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OBJECTIVE: Bisphosphonates have slowed the progression of osteoarthritis (OA) in animal models and have decreased pain in states of high bone turnover. The Knee OA Structural Arthritis (KOSTAR) study, which is the largest study to date investigating a potential structure-modifying OA drug, tested the efficacy of risedronate in providing symptom relief and slowing disease progression in patients with knee OA. METHODS: The study group comprised 2,483 patients with medial compartment knee OA and 2-4 mm of joint space width (JSW), as determined using fluoroscopically positioned, semiflexed-view radiography. Patients were enrolled in 2 parallel 2-year studies in North America and the European Union. These studies evaluated the efficacy of risedronate at dosages of 5 mg/day, 15 mg/day, 35 mg/week (in Europe), and 50 mg/week (in North America) compared with placebo in reducing signs and symptoms, as measured by the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and patient global assessment (PGA) scores, and in slowing radiographic progression. RESULTS: A reduction of approximately 20% in signs and symptoms, as measured by WOMAC subscales and PGA scores, was observed in all groups, with no treatment effect of risedronate demonstrated. Risedronate did not significantly reduce radiographic progression as measured by decreased JSW or using a dichotomous definition of progression (joint space loss of >or=0.6 mm). Thirteen percent of patients receiving placebo demonstrated significant disease progression over 2 years. A dose-dependent reduction in the level of C-terminal crosslinking telopeptide of type II collagen, a cartilage degradation marker associated with progressive OA, was seen in patients who received risedronate. No increase in the number of adverse events was demonstrated for risedronate compared with placebo. CONCLUSION: Although risedronate (compared with placebo) did not improve signs or symptoms of OA, nor did it alter progression of OA, a reduction in the level of a marker of cartilage degradation was observed. A sustained clinically relevant improvement in signs and symptoms was observed in all treatment and placebo groups. [ABSTRACT FROM AUTHOR]

Rationale: Minimum tibiofemoral joint space width in the medial compartment (JSW) is the most well-established structural outcome measure for osteoarthritis (OA) of the knee. Its usefulness as a measure of therapeutic effectiveness in short-term studies is limited by the rate and variability of joint space narrowing (JSN) in the OA population. Microfocal radiography has been shown to improve reproducibility of JSW measurement compared to standard radiography, but measurement of magnification from microfocal knee films has been problematic, and JSN is yet to be investigated in a longitudinal microfocal study., Objective: To establish the effect on JSW reproducibility of a new method of magnification measurement in microfocal radiographs. To report on and compare rates of medial tibiofemoral JSN and their variations in the placebo arms of microfocal and standard radiographic clinical trials in OA, using fluoroscopic semi-flexed (SF) knee positioning. To place in the context of published estimates of rates of JSN from comparable studies., Methods: Using microfocal radiography, 36 patients were followed at a single centre for 2 years. Using standard radiography, 86 patients were followed for 1 year at a single centre, and 549 for 2 years in a multi-centre international study. Computerised JSW measurement was undertaken using enhanced and automated versions of existing algorithms. Rates of JSN were examined in the context of a review of published rates of JSN using a variety of techniques., Results: Reproducibility of JSW measurement from microfocal radiographs was improved by the new magnification measurement. Rates of JSN were similar across the studies, but more variable when using standard radiography. The rates of JSN were also consistent with those from previously published investigations; all estimates since 2000, bar one, being consistent with the value 0.05 mm/year., Conclusion: Microfocal radiography using the new method lowered the variability of the rate of JSN, but the high cost and low availability of microfocal equipment remains a barrier to its more widespread use. The consistently low but highly variable rates of JSN seen in the review suggest that continued attempts to improve radiographic and mensural techniques are unlikely to significantly reduce required sample sizes.

