Cartilage Loss In Knee Osteoarthritis Research Articles

Sprifermin: a recombinant human fibroblast growth factor 18 for the treatment of knee osteoarthritis

ABSTRACT Introduction Osteoarthritis (OA) is a serious and incurable disease leading the disability. Surgical treatment is the last but not necessarily the best approach for patients with high risks and costs. However, there are no disease-modifying OA drugs (DMOADs) developed for the disease so far, leaving a huge unmet need for drug treatments. Sprifermin is a recombinant human fibroblast growth factor 18 (rhFGF18) and has been confirmed to have anabolic effects on articular cartilage, which makes it a promising DMOAD. Areas covered The content of this review includes overview of the market, discovery and development, molecular mechanism, preclinical studies, clinical efficacy, safety, and tolerability of sprifermin. It examines the potential of sprifermin as a disease modifying drug for the treatment of knee OA. Expert opinion Sprifermin could be one of the most promising DMOADs, especially for cartilage phenotype. Current studies show good tolerability and no safety concerns. Well-designed phase 3 clinical trials are required to examine its effects on symptoms and cartilage loss in knee OA.

Association of baseline and change in tibial and femoral cartilage thickness and development of widespread full-thickness cartilage loss in knee osteoarthritis – data from the Osteoarthritis Initiative

To investigate whether baseline cartilage thickness and its longitudinal change are associated with incident widespread full-thickness cartilage loss (wsFTCL) in knee osteoarthritis, and whether there are optimal cut-off values for predicting wsFTCL. Central medial tibial (cMT) and femoral (cMF) cartilage were assessed using quantitative magnetic resonance imaging data from the Osteoarthritis Initiative cohort (N=600 knees). Cartilage thickness was measured at baseline and 12 months. wsFTCL was defined semi-quantitatively (scores 2 and 3 from the MRI Osteoarthritis Knee Score) and its incidence at 24 months recorded. Logistic regression was used to determine the odds of developing wsFTCL for baseline and for each 0.1mm decrease in cartilage thickness. Cut-off values were investigated using the minimal-p method and area under the Receiver Operating Characteristic curves (AUC). Incident wsFTCL was observed in 66 (12%) and 73 (14%) knees in cMT and cMF, respectively. Lower baseline cMT and cMF cartilage thickness values were associated with wsFTCL (OR=1.20; 95% CI: 1.11, 1.28 and OR=1.15; 95% CI: 1.06 to 1.24, respectively). Optimal cut-off AUCs for the tibia and femur were 0.64 (0.57-0.70) and 0.63 (0.57-0.69), respectively. Longitudinal decrease in femoral, but not tibial, cartilage thickness was associated with incident wsFTCL (OR=1.77; 95% CI: 1.30 to 2.40); optimal cut-off AUC 0.65 (95% CI: 0.58-0.72). Lower baseline cMT and baseline/change (decrease) over 12 months in cMF cartilage thickness were associated with incident, location-specific, wsFTCL at 24 months. Optimal cut-off values were relatively low and of uncertain utility for predicting incident wsFTCL.

Location-independent analysis of structural progression of osteoarthritis—Taking it all apart, and putting the puzzle back together makes the difference

The metric accepted by regulatory bodies for determining structural progression in clinical trials of knee osteoarthritis (OA) remains change in radiographic joint space width in the medial femorotibial compartment. However, magnetic resonance imaging has revealed that cartilage loss is spatially heterogeneous, and that it is enigmatic which knee will lose cartilage at which location. Whereas previous reviews have focused on imaging in general, the purpose of this particular perspective is to highlight availability and applications of location-independent analysis methodology in measuring structural progression in epidemiological and interventional clinical trials, and to highlight its specific advantages over existing methodologies. Narrative review/perspective based on a Pubmed search of original articles from 2009 to current. Ordering longitudinal change in subregion cartilage thickness by magnitude and direction, and averaging such ordered values or sums of negative and positive changes across knees is shown to be superior in detecting risk factors and interventional effects on structural progression of knee OA. Further, the methodology permits exploration of cartilage loss and gain simultaneously, phenomena that are missed when measurements are confined to cartilage volume or thickness loss in plates or compartments. Given spatial heterogeneity of cartilage loss in knee OA, location-independent analysis by MRI may provide opportunity for a paradigm shift. The authors recommend use of a location-independent metrices as the structural endpoints in epidemiological and intervention trials, particularly when examining anabolic and catabolic drug effects. Location-independent methods may be translated to analysis of cartilage composition and other articular tissues.

