Dorothy D. Dunlop

Knee adduction moment, serum hyaluronan level, and disease severity in medial tibiofemoral osteoarthritis

OBJECTIVE The adduction moment at the knee during gait is the primary determinant of medial-to-lateral load distribution. If the adduction moment contributes to progression of osteoarthritis (OA), then patients with advanced medial tibiofemoral OA should have higher adduction moments. The present study was undertaken to investigate the hypothesis that the adduction moment normalized for weight and height is associated with medial tibiofemoral OA disease severity after controlling for age, sex, and pain level, and to examine the correlation of serum hyaluronan (HA) level with disease severity and with the adduction moment in a subset of patients. METHODS Fifty-four patients with medial tibiofemoral OA underwent gait analysis and radiographic evaluation. Disease severity was assessed using the Kellgren-Lawrence (K-L) grade and medial joint space width. In a subset of 23 patients with available sera, HA was quantified by sandwich enzyme-linked immunosorbent assay. Pearson correlations, a random effects model, and multivariate regression models were used. RESULTS The adduction moment correlated with the K-L grade in the left and right knees (r = 0.68 and r = 0.60, respectively), and with joint space width in the left and right knees (r = -0.45 and r = -0.47, respectively). The relationship persisted after controlling for age, sex, and severity of pain. The partial correlation between K-L grade and adduction moment was 0.71 in the left knees and 0.61 in the right knees. For every 1.0-unit increase in adduction moment, there was a 0.63-mm decrease in joint space width. In the subset of patients in whom serum HA levels were measured, HA levels correlated with medial joint space width (r = -0.55), but not with the adduction moment. CONCLUSION There is a significant relationship between the adduction moment and OA disease severity. Serum HA levels correlate with joint space width but not with the adduction moment. Longitudinal studies will be necessary to determine the contribution of the adduction moment, and its contribution in conjunction with metabolic markers, to progression of medial tibiofemoral OA.

The mechanism of the effect of obesity in knee osteoarthritis: the mediating role of malalignment.

OBJECTIVE Obesity is most strongly linked to osteoarthritis (OA) at the knee. Varus malalignment was examined as a possible local mediator that may increase the impact of body weight at the knee, versus the hip or ankle. Compartment load distribution is more equitable in valgus than in varus knees, and valgus knees may better tolerate obesity. We therefore tested whether 1) body mass index (BMI) is correlated with OA severity in varus knees, 2) the BMI-OA severity correlation is weaker in valgus than in varus knees, 3) BMI is correlated with the severity of varus malalignment, and 4) the BMI-medial tibiofemoral OA severity relationship is reduced after controlling for varus malalignment. METHODS In 300 community-recruited patients with knee OA, 2 groups (varus and valgus) were identified based on dominant knee alignment on a full-limb radiograph, i.e., the angle formed by the intersection of the femoral and tibial mechanical axes. Severity of knee OA was assessed by measurement of the narrowest joint space width on radiographs of knees in a fluoroscopy-confirmed semiflexed position. RESULTS Alignment direction was symmetric (or neutral in 1 limb) in 87% of patients. One hundred fifty-four patients had varus knees and 115 had valgus knees. BMI correlated with OA severity in the varus group (r = -0.29, P = 0.0009) but not in the valgus group (r = -0.13, P = 0.17). BMI correlated with malalignment in those with varus knees (r = 0.26) but not in those with valgus knees (r = 0.16). The partial correlation of BMI and OA severity, controlling for sex, was reduced from 0.24 (P = 0.002) to 0.04 (P = 0.42) when varus malalignment was added to the model. CONCLUSION BMI was related to OA severity in those with varus knees but not in those with valgus knees. Much of the effect of BMI on the severity of medial tibiofemoral OA was explained by varus malalignment, after controlling for sex. Whether it precedes or follows the onset of disease, varus malalignment is one local factor that may contribute to rendering the knee most vulnerable to the effects of obesity.