Objectives: To determine whether risedronate (RIS) slows down trabecular bone loss in the medial compartment of the proximal tibia, a characteristic of patients with progressive knee osteoarthritis (OA)., Methods: Initially, 100 patients were randomly selected from each treatment group (each N approximately 300) comprising placebo and RIS 5 mg/day, 15 mg/day and 50 mg/week from a double blind, multi-centre, placebo-controlled, 2 yr investigation of OA knee patients in North America. Using fluoroscopic semi-flexed standard radiography, baseline and exit knee radiographs were digitized by laser scanner. Following computerized measurement of minimum medial compartment joint space width, each group was subdivided into joint space narrowing (JSN) non-progressor or JSN-progressor (JSN >or=0.6 mm measured at any point post-baseline). Computerized method of fractal signature analysis (FSA) quantified longitudinal changes separately in horizontal and vertical trabeculae in region of interest (three-fourth width of tibial compartment x 6 mm height) in the medial compartment. Following the initial study, all JSN-progressor knees within the entire patient cohort (N = 1232) were similarly analysed., Results: OA knees in JSN non-progressor group had a slight decrease in FSA for vertical and horizontal trabeculae and showed no drug effect. In JSN-progressor knees, bone loss was greater in both placebo and RIS 5 mg/day groups compared with those in RIS 15 mg/day group in which trabeculae were retained, and in the RIS 50 mg/week group in which the vertical trabecular number increased significantly (P < 0.05)., Conclusion: This preliminary study showed that patients with marked cartilage loss (JSN>or=0.6 mm) receiving RIS 15 mg/day retained vertical trabecular structure, and those receiving RIS 50 mg/week increased vertical trabecular number, thereby preserving the structural integrity of subchondral bone in knee OA.

Rationale: Superimposition of the rims of the medial tibial plateau to within 1mm is an aim of fluoroscopic knee positioning protocols for osteoarthritic (OA) knee radiography and has also been proposed as a measure of quality for non-fluoroscopic methods., Objective: To evaluate the effect of tibial rim alignment (TRA) on reproducibility of joint space width (JSW) measurement, both were measured from radiographs taken with each tibial plateau at a range of angles determined by different non-fluoroscopic views., Methods: TRA and JSW measurements were taken from both knees of 100 OA patients each radiographed in fully extended, schuss/tunnel, and MTP views. Degree of TRA was compared with JSW reproducibility using correlation, and between groups defined both by the 1mm threshold and by TRA-defined quartiles., Results: JSW reproducibility was dependent on the degree of TRA in the fully extended and schuss/tunnel flexed knee views, although the use of the specific TRA threshold of 1mm was not supported. In the MTP view, JSW measurement was found to be highly reproducible across the full range of TRA values., Conclusion: These results contradict claims that TRA to within 1mm is essential for useful measurement of JSW. It is an arbitrary threshold, of use in quality control (QC) for protocols which explicitly require such alignment, and the choice of QC criteria for other protocols should be evaluated on a view-by-view basis. The results confirm previous studies showing the MTP view to afford highly reproducible JSW measurement.

The development of pharmaceutical treatments for bone disease can be enhanced by mathematical models that predict their effects on matrix apposition during cancellous bone remodelling. Therefore, a mathematical model was constructed to simulate the rate of focal bone formation from the number of osteoid-forming osteoblasts at one microsite and their rate of activity. The number of mature osteoid-forming cells was simulated from a relationship describing the proliferation of preosteoblasts. Osteoblast activity was described by Michaelis-Menten enzyme kinetic equations adapted to describe cellular activity. The model incorporates the negative feedback effects on the rates of bone apposition due to the reduction in size of mature osteoblasts with continuing differentiation and the reduction in number of osteoid-forming cells with apoptosis and osteocyte formation. In addition, the rate of mineralisation is limited according to osteoid substrate availability. Results of sensitivity analysis revealed the amount of bone formed at one microsite to be more sensitive to changes in factors that controlled cell growth during proliferation and the number of mature osteoid-forming osteoblasts than to those that determined cellular activity. Matrix and osteocyte signalling were shown to have potentially important roles in controlling rates of osteoid apposition in normal, healthy bone. This simple model supports the critical role of controlled mitotic growth in normal bone apposition. It can also help to explain how the homeostatic processes of bone resorption and apposition during remodelling can be disrupted by growth factors that affect the mitotic fraction and division time of proliferative preosteoblast cells.

The purpose of this study was to determine whether fractal analysis (FSA) of macroradiographs or bone mineral density (BMD) is more sensitive in detecting disease-related cancellous bone alterations in knee osteoarthritis (OA). Differences in BMD between 11 OA (6 females) and 11 non-OA reference (7 females) tibiae were compared with differences in trabecular organization measured by computerized method of fractal signature analysis (FSA) of digitized macroradiographs (x3.5 to x5). OA knees had anatomic and radiographic evidence of medial compartment disease. FSA measured cancellous bone organization at 4 regions of interest (ROI): medial and lateral subchondral (Sc) and subarticular (Sa) sites, dual X-ray absorptiometry (DXA) measured BMD at the same ROIs. Compared to non-OA, OA tibiae had significant increased (P < 0.05) in FSA of vertical trabeculae in the medial Sa region (trabecular size range: 0.42-0.54; 0.90-1.98 mm) and significant decrease (P < 0.05) in FSA for some horizontal trabeculae in the Sc region (trabecular size range: medial side 0.12-0.18 mm; lateral side 0.12-0.24 mm). Compared to non-OA, BMD of OA tibiae was not significantly different at any ROI. BMD was not sensitive to changes in trabecular organization detected by FSA. The increase in FSA of vertical trabeculae in the medial Sa region was consistent with trabecular fenestration and thinning, which may have been detected as decreased BMD in a larger sample. For studies involving small sample sizes, quantifying changes in trabecular organization is more sensitive than BMD for detecting bone alterations in knee OA.