Aspirin is associated with reduced cartilage loss in knee osteoarthritis: Data from a cohort study

ObjectivesAspirin, widely used in the prevention of cardiovascular disease, in low dose, has anti-inflammatory and vasculoprotective effects: both of these processes contribute to the pathogenesis of osteoarthritis. We examined whether use of low dose aspirin affects change in knee cartilage volume in osteoarthritis. MethodsParticipants from the Melbourne osteoarthritis cohort were classified as users and non-users of aspirin, according to baseline use (≤300mg/day). Their knees were imaged twice over 2 years. Tibial cartilage volumes were measured and change calculated. ResultsTwenty one (18%) of 117 eligible participants were aspirin users. Annual change in medial tibial cartilage volume was −43mm3 (95% confidence intervals (CI) −93, 10) in aspirin users and −101mm3 (95% CI −125, −77) in non-users (p=0.043 for difference) after adjusting for age, gender, BMI and radiographic severity. Similar results were seen for annual percentage loss (1.9% vs 5.4%, p=0.034). No difference was observed for lateral tibial cartilage change and annual change (p=0.98, 0.87 respectively) ConclusionLow dose aspirin use was associated with reduced medial tibial cartilage loss over 2 years in people with knee osteoarthritis. This data is hypothesis generating and clinical trials are required to confirm efficacy. If this hypothesis is confirmed, low dose aspirin may be used to reduce the progression of knee osteoarthritis.

An update on risk factors for cartilage loss in knee osteoarthritis assessed using MRI-based semiquantitative grading methods.

Arthroscopy-based semiquantitative scoring systems such as Outerbridge and Noyes' scores were the first to be developed for the purpose of grading cartilage defects. As magnetic resonance imaging (MRI) became available for evaluation of the osteoarthritic knee joint, these systems were adapted for use with MRI. Later on, grading methods such as the Whole Organ Magnetic Resonance Score, the Boston-Leeds Osteoarthritis Knee Score and the MRI Osteoarthritis Knee Score were designed specifically for performing whole-organ assessment of the knee joint structures, including cartilage. Cartilage grades on MRI obtained with these scoring systems represent optimal outcome measures for longitudinal studies, and are designed to enhance understanding of the knee osteoarthritis disease process. The purpose of this narrative review is to describe cartilage assessment in knee osteoarthritis using currently available MRI-based semiquantitative whole-organ scoring systems, and to provide an update on the risk factors for cartilage loss in knee osteoarthritis as assessed with these scoring systems.

Is loss in femorotibial cartilage thickness related to severity of contra-lateral radiographic knee osteoarthritis? – Longitudinal data from the Osteoarthritis Initiative

Anti-catabolic disease modifying drugs (DMOADs) aim to reduce cartilage loss in knee osteoarthritis (KOA). Testing such drugs in clinical trials requires sufficient rates of loss in the study participants to occur, preferably at a mild disease stage where cartilage can be preserved. Here we analyze a "progression" model in mild radiographic KOA (RKOA), based on contra-lateral radiographic status. We studied 837 participants (62.4 ± 9 yrs; 30 ± 4.9 kg/m²; 61.8% women) from the Osteoarthritis Initiative (OAI) with mild to moderate RKOA (Kellgren Lawrence grade [KLG] 2-3) and with/without Osteoarthritis Research Society International (OARSI) atlas radiographic joint space narrowing (JSN). These had quantitative measurements of subregional femorotibial cartilage thickness from magnetic resonance imaging (MRI) at baseline and 1-year follow-up. They were stratified by contra-lateral knee status: no (KLG 0/1), definite (KLG2) and moderate RKOA (KLG 3/4). KLG2 knees with JSN and moderate contra-lateral RKOA had (P = 0.008) greater maximum subregional cartilage loss -220 μm [95% confidence interval (CI) -255, -184 μm] than those without contra-lateral RKOA -164 μm [-187, -140 μm]. Their rate of subregional cartilage loss was similar and not significantly different (P = 0.61) to that in KLG 3 knees without contra-lateral RKOA (-232 μm; [-266; -198 μm]). The effect of contra-lateral RKOA status was less in KLG2 knees without JSN, and in KLG3 knees. KLG2 knees with JSN and moderate contra-lateral RKOA, display relatively high rates of subregional femorotibial cartilage loss, despite being at a relatively mild stage of RKOA. They may therefore provide a unique opportunity for recruitment in clinical trials that explore the efficacy of anti-catabolic DMOADs on structural progression.

