Faculty Bibliography

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 confirm preclinical data suggesting that doxycycline can slow the progression of osteoarthritis (OA). The primary outcome measure was joint space narrowing (JSN) in the medial tibiofemoral compartment. METHODS: In this placebo-controlled trial, obese women (n = 431) ages 45-64 years with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with 100 mg doxycycline or placebo twice a day. Tibiofemoral JSN was measured manually in fluoroscopically standardized radiographic examinations performed at baseline, 16 months, and 30 months. Severity of joint pain was recorded at 6-month intervals. RESULTS: Seventy-one percent of all randomized subjects completed the trial. Radiographs were obtained from 85% of all randomized subjects at 30 months. Adherence to the dosing regimen was 91.8% among subjects who completed the study per protocol. After 16 months of treatment, the mean +/- SD loss of joint space width in the index knee in the doxycycline group was 40% less than that in the placebo group (0.15 +/- 0.42 mm versus 0.24 +/- 0.54 mm); after 30 months, it was 33% less (0.30 +/- 0.60 mm versus 0.45 +/- 0.70 mm). Doxycycline did not reduce the mean severity of joint pain, although pain scores in both treatment groups were low at baseline and remained low throughout the trial, suggesting the presence of a floor effect. However, the frequency of followup visits at which the subject reported a > or = 20% increase in pain in the index knee, relative to the previous visit, was reduced among those receiving doxycycline. In contrast, doxycycline did not have an effect on either JSN or pain in the contralateral knee. In both treatment groups, subjects who reported a > or = 20% increase in knee pain at the majority of their followup visits had more rapid JSN than those whose pain did not increase. CONCLUSION: Doxycycline slowed the rate of JSN in knees with established OA. Its lack of effect on JSN in the contralateral knee suggests that pathogenetic mechanisms in that joint were different from those in the index knee

OBJECTIVE: To determine if intraarticular (IA) injection of hyaluronan (HA) into the canine knee after anterior cruciate ligament transection (ACLT) alters the progression of osteoarthritis (OA) and the perception of pain in this model. METHODS: OA was induced in 30 adult dogs of mixed breed by ACLT. The dogs were divided into 3 groups and given 5 weekly IA injections into the unstable knee during Weeks 1-5 and 13-17. The prophylactic treatment group received HA in the first series and saline during the second series. The therapeutic group received saline in the first series and HA in the second series. The control group received saline during both injection series. The progression of joint damage of OA was evaluated by arthroscopy 12 weeks after ACLT and by gross examination 32 weeks after ACLT. Histologic and biochemical changes of OA were evaluated. Loading of the unstable limb during gait was determined by force-plate analysis before surgery, after each series of injections, and the week before euthanasia. RESULTS: Arthroscopic examination 12 weeks after ACLT revealed OA changes in the cruciate-deficient knees. Chondropathy scores ranged from 0 to 8 (possible range 0-65). The mean chondropathy score was 2.5 +/- 1.3 (mean +/- SD) for the controls, 2.5 +/- 2.5 for the therapeutic group, and 2.1 +/- 1.3 for the prophylactic group. At the termination of the experiment 32 weeks after ACLT, the gross chondropathy scores were 14.0 +/- 5.2 for controls, 17.6 +/- 6.8 for the therapeutic group, and 13.3 +/- 5.0 for the prophylactic group. There were no significant differences among the means of the gross scores, the histologic scores, or biochemical composition of articular cartilage. The peak vertical ground reaction force (VGRF) generated by the unstable limb was reduced by ~60% after ACLT, and slowly increased to ~75% of the baseline value over the 32 weeks after ACLT. HA injection had no effect on the VGRF or on the pathologic changes of OA. CONCLUSION: Intraarticular HA injection did not alter the progression of OA in the cruciate-deficient canine knee or alter the loading of the unstable limb

OBJECTIVE: To describe the methods by which remarkable levels of subject retention and adherence were achieved in a 30-month multicenter randomized placebo-controlled trial (RCT) of a disease-modifying osteoarthritis drug (DMOAD). METHODS: Subjects were obese 45-64-year-old women with unilateral knee osteoarthritis. Before randomization, each volunteer completed a 4-week 'faintness-of-heart' (FOH) test, during which she was required to demonstrate reliable appointment keeping and > or =80% adherence to the dosing regimen. Subjects who passed the FOH test were randomized to treatment with doxycycline or placebo for 30 months. The double-blind phase entailed 15 bimonthly followup visits; intervisit adherence data were downloaded from the dosing monitor and used to estimate therapeutic coverage and to identify correctable patterns of nonadherence. Subjects received token incentives and a small cash payment at each followup visit. Measures to prevent or treat side effects of doxycycline were dispensed free of charge. Study coordinators monitored safety and reinforced participation through between-visit telephone calls. RESULTS: Of 463 eligible volunteers, 32 (7%) failed the FOH test and were excluded from the double-blind phase. Among the 431 subjects randomized to treatment groups, 307 (71%) completed the 30-month RCT and 124 discontinued the study drug prematurely. Nearly half of the dropouts returned for their 16- and 30-month radiographs, resulting in loss to followup of 14.8% of randomized subjects. The 2 treatment groups did not differ significantly with respect to rates of discontinuation or retention. Therapeutic coverage over 30 months was very high in both groups. CONCLUSION: The rate of discontinuation in this 30-month RCT (29%) was lower than that of any DMOAD trial of > or =2 years duration published to date. The proportion of subjects for whom 30-month radiographs were available (85%) and adherence to the dosing regimen (mean >80%) also were remarkably high