To determine the efficacy and safety of risedronate in patients with knee osteoarthritis (OA), the British study of risedronate in structure and symptoms of knee OA (BRISK), a 1-year prospective, double-blind, placebo-controlled study, enrolled patients (40-80 years of age) with mild to moderate OA of the medial compartment of the knee. The primary aims were to detect differences in symptoms and function. Patients were randomized to once-daily risedronate (5 mg or 15 mg) or placebo. Radiographs were taken at baseline and 1 year for assessment of joint-space width using a standardized radiographic method with fluoroscopic positioning of the joint. Pain, function, and stiffness were assessed using the Western Ontario and McMaster Universities (WOMAC) OA index. The patient global assessment and use of walking aids were measured and bone and cartilage markers were assessed. The intention-to-treat population consisted of 284 patients. Those receiving risedronate at 15 mg showed improvement of the WOMAC index, particularly of physical function, significant improvement of the patient global assessment (P < 0.001), and decreased use of walking aids relative to patients receiving the placebo (P = 0.009). A trend towards attenuation of joint-space narrowing was observed in the group receiving 15 mg risedronate. Eight percent (n = 7) of patients receiving placebo and 4% (n = 4) of patients receiving 5 mg risedronate exhibited detectable progression of disease (joint-space width >or= 25% or >or= 0.75 mm) versus 1% (n = 1) of patients receiving 15 mg risedronate (P = 0.067). Risedronate (15 mg) significantly reduced markers of cartilage degradation and bone resorption. Both doses of risedronate were well tolerated. In this study, clear trends towards improvement were observed in both joint structure and symptoms in patients with primary knee OA treated with risedronate.

The development of pharmaceutical treatments for bone disease can be enhanced by computational models that predict their effects on resorption and rates of remodeling. Therefore, a simple mathematical model was formulated to simulate erosion depth and duration of resorption, using Michaelis-Menten (M-M) equations to describe changing rates of cellular activity during the two phases of bone resorption. The model was based on histomorphometric data and cellular interactions that occur in the bone microenvironment cited from the literature. Availability of bone substrate for osteoclastic activity during Phase I was assumed to be limited by the ratio of RANKL (ligand for receptor activator for nuclear factor kappaB) to osteoprotegerin (OPG) ('effective RANKL'). The required presence of marrow stromal cell produced macrophage-colony stimulating factor (M-CSF) for osteoclast action was represented as a factor equal to 1 for healthy bone. Growth factors released from the matrix during Phase I were assumed to cause two negative feedback effects: (1) the inhibitory effect of transforming growth factor-beta1 (TGFbeta1)-induced production of OPG by marrow osteoblast stromal cells, reducing effective RANKL; (2) the apoptosis of osteoclast nuclei assumed to occur at high concentrations of TGFbeta. This signaled the end of Phase I. During Phase II, cellular activity to remove the collagen fibrils left behind by osteoclasts was also simulated by Michaelis-Menten kinetic equations. Results of sensitivity analysis revealed variation in resorption depth and duration to fluctuate within 6% and 7% of the baseline value for changes in most input parameters. However, resorption depth was reduced and the duration of resorption lengthened by both a decrease in matrix TGFbeta and an increase the apoptotic threshold. Furthermore, the duration of resorption, but not erosion depth, was sensitive to changes in the maximum rate of cellular activity during removal of collagen fibrils. This mathematical model, which simulates the changing rates of cellular activity, has identified factors that reduce the duration and depth of resorption. It also suggests new targets for modeling therapeutic intervention to slow the rate of bone remodeling.