Local Area Cartilage Segmentation: A Semiautomated Novel Method of Measuring Cartilage Loss in Knee Osteoarthritis

To assess the responsiveness and reader time of a novel semiautomated tool to detect knee cartilage loss over 2 years in subjects with knee osteoarthritis. A total of 122 subjects from the Osteoarthritis Initiative progression cohort were selected. A reader used the software method to segment cartilage on double-echo steady-state sequence scans in the medial compartment of the femur from the baseline and 24-month visits. Change in cartilage volume (ΔV) was measured at a fixed weight-bearing (WB) location with respect to the 3-dimensional coordinate system based on cylindrical coordinates. Change was measured for 5 regions of varying WB surface area centered on the fixed point. The average change (ΔV), the SD of ΔV, and the standardized response mean (SRM) are reported. The SRM was −0.52 for the largest region and decreased in magnitude as smaller regions of cartilage were probed. The average evaluation time was <20 minutes per knee compartment, split approximately evenly between a technician and a trained reader. The results establish that measurement of cartilage loss in a local region can be done efficiently and that the resultant measures are responsive to loss of cartilage over time. The coordinate system can potentially be used to objectively examine and establish a consistent location for all knees that is most responsive to change in cartilage volume. This technique can provide rapidly an objective quantitative measure of cartilage loss and could substantially reduce study costs for large trials and data sets.

Aspirin is associated with reduced cartilage loss in knee osteoarthritis: data from a cohort study

Aspirin is associated with reduced cartilage loss in knee osteoarthritis: data from a cohort study

Responsiveness of a semi-automated novel method of measuring cartilage loss in knee osteoarthritis over two years using 3.0T DESS 3D MRI