Quadriceps strength and osteoarthritis progression in malaligned and lax knees

Context Experts routinely recommend that adults with knee osteoarthritis strengthen leg muscles. Contribution This 18-month cohort study of 237 adults with primary knee osteoarthritis found that greater baseline quadriceps strength was associated with greater risk for progressive tibiofemoral joint space narrowing among adults with malaligned or very lax knees. Implications Maximization of quadriceps strength in osteoarthritic patients with malaligned or very lax knees may not be joint protective and should be studied in trials that include joint structure outcomes. Cautions These results do not imply that physical activity in adults with knee osteoarthritis is harmful. The Editors Knee osteoarthritis is responsible for more chronic disability in elderly persons than any other medical condition (1). Quadriceps strengthening is widely recommended for knee osteoarthritis (2, 3), based on cross-sectional studies identifying strength (maximal voluntary muscle force generation) as a correlate of physical function (4-8) and on trials, predominantly short term, suggesting that quadriceps strengthening reduces pain and improves function (9, 10). The impact of quadriceps strength on the course of osteoarthritic disease itself is not well understood. A longitudinal study has shown that, in healthy knees, strong quadriceps offer some protection against new osteoarthritis development (11). However, whether quadriceps strength protects against progression or advancement of osteoarthritis in already arthritic knees has not been demonstrated. Brandt and colleagues (12) found no difference in baseline quadriceps strength between those with and those without disease progression. The effect of quadriceps strength on osteoarthritis disease progression is particularly important given the frequency with which quadriceps strengthening exercises are prescribed for persons with knee osteoarthritis. Muscle effects are less predictable in arthritic knees than in healthy knees. On the positive side, muscle activity promotes cartilage health and stabilizes the joint. During activity, muscles contract at different levels and protective reflexes are applied to shield knee tissues from injury (13). Coactivation, the dual drive of agonist and antagonist muscles, provides control for the stop and start of motion as well as compensation for gravity. Implicit in the recommendation of quadriceps strengthening for knee osteoarthritis is the assumption that greater strength will enhance these positive effects. If this enhancement comes without cost, greater strength may indeed protect arthritic joints from osteoarthritis progression. On the negative side, greater quadriceps strength may be associated with forces that could damage the vulnerable articular cartilage of osteoarthritis. The compensatory increase in muscle forces in osteoarthritis may increase the joint reaction force (14). A higher coactivation level in the agonist versus antagonist muscles can impair motion regulation and reduce ligament-protecting actions (13). The net impact of quadriceps strength on osteoarthritis progression depends on which effectspositive or negativeare greater. Which muscle effects prevail is likely to depend on the local mechanical environment. Local factors that alter load distribution, such as laxity and malalignment, influence how well the joint copes with muscle forces. Woo and associates (15) liken this situation to a hammer (muscle) driving a nail (the joint), while a hand (ligaments and, more broadly, local environment) holds the nail in place. The stabilizing hand allows greater force from the hammer. In other words, a healthy environment contributes to safe muscle force distribution over the menisci, articular cartilage, and other tissues. However, with laxity or malalignment, muscle forces may increase stress on localized areas of cartilage. Similarly, Marks and colleagues (16) theorized that local joint abnormalities can render muscle forces pathogenic. Malalignment and laxity are key local abnormalities. Any shift from a neutral hipkneeankle alignment alters load distribution; varus and valgus alignments increase medial and lateral compartment forces, respectively (17). Alignment influences the outcome of most knee surgeries, as well as natural disease progression and functional decline in osteoarthritis (18). Knee laxityabnormal displacement of the tibia with respect to the femur (19)shifts opposing surfaces of tibiofemoral contact so that congruence is reduced and increases shear and compression forces. Varusvalgus laxity has been linked to greater likelihood of osteoarthritis after ligament injury (20, 21). In other studies, laxity was present in patients with osteoarthritis before full-blown disease and was worsened by aspects of disease (22), was associated with worse function, and altered the strengthfunction relationship (23). If greater quadriceps strength improves