OBJECTIVE:: The objective of this study was to evaluate a nurse-directed self-management intervention for managed care patients with knee osteoarthritis (OA), emphasizing nonpharmacologic (NonPharm) management of pain and functional impairments and minimization of exposure to the risks and costs of nonsteroidal antiinflammatory drugs (NSAIDs). METHODS:: Subjects were 186 patients from a large health maintenance organization (HMO) who satisfied American College of Rheumatology clinical criteria for knee OA. Two of 4 HMO sites (and their patient cohorts) were randomly assigned to the education group; the other 2 served as a delayed-intervention control group. At each location of care for the education group, an arthritis nurse educator, in consultation with the patient's primary care physician (PCP), followed a detailed algorithm for implementing and monitoring the response to NonPharm treatment modalities (eg, quadriceps strengthening exercises, counseling in principles of joint protection, use of thermal modalities). The nurses apprised the PCP of the patient's progress and made algorithm-based recommendations, as appropriate, for reduction of dose, and eventual discontinuation, of NSAIDs in favor of acetaminophen. Outcomes (measured at baseline, 3, 6, and 12 months) included pain and function scales from the Western Ontario and McMaster Universities (WOMAC) OA Index. RESULTS:: The treatment groups were similar at baseline with respect to sociodemographic and clinical characteristics. Medical record audits revealed that NonPharm treatments (most often exercise) were implemented by 75% of patients in the education group but by only 18% of patients receiving routine care (P < 0.00001). Over the subsequent 12 months, 20 patients (26%) in the education group, but only 3 (5%) in the control group (P = 0.002), underwent changes in drug treatment of OA pain consistent with the NSAID-sparing goals of the intervention, ie, acetaminophen as initial drug of choice; reduction in dose, or discontinuation, of NSAID; switch from an NSAID to an analgesic. Only one patient in the education group required reinstitution of NSAIDs because of an increase in knee pain. Mean WOMAC scores indicated no deterioration of pain control or function over 12 months in the group treated according to the algorithm. CONCLUSION:: Incorporation into the primary care setting of self-care education for patients with knee OA, with collaboration between a proactive arthritis nurse and the patient's PCP, can reduce reliance on NSAIDs without a resultant increase in OA pain and disability

OBJECTIVE: To identify changes in joint pain, stiffness, and functional ability in patients with knee osteoarthritis (OA) after use of a knee sleeve that prevents loss of body heat by the joint. METHODS: Subjects with symptomatic knee OA (n = 52) were randomized to 2 treatment groups: verum sleeve (specially fabricated to retain body heat) or placebo sleeve (standard cotton/elastane sleeve). Subjects wore the sleeve over the more painful OA knee for at least 12 hours daily for 4 weeks. Pain, stiffness, and functional impairment (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) in the index knee were measured at baseline and after 4 weeks of wear, after which sleeve use was discontinued. Telephone followup interviews were conducted 2 and 4 weeks later. RESULTS: After 4 weeks of sleeve wear, subjects in the active treatment group reported a 16% decrease in mean WOMAC pain score relative to baseline (P = 0.001). Those who wore the placebo sleeve reported a 9.7% decrease from baseline (P = 0.002). The difference between treatment groups was not statistically significant (P = 0.12). However, it was found that the 12 subjects who believed correctly that they had received the verum sleeve reported a highly significant decrease in WOMAC pain score (-27.5% relative to baseline, P = 0.0001). In comparison, subjects who received the verum sleeve but believed they had received the placebo sleeve exhibited only a marginally significant improvement in pain (-13.0% relative to baseline, P = 0.07). In the placebo group, the modest improvement in pain scores appeared unrelated to the subject's impression of the type of sleeve worn. CONCLUSION: This pilot study was insufficiently powered to be a definitive trial of the heat-retaining sleeve. Given the magnitude of changes in knee pain in the active treatment group, heat retention merits further scientific investigation as a treatment modality for patients with knee OA