s / Osteoarthritis and Cartilage 20 (2012) S54–S296 S222 Further, no differences in the mean or SD signal intensity in any of the muscle regions were noted at baseline (data not shown). Changes in ACSAs over 2 years also did not significantly differ between progressor and non-progressor knees (Table 1). When stratifying comparisons for cases with little baseline pain (WOMAC score of 0-1; n1⁄47) vs. those with a score of 5-8 (n1⁄48), the findings were similar (data not shown). Conclusions: Progressor (case) and non-progressor (control) knees in this study were carefully selected from a large subsample, based on two independent measures of structural OA progression (MRI cartilage loss and JSW reduction in X-rays). Further, cases and controls were carefully matched for measures known to be associated with progression or with muscle area. The results of this exploratory study do not provide support that, once radiographic knee OA is established, baseline or longitudinal changes in thigh muscle ACSAs or strength predict (or are associated) with structural progression. 438 EVALUATION OF THE DEPENDENCY OF GLYCOSAMINOGLYCAN (GAG) CHEMICAL EXCHANGE SATURATION TRANSFER (GAGCEST) IMAGING ON CARTILAGE GAG CONTENT IN THE ANKLE AT 3 T B. Schmitt, M. Brix, J. Hofstaetter, R. Windhager, S. Trattnig, S. Domayer. Med. Univ. of Vienna, Vienna, Austria Purpose: This study was performed to evaluate the feasibility of gagCEST imaging in the ankle on a clinical 3-Tesla MR scanner. The dependency of gagCEST signal on cartilage GAG content was investigated by comparison of MRI data with quantitative biochemical assessment of cartilage GAG content. Methods: The study comprised 7 ankle samples from human cadavers, which were examined on a clinical 3 T MR System with a standard knee coil. PDw were acquired with turbo spin-echo (TSE) imaging and fatsat (FS) in the sagittal plane (TE1⁄426ms, TR1⁄44000ms, resolution1⁄40.4x0.4x3mm3). GagCEST imaging was performed using a segmented 3D RF-spoiled gradient-echo (GRE) sequence (TE1⁄43.49ms, TR 1⁄49.1ms, resolution1⁄40.6x0.6x3.3mm3, scan time 10:30 min). Selective RF presaturation was achieved using a series of 3 Gaussian RFPulses with pulse duration sp1⁄4100ms, an interpulse delay sd1⁄410ms and a B1 of 2.6mT. Z-spectra from images were corrected for B0 inhomogeneities on a pixel-by-pixel basis by a smoothing spline method. The asymmetry of the magnetization transfer rate (MTR) as determined by MTRasym (d) 1⁄4 MTR(+d)-MTR(-d) was integrated over the offset range from 0.5 2ppm, which corresponds to the resonance signal distribution from exchangeable GAG -OH protons, and used as signal intensity for gagCEST images. For quantitative biochemical analysis of absolute GAG content in cartilage, as gold standard, the tibial and talar cartilage compartments were divided into three segments (lateral, central, medial) with 1cm width in the sagittal plane (Fig. 1a). In each segment, 5 contiguous cartilage samples were taken, and a GAG assay (Blyscan B3000 GAG Assay) was used to determine absolute GAG content (mg/mg) and water content of the probes. The calculated GAG concentrations were expressed as the relative weight per cartilage wet weight [% GAG/mg WWt]. To compare MRI data to biochemical analysis, cartilage areas were segmented in MR images and gagCEST values were averaged in regions corresponding to the division used for biochemical analysis. The correlation coefficient (r) for gagCEST and biochemical essay was determined using Pearson correlation analysis. To account for individual differences in cartilage water content, which can alter chemical exchange effects, measured gagCEST signals were scaled to the fictive case of 90 % water content in cartilage. Results: All examined ankles showed morphologically intact cartilage on PDw MR images. From the 42 available cartilage samples (7 patients x 2 cartilage surfaces x 3 cartilage segments 1⁄4 42), 4 samples from ankle # 6 were excluded from analysis due to extremely thin (<< 0.8 mm) cartilage in the medial and lateral segments. The remaining 38 data points showed a linear correlation between gagCEST signal intensities and GAG concentrations with r 1⁄4 0.797 if differences in water contents were neglected. If these differences were accounted for, a higher correlation coefficient of r 1⁄40.859 was obtained (Fig. 1b). The average measured gagCEST signal intensity (Fig. 1c) was 5.47 3.52 % (mean SD), and 8.11 5.32 % with normalized water content. The average GAG content as determined by biochemical analysis was 6.49 1.14 % GAG/mg WWt. The relative water content in cartilage had a mean of 68.85 4.54 %.

Clinical, radiographic, molecular and MRI-based predictors of cartilage loss in knee osteoarthritis

ObjectiveTo examine the relationship of baseline clinical, radiographic, molecular and MRI measures with structural progression (subregional MRI-based femorotibial cartilage loss) in knee osteoarthritis (OA).MethodsSingle knees of 75 female participants with...

Varus–valgus alignment: Reduced risk of subsequent cartilage loss in the less loaded compartment

Varus-valgus alignment has been linked to subsequent progression of osteoarthritis (OA) within the mechanically stressed (medial for varus, lateral for valgus) tibiofemoral compartment. Cartilage data from the off-loaded compartment are sparse. The purpose of this study was to examine our hypotheses that neutral and valgus (versus varus) knees each have reduced odds of cartilage loss in the medial subregions and that neutral and varus (versus valgus) knees each have reduced odds of cartilage loss in the lateral subregions. Patients with knee OA underwent knee magnetic resonance imaging at baseline and 2 years. The mean cartilage thickness was quantified within 5 tibial and 3 femoral subregions. We used logistic regression with generalized estimating equations to analyze the relationship between baseline alignment and subregional cartilage loss at 2 years, adjusting for age, sex, body mass index, and disease severity. A reduced risk of cartilage loss in the medial subregions was associated with neutral (versus varus) alignment (external tibial, central femoral, external femoral) and with valgus (versus varus) alignment (central tibial, external tibial, central femoral, external femoral). A reduced risk of cartilage loss in the lateral subregions was associated with neutral (versus valgus) alignment (central tibial, internal tibial, posterior tibial) and with varus (versus valgus) alignment (central tibial, external tibial, posterior tibial, external femoral). Neutral and valgus alignment were each associated with a reduction in the risk of subsequent cartilage loss in certain medial subregions and neutral and varus alignment with a reduction in the risk of cartilage loss in certain lateral subregions. These results support load redistribution as an in vivo mechanism of the long-term alignment effects on cartilage loss in knee OA.

