OBJECTIVE:To determine whether computer-based analysis can detect features predictive of osteoarthritis (OA) development in radiographically normal knees. METHOD:A systematic computer-aided image analysis method weighted neighbor distances using a compound hierarchy of algorithms representing morphology (WND-CHARM) was used to analyze pairs of weight-bearing knee X-rays. Initial X-rays were all scored as normal Kellgren-Lawrence (KL) grade 0, and on follow-up approximately 20 years later either developed OA (defined as KL grade=2) or remained normal. RESULTS:The computer-aided method predicted whether a knee would change from KL grade 0 to grade 3 with 72% accuracy (P<0.00001), and to grade 2 with 62% accuracy (P<0.01). Although a large part of the predictive signal comes from the image tiles that contained the joint, the region adjacent to the tibial spines provided the strongest predictive signal. CONCLUSION:Radiographic features detectable using a computer-aided image analysis method can predict the future development of radiographic knee OA.

Outcomes S113clinical ACR criteria of knee OA on persisting knee complaints, increase of disability (WOMAC function score), and increase of absence of work through illness after one year follow-up was assessed.Results: 549 patients were included in the study of which 480 (87.4%) were available for follow-up.The studied population contained 236 (49.2%) women, mean age 53.6 (sd 11.3), mean BMI 27.1 (sd 4.2), 288 (60.0%) patients had payed employment (>8 hours/week), and 292 (60.8%) patients fulfilled the ACR clinical criteria of knee OA.After one year follow-up, 236 (49.2%) patients reported persisting knee complaints, 84 (17.5%) reported an increase of disability, and 5 (1%) patients reported an increase of absence of work through illness.There was no association between fulfilling the ACR clinical criteria of knee OA and persisting knee complaints (OR 1.15; 95% CI 0.80, 1.67), increase of disability (OR 1.05; 95% CI 0.43, 2.58), and increase of absence of work through illness (OR 0.97; 95% CI 0.16, 5.83) after one year follow-up.Conclusions: The ACR clinical classification criteria of knee OA have no prognostic value in adult patients with non-traumatic knee complaints in general practice during the period of one year follow-up.

OBJECTIVE:To test the hypothesis that early knee and hand osteoarthritis (OA) development is characterized by detectable changes in serum proteins relevant to inflammation, cell growth, activation, and metabolism several years before OA becomes radiographically evident. METHODS:Using microarray platforms that simultaneously test 169 proteins relevant to inflammation, cell growth, activation and metabolism, we conducted a case-control study nested within the Baltimore Longitudinal Study of Aging (BLSA). Subjects included 22 incident cases of OA and 66 age-, sex- and body mass index (BMI)-matched controls. Serum samples tested were obtained at the time of radiographic classification as either case or control, and up to 10 years earlier at a time when all participants were free of radiographic OA. Proteins with mean signal intensities fourfold higher than background were compared between cases and controls using multivariate techniques. RESULTS:Sixteen proteins were different between OA cases compared to controls. Four of these proteins [matrix metalloproteinase (MMP)-7, interleukin (IL)-15, plasminogen activator inhibitor (PAI)-1 and soluble vascular adhesion protein (sVAP)-1] were already different in samples obtained 10 years before radiographic classification and remained different at the time of diagnosis. Six additional proteins were only associated with subsequent OA development and not with established OA. CONCLUSIONS:Changes in serum proteins implicated in matrix degradation, cell activation, inflammation and bone collagen degradation products accompany early OA development and can precede radiographic detection by several years.

Table 2 Loss (mm) SD (mm) SRM JSW (x = 0.7) 0.50 0.86 0.59 JSW (x = 0.725) 0.41 0.85 0.49 JSW (x = 0.75) 0.36 0.87 0.42 JSW (x = 0.775) 0.29 0.86 0.34 JSW (x = 0.8) 0.21 0.79 0.27 JSW (x = 0.825) 0.24 0.78 0.30 JSW (x = 0.85) 0.23 0.86 0.27 JSW (x = 0.875) 0.26 0.93 0.28 JSW (x = 0.9) 0.27 0.89 0.31 mJSW 0.07 0.58 0.12

Clinical Pharmacology & Therapeutics (2007) 81, S10–S12. doi:10.1038/sj.clpt.6100173