OBJECTIVE: Computerized measurement of changes in joint space width (JSW) on serial radiographs of the knee in the semiflexed, anteroposterior (SF-AP) view has been used recently as a primary outcome measure in clinical trials of disease-modifying osteoarthritis drugs (DMOADs). In the use of fluoroscopy to achieve reproducible alignment of the medial tibial plateau and x-ray beam, the SF-AP radiographic protocol affords greater sensitivity in the detection of joint space narrowing (JSN) than that achieved by conventional radiographic positioning techniques. However, the utility of the SF-AP view is compromised by the variation in x-ray penetration in each examination, which may confound the correction of the automated measurement of JSW for the radiographic magnification inherent in an AP view of the knee. A recent DMOAD trial using the SF-AP protocol showed an improbable increase in JSW of > or =0.50 mm (i.e., greater than the measurement error). The present report provides an analysis of this problem, and the study aim was to demonstrate that substitution of the automated estimates of JSW with precise manual measurements can markedly reduce the problem attributable to radiographic magnification. METHODS: SF-AP radiographs were obtained at baseline and at 16 months and 30 months thereafter from subjects enrolled in a 6-center DMOAD trial. For each examination, a 6.35-mm steel ball was affixed to the skin over the head of the fibula to permit estimation of the percentage of radiographic magnification (%Mag) and correction of JSW measurements. Measurements of the minimum interbone distance (IBD) in the medial tibiofemoral compartment and the %Mag were obtained by an automated method (edge detection) and manually. Combinations of automated and manual measurements of the IBD and %Mag in estimates of magnification-corrected JSW were compared with respect to their reproducibility, agreement, and sensitivity to JSN. RESULTS: With fully automated measurements, variations in x-ray penetration in analog radiographs and edge enhancement in digital radiographs resulted in the computer 'seeing' a metal ball whose diameter was artifactually reduced, resulting in an inflated measurement of JSW. Use of manual measurement of the IBD and %Mag largely eliminated these problems and reduced, from 16% to 2%, the frequency of knees exhibiting an increase in JSW > or =0.50 mm. In 14 of the 15 knees in which a significant increase in JSW was noted with the manual method, this increase in JSW could be explained by the development of significant lateral compartment narrowing during the study or poor alignment of the medial plateau. CONCLUSION: Although automated and manual methods of JSW measurement of the knee in the SF-AP view possess comparable intrareader reproducibility, the manual method is less susceptible to technical factors that affect the correction of raw JSW estimates for radiographic magnification. Until we can identify practical, effective solutions to these technical problems, use of any radiographic protocol involving AP imaging of the knee in a DMOAD trial must be viewed with caution

OBJECTIVE: To determine the predictive value of bone scintigraphy with respect to joint space narrowing (JSN) in patients with knee osteoarthritis (OA), based on quantitative estimates of uptake of a bone-seeking radiopharmaceutical and fluoroscopically standardized knee radiography. METHODS: Our study group included 86 obese women, 45-64 years of age, with unilateral knee OA. Uptake of technetium medronate (99mTc-MDP) in late-phase bone scans was measured at baseline in 5 regions of interest (ROI: lateral femur, lateral tibia, medial femur, medial tibia, and patellofemoral joint) and was adjusted for uptake (i.e., expressed as a ratio to uptake) in a ROI in the shaft of the tibia, which served as an internal standard. Each subject underwent a fluoroscopically standardized radiograph of the knees (semiflexed anteroposterior view) at baseline, 16, and 30 months. Magnification-corrected minimum joint space width in the medial tibiofemoral compartment was measured by digital image analysis. RESULTS: Followup was available for 79 patients (92%) at 16 months and from 73 patients (85%) at 30 months. On average, 99mTc-MDP uptake in each ROI and in the whole knee (average of 4 tibiofemoral ROI) was 170-240% of that in the tibial shaft. Uptake in the medial tibia and in the whole knee was significantly correlated with JSN at 16 and 30 months (r = 0.22-0.30, p < 0.05). However, after controlling for age, body mass index, and radiographic severity of OA, the associations between adjusted uptake and JSN were not significant. The rate of JSN in knees of patients with OA who were in the lower tertile with respect to adjusted 99mTc-MDP uptake in the medial tibia was significantly less rapid than in patients in whom uptake was in the middle and upper tertiles (0.04 mm/yr vs 0.18 mm/yr; p < 0.05). However, after controlling for overall radiographic severity at baseline, the difference in 30-month JSN in knees of patients with OA in the lower versus middle/upper tertiles was not significant. CONCLUSION: The predictive utility of bone scintigraphy is confirmed by these data. However, its practical value is considerably diminished, insofar as similarly predictive information may be obtained by routine radiographic examination, without the radiation exposure and cost of scintigraphy

Osteoarthritis (OA) represents failure of the diarthrodial joint and may be due to a primary abnormality in any of the tissues of the joint, e.g. articular cartilage, subchondral bone, synovium, periarticular muscle, or sensory nerves whose termini lie within the joint. Neuropathic arthropathy, due to severe sensory neuropathy, causes severe and rapid breakdown of joints. We have shown that interruption of sensory input from the ipsilateral hind limb strikingly accelerates progression of OA after anterior cruciate ligament transection in the dog; a clinical correlate exists in humans with diabetic neuropathy who sustain even minor joint trauma. Knee OA in humans is accompanied by defects in proprioception, although it is not clear whether the neurological abnormality is primary or a consequence of intra-articular pathology. The magnitude of the load on a joint and, especially, the rate of impulsive loading, influence development of OA. It is relevant, therefore, that quadriceps weakness may precede development of knee OA in some people, insofar as this may diminish the effectiveness of protective muscular reflexes and thereby increase deleterious joint loading. Individuals vary with respect to how they load their joints, perhaps because of genetic differences in central program generators