Quantitative Cartilage Imaging in Knee Osteoarthritis

Quantitative measures of cartilage morphology (i.e., thickness) represent potentially powerful surrogate endpoints in osteoarthritis (OA). These can be used to identify risk factors of structural disease progression and can facilitate the clinical efficacy testing of structure modifying drugs in OA. This paper focuses on quantitative imaging of articular cartilage morphology in the knee, and will specifically deal with different cartilage morphology outcome variables and regions of interest, the relative performance and relationship between cartilage morphology measures, reference values for MRI-based knee cartilage morphometry, imaging protocols for measurement of cartilage morphology (including those used in the Osteoarthritis Initiative), sensitivity to change observed in knee OA, spatial patterns of cartilage loss as derived by subregional analysis, comparison of MRI changes with radiographic changes, risk factors of MRI-based cartilage loss in knee OA, the correlation of MRI-based cartilage loss with clinical outcomes, treatment response in knee OA, and future directions of the field.

Can cartilage loss be detected in knee osteoarthritis (OA) patients with 3–6 months' observation using advanced image analysis of 3 T MRI?

Prior investigations of magnetic resonance imaging (MRI) biomarkers of cartilage loss in knee osteoarthritis (OA) suggest that trials of interventions which affect this biomarker with adequate statistical power would require large clinical studies of 1-2 years duration. We hypothesized that smaller, shorter duration, "Proof of Concept" (PoC) studies might be achievable by: (1) selecting a population at high risk of rapid medial tibio-femoral (TF) progression, in conjunction with; (2) high-field MRI (3T), and; (3) using advanced image analysis. The primary outcome was the cartilage thickness in the central medial femur. Multi-centre, non-randomized, observational cohort study at four sites in the US. Eligible participants were females with knee pain, a body mass index (BMI)> or =25 kg/m(2), symptomatic radiographic evidence of medial TF OA, and varus mal-alignment. The 29 participants had a mean age of 62 years, mean BMI of 36 kg/m(2), with eight index knees graded as Kellgren-Lawrence (K&L)=2 and 21 as K&L=3. Eligible participants had four MRI scans of one knee: two MRIs (1 week apart) were acquired as a baseline with follow-up MRI at 3 and 6 months. A trained operator, blind to time-point but not subject, manually segmented the cartilage from the Dual Echo Steady State water excitation MR images. Anatomically corresponding regions of interest were identified on each image by using a three-dimensional statistical shape model of the endosteal bone surface, and the cartilage thickness (with areas denuded of cartilage included as having zero thickness - ThCtAB) within each region was calculated. The percentage change from baseline at 3 and 6 months was assessed using a log-scale analysis of variance (ANOVA) model including baseline as a covariate. The primary outcome was the change in cartilage thickness within the aspect of central medial femoral condyle exposed within the meniscal window (w) during articulation, neglecting cartilage edges [nuclear (n)] (nwcMF x ThCtAB), with changes in other regions considered as secondary endpoints. Anatomical mal-alignment ranged from -1.9 degrees to 6.3 degrees , with mean 0.9 degrees . With one exception, no changes in ThCtAB were detected at the 5% level for any of the regions of interest on the TF joint at 3 or 6 months of follow-up. The change in the primary variable (nwcMF x ThCtAB) from (mean) baseline at 3 months from the log-scale ANOVA model was -2.1% [95% confidence interval (CI) (-4.4%, +0.2%)]. The change over 6 months was 0.0% [95% CI (-2.7%, +2.8%)]. The 95% CI for the change from baseline did not include zero for the cartilage thickness within the meniscal window of the lateral tibia (wLT x ThCtAB) at 6 month follow-up (-1.5%, 95% CI [-2.9, -0.2]), but was not significant at the 5% level after correction for multiple comparisons. The small inconsistent compartment changes, and the relatively high variabilities in cartilage thickness changes seen over time in this study, provide no additional confidence for a 3- or 6-month PoC study using a patient population selected on the basis of risk for rapid progression with the MRI acquisition and analyses employed.