the load imbalance created by malalignment or attenuated load in malaligned knees, it might protect against osteoarthritis progression in patients with maligned knees. Alternatively, malalignment may alter the line of action of quadriceps forces, distributing them inequitably across the joint surface (16); in this case, strength might increase the likelihood of osteoarthritis progression. In the lax knee, strength might be protective if greater quadriceps strength enhances dynamic stabilization. However, if the cost of this compensationthat is, greater joint reaction forceexceeds the stabilization benefit, the likelihood of osteoarthritis progression might increase. Our objective was to determine whether greater quadriceps strength was associated with greater probability of tibiofemoral osteoarthritis progression among all knees in persons with osteoarthritis and in two subsets, malaligned knees and high-laxity knees. Methods Participants Mechanical Factors in Arthritis of the Knee (MAK) is a natural history study of knee osteoarthritis at Northwestern University in Chicago, Illinois. Participants in MAK were recruited through periodicals targeting senior citizens, 67 neighborhood organizations, the registry of the Northwestern University Buehler Center on Aging, and medical center referrals. Inclusion and exclusion criteria were based on those developed for osteoarthritis progression studies at a workshop sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging (24). Inclusion criteria were definite osteophyte presence (Kellgren and Lawrence radiographic grade 2) in one or both knees and at least a little difficulty (Likert category) with at least two items in the Western Ontario and McMaster University osteoarthritis index physical function scale. Exclusion criteria were corticosteroid injection within 3 months, avascular necrosis, rheumatoid or other inflammatory arthritis, periarticular fracture, Paget disease, villonodular synovitis, joint infection, ochronosis, neuropathic arthropathy, acromegaly, hemochromatosis, Wilson disease, osteochondromatosis, gout, pseudogout, osteopetrosis, bilateral total knee replacement, or plan for knee replacement within the next year. Persons with past unilateral knee replacement were eligible if they had osteoarthritis in the nonreplaced knee. The institutional review board of Northwestern University approved the study, and all participants gave informed consent. Measurement of Key Factors All measurements were obtained in both knees. Isokinetic quadriceps strength was tested by using a computer-driven isokinetic dynamometer (Cybex, Avocent, Huntsville, Alabama) to assess maximal torque during movement. One tester assessed all participants by following a previously described protocol (23). The computer recorded data in foot-pounds (ft-lbs) and corrected for gravity effects. Reliability, determined by using test repetitions, was high (intraclass correlation coefficients > 0.98) (23). To assess alignment, a single anteroposterior radiograph of both lower extremities was obtained by using a graduated grid cassette (51 14 inches), adhering to a protocol we have described elsewhere (18). Alignment was defined as the measure of the angle formed by the intersection of the line connecting the centers of the femoral head and intercondylar notch and the line connecting the centers of the ankle talus and tibial spines (17, 25, 26). Knees were considered more neutral if the angle was less than 5 degrees in a varus or valgus direction and malaligned if the angle was 5 degrees or more. One experienced reader made all measurements. Reliability, based on a set of radiographs from patients with osteoarthritis (18), was high for varus and valgus alignment (intraclass correlation coefficients, 0.99 and 0.98, respectively). Varus-valgus laxity was measured with a device designed for the MAK study by Dr. Thomas Buchanan (22, 23). The measurement protocol has been described elsewhere (22, 23). Angular deviation was measured at the foot with application of varus or valgus load. Varusvalgus laxity was analyzed as the sum of varus and valgus rotation for each knee (27-29). Because a definition of high and low laxity is not available, knees in the highest laxity tertile ( 5.75 degrees) were designated as high laxity. Laxity measurements were performed by the same examiner and assistant, and reliability was very good in participants with osteoarthritis (within-session intraclass correlation coefficients, 0.85 to 0.96; between-sessions intraclass correlation coefficients, 0.84 to 0.90) (22). Measurement of Outcome Knee radiographs were obtained at baseline and at 18 months, following the semi-flexed, fluoroscopically confirmed protocol developed by Buckland-Wright (24, 30, 31). Knee position, beam alignment, markers to account for magnification, and measurement landmarks were specified. The standing semi-flexed position superimposes anterior and posterior medial tibial margins. Knee position was confir

