opposed to a knee in which radiographic changes of OA would have been apparent in a more extensive radiographic examination., Methods: Subjects were 180 obese women, aged 45-64 years, with unilateral knee OA, based on the standing anteroposterior (AP) view. Subjects underwent a series of radiographic knee examinations: semiflexed AP, supine lateral, and Hughston (patellofemoral (PF)) views. Bony changes of OA were graded by consensus of two readers. Medial tibiofemoral joint space width was measured by digital image analysis. Knee pain was assessed by the WOMAC OA Index after washout of all OA pain drugs., Results: Despite the absence of evidence of knee OA in the standing AP radiograph, only 32 knees (18%) were radiographically normal in all other views. Ninety four knees (52%) exhibited TF knee OA in the semiflexed AP and/or lateral view. PF OA was seen in 121 knees (67%). Subjects with PF OA reported more severe knee pain than those without PF OA (mean WOMAC scores 9.9 v 8.3, p<0.05)., Conclusion: The Chingford knee is not a radiographically normal joint. The high rate of incidence of OA reported previously for this knee ( approximately 50% within two years) may also reflect progression of existing OA or changes in radioanatomical positioning at follow up that showed evidence of stable disease that was present at baseline.

Objective: To estimate the reproducibility of the semiflexed metatarsophalangeal (MTP) view in repeat radiographic examinations of the knee of subjects with osteoarthritis (OA) with respect to radioanatomic alignment of the medial tibial plateau and the central x-ray beam and the precision of measurements of minimum medial tibiofemoral joint space width (JSW)., Methods: Thirty-eight subjects with definite knee OA underwent 2 semiflexed MTP examinations on the same day. Radioanatomic alignment of the medial tibial plateau and the x-ray beam (distance between anterior and posterior margins of the plateau) was measured manually (Lequesne method). Manual measurements of the JSW in repeat radiographs also were obtained. The reproducibility of JSW measurements was estimated by the method of Bland and Altman., Results: Only 29% of the initial semiflexed MTP radiographs exhibited satisfactory radioanatomic alignment (intermargin distance < or =1 mm). However, intermargin distances in initial and repeat radiographs were highly correlated (r = 0.86, P < 0.01). In 89% of knees, the intermargin distance in the first examination was reproduced (+/- 1 mm) in the second examination. The standard error of measurement (mean of within-knee standard deviations of repeat JSW values) was 0.30 mm. The magnitude of discrepancy between repeat measurements of JSW was related positively to overall radiographic severity of knee OA (P < 0.05)., Conclusion: The semiflexed MTP protocol affords highly reproducible radioanatomic positioning of the knee, although misalignment of the medial tibial plateau and the x-ray beam occurs in >70% of cases. Precision of measurement of JSW in the semiflexed MTP view approaches that associated with fluoroscopically assisted positioning protocols. However, the consequences of poor, albeit reproducible, alignment of the knee in serial semiflexed MTP radiographs in longitudinal studies of OA progression are currently unknown.