Within‐subregion relationship between bone marrow lesions and subsequent cartilage loss in knee osteoarthritis

Bone marrow lesions are believed to increase risk of knee osteoarthritis (OA) progression. Whether their effect is local and whether it can be explained by other types of bone lesions concomitantly present in the same subregion is unclear. We evaluated bone lesion frequency in subregions without cartilage lesions and cartilage lesion frequency in subregions without bone lesions, and investigated the within-subregion bone marrow lesion/subsequent cartilage loss relationship after adjusting for other types of bone lesions at baseline. Individuals with knee OA had magnetic resonance imaging at baseline and 2 years later. Cartilage integrity and bone marrow lesions, cysts, and attrition were scored within tibiofemoral subregions. Logistic regression, with generalized estimating equations to account for correlation among multiple subregions within a knee, was used to estimate odds ratios (ORs) for cartilage loss associated with bone marrow lesions, adjusting for age, sex, body mass index, and bone attrition and cysts in the same subregion. Analyzing 1,953 subregions among 177 knees, 90% of subregions had no bone lesions at baseline. Only 0-3% of subregions without cartilage lesions had bone lesions in the same subregion; in contrast, 5-33% of subregions without bone lesions had cartilage lesions. Bone marrow lesions at baseline were associated with cartilage loss in the same subregion at 2 years, adjusting for other types of bone lesions at baseline (adjusted OR 3.74, 95% confidence interval 1.59-8.82). In subjects with knee OA, bone marrow lesions were rare at early disease stages but predicted subregional cartilage loss after accounting for the presence of other types of bone lesions in the same subregion.

Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: The Tasmanian older adult cohort study

To determine the associations between serum levels of vitamin D, sunlight exposure, and knee cartilage loss cross-sectionally and longitudinally in older adults. A total of 880 randomly selected subjects (mean age 61 years [range 51-79 years], 50% women) were studied at baseline, and 353 of these subjects were studied 2.9 years later. Serum levels of 25-hydroxyvitamin D (25[OH]D) were assessed by radioimmunoassay, and sunlight exposure was assessed by questionnaire. T1-weighted fat-suppressed magnetic resonance imaging (MRI) of the right knee was performed to determine knee cartilage volume and defects. Knee radiographic osteoarthritis (OA) and knee pain were also assessed. The mean 25(OH)D serum level was 52.8 nmoles/liter at baseline (range 13-119 nmoles/liter). Winter sunlight exposure and serum 25(OH)D level were both positively associated with medial and lateral tibial cartilage volume, and a serum 25(OH)D level<50 nmoles/liter was associated with increased medial tibiofemoral joint space narrowing (all P<0.05). Longitudinally, baseline serum 25(OH)D level predicted change in both medial and lateral tibial cartilage volume (beta=+0.04% per annum per nmole/liter for both; P<0.05), and change in serum 25(OH)D level was positively associated with change in medial tibial cartilage volume. These associations were consistent in subjects with radiographic OA and knee pain and/or in women, but not in men or in subjects without radiographic OA or knee pain. Sunlight exposure and serum 25(OH)D levels are both associated with decreased knee cartilage loss (assessed by radiograph or MRI). This is best observed using the whole range of 25(OH)D levels rather than predefined cut points and implies that achieving vitamin D sufficiency may prevent and/or retard cartilage loss in knee OA.

Protective effects of licofelone, a 5-lipoxygenase and cyclo-oxygenase inhibitor, versus naproxen on cartilage loss in knee osteoarthritis: a first multicentre clinical trial using quantitative MRI

Objective:In a multicentre study to explore the effects of licofelone as a disease-modifying osteoarthritis drug in comparison with naproxen in patients with knee osteoarthritis (OA), using MRI and x-ray examination.Methods:Patients...