Disability in activities of daily living: patterns of change and a hierarchy of disability.

OBJECTIVES This paper examines longitudinal data over 6 years to evaluate incidence rates of disability and the pattern of dependency in activities of daily living. METHODS The Longitudinal Study of Aging (n = 5151) was used to evaluate incidence of disability in activities of daily living; biennial interview data from 1984 through 1990 were used. The median age to disability onset for individual activities was estimated from survival analysis. A prevalent ordering of incident disability was identified from patterns of disability onset within individuals. RESULTS The progression of incident disability among the elderly supported by longitudinal data, based on both the ordering of median ages to disability onset and patterns of incident disability, was as follows: walking, bathing, transferring, dressing, toileting, feeding. Gender differences were found in disability incidence rates. CONCLUSIONS This study provides a mathematical picture of physical functioning as people age. These findings, based on longitudinal data, indicate a different hierarchical structure of disability than found in previous reports using cross-sectional data. Furthermore, the study documents gender differences in incident impairment, which indicate that although women outlive men, they spend more time in a disabled state.

Laxity in healthy and osteoarthritic knees

OBJECTIVE Although it is a cause of osteoarthritis (OA) in animal models, laxity in human knee OA has been minimally evaluated. Ligaments become more compliant with age; whether this results in clinical laxity is not clear. In theory, laxity may predispose to OA and/or result from OA. Our goals were to examine the correlation of age and sex with knee laxity in control subjects without OA, compare laxity in uninvolved knees of OA patients with that in older control knees, and examine the relationship between specific features of OA and knee laxity. METHODS We assessed varus-valgus and anteroposterior laxity in 25 young control subjects, 24 older control subjects without clinical OA, radiographic OA, or a history of knee injury, and 164 patients with knee OA as determined by the presence of definite osteophytes. A device was designed to assess varus-valgus laxity under a constant varus or valgus load while maintaining a fixed knee flexion angle and thigh and ankle immobilization. Radiographic evaluations utilized protocols addressing position, beam alignment, magnification, and landmark definition; the semiflexed position was used, with fluoroscopic confirmation. RESULTS In the controls, women had greater varus-valgus laxity than did men (3.6 degrees versus 2.7 degrees; 95% confidence interval [95% CI] of difference 0.38, 1.56; P = 0.004), and laxity correlated modestly with age (r = 0.29, P = 0.04). Varus-valgus laxity was greater in the uninvolved knees of OA patients than in older control knees (4.9 degrees versus 3.4 degrees; 95% CI of difference 0.60, 2.24; P = 0.0006). In OA patients, varus-valgus laxity increased as joint space decreased (slope -0.34; 95% CI -0.48, -0.19; P < 0.0001) and was greater in knees with than in knees without bony attrition (5.3 degrees versus 4.5 degrees; 95% CI of difference 0.32, 1.27; P = 0.001). CONCLUSION Greater varus-valgus laxity in the uninvolved knees of OA patients versus older control knees and an age-related increase in varus-valgus laxity support the concept that some portion of the increased laxity of OA may predate disease. Loss of cartilage/bone height is associated with greater varus-valgus laxity. These results raise the possibility that varus-valgus laxity may increase the risk of knee OA and cyclically contribute to progression.

Racial/Ethnic Differences in Rates of Depression Among Preretirement Adults

OBJECTIVES We estimated racial/ethnic differences in rates of major depression and investigated possible mediators. METHODS Depression prevalence rates among African American, Hispanic, and White adults were estimated from a population-based national sample and adjusted for potential confounders. RESULTS African Americans (odds ratio [OR] = 1.16, 95% confidence interval [CI] = 0.93, 1.44) and Hispanics (OR = 1.44, 95% CI = 1.02, 2.04) exhibited elevated rates of major depression relative to Whites. After control for confounders, Hispanics and Whites exhibited similar rates, and African Americans exhibited significantly lower rates than Whites. CONCLUSIONS Major depression and factors associated with depression were more frequent among members of minority groups than among Whites. Elevated depression rates among minority individuals are largely associated with greater health burdens and lack of health insurance, factors amenable to public policy intervention.

Increased Risk of Fracture in Patients Receiving Solid Organ Transplants

The success of organ transplantation is related to advances in immunosuppressive therapy. These medications are associated with medical complications including bone damage. The objective of this study was to estimate and compare age, gender‐specific fracture incidence between transplant recipients, and a large sample representative of the civilian noninstitutionalized United States population using the 1994 National Health Interview Survey (NHIS). This was a cohort study set in tertiary care centers. Five hundred and thirty‐nine individuals who received abdominal organ and 61 heart transplants surviving at least 30 days at our institution from 1986 to 1996 were included in the study. Incident fractures were ascertained by mail, in‐person interview, telephone survey, or medical record review. All fractures were verified. Organ‐, age‐, and gender‐specific fracture numbers and rates and person‐years of observation, were calculated for the transplant patients. Weighted age‐ and gender‐specific fracture rates from the 1994 NHIS were applied to the number of person‐years of observation for each organ‐specific age and gender category of transplant patients to generate an expected number of fractures. The ratio of observed to expected number of fractures was used to compare fracture experience of transplant patients to that of the national sample from the 1994 NHIS. Fifty‐six of 600 (9.3%) patients had at least one fracture following 1221 person‐years of observation. The sites of initial symptomatic fracture were as follows: foot (n = 22), arm (n = 8), leg (n = 7), ribs (n = 6), hip (n = 4), spine (n = 3), fingers (n = 3), pelvis (n = 2), and wrist (n = 1). Fracture incidence was 13 times higher than expected in male heart recipients age 45–64 years; nearly 5 times higher in male kidney recipients age 25–44 and age 45–64 years; and 18 times and 34 times higher in female kidney recipients age 25–44 years and 45–64 years compared with NHIS data. We have shown an increased incidence of fractures and estimated the magnitude of this problem in patients undergoing solid organ transplantation. Our work defines the need for a long‐term prospective study of fracture risk in these patients.