Objective: Osteoarthritis (OA) and vascular stiffening may share elements of common pathogenesis, but their potential relatedness has been the focus of little prior inquiry. We tested the hypothesis that these two aging-associated conditions are related to each other.Method We analyzed cross-sectional data from 256 participants of the Baltimore Longitudinal Study of Aging (BLSA), a study of normative aging. All underwent measurement of arterial pulse wave velocity (PWV), an index of vascular stiffness, as well as hand radiographs that were graded for evidence of OA. Twenty total joints across three joint groups (distal interphalangeal [DIP], proximal interphalangeal [PIP], carpal-metacarpal [CMC]) were each assigned a Kellgren-Lawrence grade (K-L) of 0 (normal) through 4 (severe), with K-L grades >= 2 considered evidence of definite CA. Radiographic hand OA was defined as definite CA changes in at least two of the three anatomic hand sites (DIP, PIP, CMC). CA burden was represented by the total number of affected CA joints, and a cumulative K-L grade was aggregated across all hand joint groups. The relationship of PWV with these three measures of hand CA was assessed by linear regression.Results: Upon univariate analysis, the presence of radiographic hand CA (beta = 218.1, P < 0.01), the total number of CA joints (beta = 32.9, P < 0.01), and the cumulative K-L grade across all joint groups (beta = 12.2, P < 0.01) were each associated with increased PWV. These associations, however, were no longer significant in age-adjusted models.Conclusion: Although significant individual relationships between PWV and several measures of hand OA were observed, these associations were largely attributable to the confounding effect of age. (C) 2006 Published by Elsevier Ltd on behalf of OsteoArthritis Research Society International.

Polypharmacy, common in older people, confers both risk of adverse outcomes and benefits. We assessed the relationship of commonly prescribed medications with anticholinergic and sedative effects to physical and cognitive performance in older individuals. The study population comprised 932 moderately to severely disabled community-resident women aged 65 years or older who were participants in the Women's Health and Aging Study I. A scale based on pharmacodynamic principles was developed and utilized as a measure of drug burden. This was related to measures of physical and cognitive function. After adjusting for demographics and comorbidities, anticholinergic drug burden was independently associated with greater difficulty in four physical function domains with adjusted odds ratios (95% confidence interval (CI)) of 4.9 (2.0-12.0) for balance difficulty; 3.2 (1.5-6.9) for mobility difficulty; 3.6 (1.6-8.0) for slow gait; 4.2 (2.0-8.7) for chair stands difficulty; 2.4 (1.1-5.3) for weak grip strength; 2.7 (1.3-5.4) for upper extremity limitations; 3.4 (1.7-6.9) for difficulty in activities of daily living; and 2.4 (95% CI, 1.1-5.1) for poor performance on the Mini-Mental State Examination. Sedative burden was associated only with impaired grip strength (3.3 (1.5-7.3)) and mobility difficulty (2.4 (1.1-5.3)). The burden of multiple drugs can be quantified by incorporating the recommended dose regimen and the actual dose and frequency of drug taken. Anticholinergic drug burden is strongly associated with limitations in physical and cognitive function. Sedative burden is associated with impaired functioning in more limited domains. The risk associated with exposure of vulnerable older women to drugs with anticholinergic properties, and to a lesser extent those with sedative properties, implies that such drugs should not be used in this patient group without compelling clinical indication.

Objective: To assess characteristics of active motor units (MUs) during volitional vastus medialis (VM) activation in adults with symptomatic knee osteoarthritis (OA) across the spectrum of radiographic severity and age-comparable healthy control volunteers.Methods: We evaluated 39 participants (age 65 3 years) in whom weight-bearing knee X-rays were assigned a Kellgren & Lawrence (KL) grade (18 with KL grade = 0; four each with KL grades = 1, 2 and 4; nine with grade 3). Electromyography (EMG) signals were simultaneously acquired using surface [surface EMG (S-EMG)] and intramuscular needle electrodes, and analyzed by decomposition-enhanced spike-triggered averaging to obtain estimates of size [surface-represented MU action potentials (S-MUAP) area], number [MU recruitment index (MURI)] and firing rates [MU firing rates (mFR)] of active MUs at 10%, 20%, 30% and 50% effort relative to maximum voluntary force [maximal voluntary isometric contraction (MVIC)] during isometric knee extension.Results: Knee extensor MVIC was lower in CA participants, especially at higher KL grades (P = 0.05). Taking the observed force differences into account, OA was also associated with activation of larger MUs (S-MUAP area/MVIC x %effort; P < 0.0001). In contrast, the estimated number of active units (MURI/MVIC x %effort) changed differently as effort increased from 10% to 50% and was higher with advanced CA (KIL = 3, 4) than controls (P = 0.0002).Conclusion: VM activation changes at the level of the MU with symptomatic knee OA, and this change is influenced by radiographic severity. Poor muscle quality may explain the pattern observed with higher KIL grades, but alternative factors (e.g., nerve or joint injury, physical inactivity or muscle composition changes) should be examined in early OA. (C) 2007 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Observational studies have shown that the use of angiotensin-converting enzyme (ACE) inhibitors (ACEIs) is associated with the maintenance of higher muscle strength and physical performance in older persons free of chronic heart failure. There is evidence of a direct role exerted by ACE-inhibitor treatment on parameters of physical performance, but the exact mechanism underlying the effects of ACEIs remains poorly understood. Since ACEIs block the production of Angiotensin II, which is a potent inhibitor of insulin-like growth factor-1 (IGF-1), it is conceivable that there is a relationship between ACEls administration and serum IGF-1 levels. Decline of IGF-1 with age is also associated with poor muscle mass and strength. The link between ACE inhibitors or other medications inhibiting renin angiotensin aldosterone system, physical performance and IGF-1 will be analyzed in this review.