Risk factors for cartilage loss in knee osteoarthritis

Risk factors for cartilage loss in knee osteoarthritis

Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis

Objective:To examine the relationship between longitudinal fluctuations in synovitis with change in pain and cartilage in knee osteoarthritis.Methods:Study subjects were patients 45 years of age and older with symptomatic knee...

Low levels of vitamin D and worsening of knee osteoarthritis: Results of two longitudinal studies

To confirm reports that 25-hydroxyvitamin D (25[OH]D) deficiency is associated with an increased risk of joint space narrowing or cartilage loss in osteoarthritis (OA). We measured 25(OH)D levels in subjects from 2 longitudinal cohort studies, the Framingham Osteoarthritis Study and the Boston Osteoarthritis of the Knee Study (BOKS). In the first, weight-bearing anteroposterior (AP) and lateral knee radiographs were obtained on subjects in 1993-1994 and again in 2002-2005 (mean interval 9 years); blood was drawn for measurement of vitamin D status in 1996-2000. In the second, subjects with symptomatic knee OA participating in a natural history study had fluoroscopically positioned semiflexed posteroanterior (PA) and lateral radiography of both knees and magnetic resonance imaging (MRI) of the more symptomatic knee performed at baseline and at 15 and 30 months. Blood was drawn at all visits, and the baseline specimen was used when available. In both studies, we defined radiographic worsening based on joint space loss in the tibiofemoral joint on either AP/PA or lateral weight-bearing views, using a semiquantitative scale (worsening defined as increase by > or =1 on a 0-3 scale). In the BOKS, we evaluated cartilage loss semiquantitatively, using the Whole-Organ Magnetic Resonance Imaging Score. In both studies, 25(OH)D levels were measured by radioimmunoassay. Analyses focused on whether vitamin D levels, defined in tertiles or as deficient (25[OH]D <20 ng/ml) versus nondeficient, predicted worsening of OA. Logistic regression analysis adjusted for age, body mass index, sex, and baseline OA level was used. The 715 subjects in the Framingham Study had a mean 25(OH)D level of 20 ng/ml at baseline, and 20.3% of the knees showed worsening, during the course of the study, with most knees having had no evidence of OA at baseline. The 277 subjects with OA in the BOKS had a mean 25(OH)D level of 20 ng/ml at baseline with 23.6% of knees showing radiographic worsening. We found no association of baseline 25(OH)D levels with radiographic worsening in either cohort, and confidence limits in the analyses of vitamin D deficiency were narrow, suggesting that results were not based on insufficient power. In fact, the risk of worsening was slightly, but not significantly, lower in persons with low levels of vitamin D than in persons with higher levels. In the BOKS, vitamin D levels were unrelated to cartilage loss seen on MRI. The findings indicate that vitamin D status is unrelated to the risk of joint space or cartilage loss in knee OA.

Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: A randomized, controlled trial

To determine whether chondroitin sulfate (CS) is effective in inhibiting cartilage loss in knee osteoarthritis (OA). In this randomized, double-blind, placebo-controlled trial, 300 patients with knee OA were recruited from an outpatient clinic, from private practices, and through advertisements. Study patients were randomly assigned to receive either 800 mg CS or placebo once daily for 2 years. The primary outcome was joint space loss over 2 years as assessed by a posteroanterior radiograph of the knee in flexion; secondary outcomes included pain and function. Of 341 patients screened, 300 entered the study and were included in the intent-to-treat analysis. The 150 patients receiving placebo had progressive joint space narrowing, with a mean +/- SD joint space loss of 0.14 +/- 0.61 mm after 2 years (P = 0.001 compared with baseline). In contrast, there was no change in mean joint space width for the 150 patients receiving CS (0.00 +/- 0.53 mm; P not significant compared with baseline). Similar results were found for minimum joint space narrowing. The differences in loss of joint space between the two groups were significant for mean joint space width (0.14 +/- 0.57 mm; P = 0.04) and for minimum joint space width (0.12 +/- 0.52 mm; P = 0.05). CS was well tolerated, with no significant differences in rates of adverse events between the two groups. While there was no significant symptomatic effect in this study, long-term treatment with CS may retard radiographic progression in patients with OA of the knee. However, the clinical relevance of the observed structural results has to be further evaluated, and further studies are needed to confirm the structural effects of CS.