Relationship of meniscal damage, meniscal extrusion, malalignment, and joint laxity to subsequent cartilage loss in osteoarthritic knees.

OBJECTIVE Progressive knee osteoarthritis (OA) is believed to result from local factors acting in a systemic environment. Previous studies have not examined these factors concomitantly or compared quantitative and qualitative cartilage loss outcomes. The aim of this study was to test whether meniscal damage, meniscal extrusion, malalignment, and laxity each predicted tibiofemoral cartilage loss after controlling for the other factors. METHODS Laxity and alignment were measured at baseline in individuals with knee OA. Magnetic resonance imaging included spin-echo coronal and sagittal imaging for meniscal scoring and axial and coronal spoiled gradient echo sequences with water excitation for cartilage quantification. Tibial and weight-bearing femoral condylar subchondral bone area and cartilage surface were segmented. Cartilage volume, denuded bone area, and cartilage thickness were quantified in each plate, with progression defined as cartilage loss >2 times the coefficient of variation for each plate. Qualitative outcome was assessed as worsening of the cartilage score. Logistic regression analysis with generalized estimating equations yielded odds ratios for each factor, adjusting for age, sex, body mass index, and the other factors. RESULTS We studied 251 knees in 153 persons. After full adjustment, medial meniscal damage predicted medial tibial cartilage volume loss and tibial and femoral denuded bone increase, while varus malalignment predicted medial tibial cartilage volume and thickness loss and tibial and femoral denuded bone increase. Lateral meniscal damage predicted every lateral outcome. Laxity and meniscal extrusion had inconsistent effects. After full adjustment, no factor except medial laxity predicted qualitative outcome. CONCLUSION Using quantitative cartilage loss assessment, local factors that independently predicted tibial and femoral loss included medial meniscal damage and varus malalignment (medially) and lateral meniscal damage (laterally). A measurement of quantitative outcome was more sensitive at revealing these relationships than a qualitative approach.

Varus and valgus alignment and incident and progressive knee osteoarthritis

Objective Varus and valgus alignment increase medial and lateral tibiofemoral load. Alignment was associated with tibiofemoral osteoarthritis progression in previous studies; an effect on incident osteoarthritis risk is less certain. This study tested whether alignment influences the risk of incident and progressive radiographic tibiofemoral osteoarthritis. Methods In an observational, longitudinal study of the Multicenter Osteoarthritis Study cohort, full-limb x-rays to measure alignment were acquired at baseline and knee x-rays were acquired at baseline and knee x-rays at baseline and 30 months. Varus alignment was defined as ≤178° and valgus ≥182°. Using logistic regression and generalised estimating equations, the associations of baseline alignment and incident osteoarthritis at 30 months (in knees without baseline osteoarthritis) and alignment and osteoarthritis progression (in knees with osteoarthritis) were examined, adjusting. For age, gender, body mass index, injury, laxity and strength, with neutral knees as referent. Results 2958 knees (1752 participants) were without osteoarthritis at baseline. Varus (adjusted OR 1.49, 95% CI 1.06 to 2.10) but not valgus alignment was associated with incident osteoarthritis. 1307 knees (950 participants) had osteoarthritis at baseline. Varus alignment was associated with a greater risk of medial osteoarthritis progression (adjusted OR 3.59, 95% CI 2.62 to 4.92) and a reduced risk of lateral progression, and valgus with a greater risk of lateral progression (adjusted OR 4.85, 95% CI 3.17 to 7.42) and a reduced risk of medial progression. Conclusion Varus but not valgus alignment increased the risk of incident tibiofemoral osteoarthritis. In knees with osteoarthritis, varus and valgus alignment each increased the risk of progression in the biomechanically stressed compartment.

The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: A report from the glucosamine/chondroitin arthritis intervention trial

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.