CC51 more, RNA was isolated to evaluate the response to ALK5 or ALK1 signaling on expression of aggrecan, collagen type II and MMP-13.In addition, knee joints were isolated from mice aged 1 or 2 years, OA prone STR/ort mice (aged 3, 6 and 9 months and 1 year) and mice in which OA was induced by destabilizing the medial meniscus (DMM model).Immunohistochemistry for ALK5 and ALK1 was performed and the number of cells staining positive for each receptor in tibial cartilage was measured with a computerized imaging system.Results: TGF-beta signaled in chondrocytes both via Smad2/3 and Smad1/5/8.Transfection of chondrocytes with caALK5 specifically led to Smad2/3 phosphorylation, whereas caALK1 specifically led to Smad1/5/8 phosphorylation.Chondrocytes that over expressed caALK5 showed enhanced aggrecan expression and slightly reduced collagen type II expression.Chondrocytes over expressing caALK1 had elevated expression of aggrecan, collagen type II and MMP-13, thereby displaying an OA-phenotype.From 1 year old to 2 year old mice ALK5 decreased 88% in the medial tibial cartilage and 76% in the lateral tibial cartilage.ALK1 also was reduced, but only 51% in the medial tibial cartilage and 33% on the lateral side.In the DMM model no change was observed on the lateral side, but a reduction of 91% ALK5 positive cells compared to 75% ALK1 positive cells in the OA developing medial side.In the STR/ort model, the number of cells staining positive for ALK5 was already reduced to 7% in the medial tibial cartilage by 3 months of age.This rapidly declined to less than 1% by 9 months.On the lateral side there was still abundant ALK5 expression at 3 months of age, however, this rapidly decreases in time to less than 10% by 9 months and 1 year of age.ALK1 expression however, although slightly decreased stayed relatively high and even increased again by 1 year of age compared to 9 months of age.Overall a significant increase in the ALK1/ALK5 ratio with age and OA progression was demonstrated.Conclusions: Our data show that ALK1 over expression in chondrocytes induced an OA-like phenotype in chondrocytes.Moreover, a clear switch of chondrocyte ALK5 to ALK1 expression was associated with ageing and OA progression.Our data suggest a role for ALK1 in deviant chondrocyte behavior during ageing and OA development.

ObjectiveWe tested the hypothesis that intrusion of the knee joint capsule alters quadriceps muscle metabolism and function independently from the damage induced to knee cartilage.MethodsAdult rats were separated into four groups: intraarticular injections of saline (SAL; n=9); intraarticular injections of papain, a model for osteoarthritis (PIA; n=7); sham injections (SHAM; n=8); and controls (CTL; n=5). 31P magnetic resonance spectroscopy (31P-MRS) was performed after 2 weeks. Spectra were obtained from the left quadriceps: two at baseline, eight during electrical stimulation with simultaneous measurement of contractile force, and 15 during recovery. 31P-MRS data were presented as the ratio of inorganic phosphate (Pi) to phosphocreatine (PCr), concentrations of PCr [PCr], intramuscular pH, and the rates and time constants of PCr breakdown during stimulation and PCr recovery. Intramuscular cytokine concentrations were measured within the quadriceps. Histologic slides of the knees were scored for severity of cartilage damage.ResultsThe interventional groups produced values of Pi/PCr ratio, [PCr], contractile force and pH that were significantly different from CTL. These changes in muscle function were accompanied by higher concentrations of interleukin-1 observed with PIA and SAL. We did not observe any effect of cartilage damage on muscle function or metabolism.ConclusionsKnee joint intrusion alters quadriceps muscle metabolism with accelerated depletion of energy stores and fatigue during stimulation. This study demonstrates that needle intrusion into the knee joint results in muscle dysfunction, independently from the extent of cartilage damage.

Context: An age-associated decline in testosterone (T) levels and an increase in proinflammatory cytokines contribute to chronic diseases in older men. Whether and how these changes are related is unclear.Objective: We hypothesized that T and inflammatory markers are negatively correlated in older men.Design: This was a cross-sectional study.Setting: A population-based sample of older men was studied.Participants and Measures: After excluding participants taking glucocorticoids or antibiotics or those with recent hospitalization, 467 men, aged 65 yr or older, had complete determinations of total T, bioavailable T, SHBG, albumin, IL-6, soluble IL-6 receptor (sIL-6r), TNF-alpha, IL-1 beta, and C-reactive protein.Results: After adjusting for potential confounders, sIL-6r was significantly and inversely correlated with total T (r = -0.20; P < 0.001) and bioavailable T (r = -0.12; P < 0.05). T was not correlated with any other inflammatory marker.Conclusions: These preliminary findings suggest an inverse relationship between T and sIL-6r. Longitudinal studies are needed to establish the causality of this association.