Objective: Fractal signature analysis (FSA), a computerized method of textural analysis, permits the separate measurement of changes in vertical and horizontal trabeculae based on the fractal dimension over a range of trabecular widths (fractal signature). We determined whether the FSA of high-definition macroradiographs (x5 magnification) quantified radiographic changes at sites of osteopenia and erosion formation in the rheumatoid arthritis (RA) hand., Methods: Sixty-seven RA patients had macroradiographs of the left wrist and hand. The distal radius was scored and grouped from very mild (RA1) to moderate (RA4) disease. Macroradiographs were digitized and FSA of horizontal and vertical trabecular organization was performed in the radius at sites of periarticular osteopenia, erosion formation and at a mid-metaphyseal site. The RA groups were compared with 11 healthy non-arthritic subjects using ANOVA and Dunnett's tests., Results: Compared to the non-arthritic hands, FSA at the distal radius in groups RA1 to RA4 measured significantly lower (P<0.05) fractal signatures. The fractal signatures were lowest in RA4 involving small, medium to large sized vertical trabeculae at the periarticular osteopenic (0.18 to 0.84 mm, P<0.01) and mid-metaphyseal sites (0.12 to 0.60 and 0.84 to 1.02 mm, P

Objective: To determine the baseline and longitudinal consistency in reproducibility of the semiflexed metatarsophalangeal (MTP) position in repeat examinations of patients with knee osteoarthritis (OA) recruited for a multicenter clinical trial that terminated within one year (mean duration 0.81 yr), based on precise measurements both of minimum medial tibiofemoral compartment joint space width (JSW) and of tibial inter-rim distance., Methods: Two technologists from 8 and one technologist from 14 clinical radiology units had received previous training in performing nonfluoroscopic semiflexed MTP knee examinations and in quality control criteria for film acceptance. Patients (N = 402; F = 269) were recruited from 58 rheumatology sites and referred to 22 centers, or "x-ray hubs," across North America. At baseline and at study exit, both knees were x-rayed twice on the same day. All films had quality control, and accepted films were digitized at the Central Radiographic Facility and transmitted to the Central Analysis Facility for computerized measurement of minimum medial compartment JSW and tibial inter-rim distance. JSW loss was calculated in the placebo group for the study period., Results: The median SD of the difference in JSW between same-day test/retest film pairs was 0.9 mm for 767 baseline film pairs (knees with JSW > 0 mm), and 0.08 mm for 631 exit film pairs. JSW reproducibility was unaffected by subject's sex, age, and degree of JSW loss. Among all x-ray hubs, JSW reproducibility was excellent in 14 (SD < 0.1 mm), good in 6 (0.1 < SD < 0.2 mm), and moderate in 2 hubs (0.2 < SD < 0.3 mm). No statistical difference was found in technologists' ability either in positioning OA knees or in their test/retest reproducibility in repositioning joints at baseline and at study exit. JSW did not alter significantly during the study period., Conclusion: The protocol for the semiflexed MTP knee position provides a highly reproducible method for anatomically repositioning the knee and for measuring JSW, necessary for OA clinical trials. It is a simple method that can be employed readily at clinical radiology units, as shown by the similarity in JSW precision between x-ray hubs. The results from this large dataset show that throughout the study precise measurements of JSW were obtained from same-day repeat radiographs, findings that together with previous single-center studies confirm the reliability of this method for clinical trial use.

The objective of this study was to determine whether fractal signature analysis (FSA) of digitized macroradiographs of knees with prosthetic implants quantifies alterations in tibial trabecular structure surrounding the implant over a 3-year period. Nineteen knees (16 patients) with arthroplasty had macroradiographs (x4) at baseline and annually for 3 years. The regions of interest (ROIs) were located in the medial and lateral plateau, midstem, and apical sites. FSA of horizontal and vertical trabecular organization was measured at each ROI, and the changes at the yearly visits were compared to the baseline values. Compared to the baseline values, FSA of the first-year radiographs detected a significant ( P < 0.05) decrease in the number of vertical trabeculae in the medial compartment, and vertical, and horizontal trabeculae in the lateral compartment. During the second year, bone remodeling led to an increase in the number of horizontal trabeculae in the medial compartment, and vertical, and horizontal trabeculae in the lateral compartment. During the third year, there was a significant increase ( P < 0.05) in the number of vertical and some horizontal trabeculae in both the medial and lateral compartments. Overall trabecular changes were significantly greater in the lateral than in the medial compartment. Following total knee arthroplasty, the response of bone showed that the first year was characterized by trabecular loss in response to posttraumatic osteopenia following surgery. By the third year, this process had reversed, with a significant increase in mainly vertical and some horizontal trabeculae in both the medial and lateral compartments, with only the lateral compartment showing an overall loss in small- and medium-sized trabeculae by the end of the study period.

Objective: To determine the reproducibility of x-ray technologists, 26 in North America (NA), 24 in Europe (EU), in reliably repositioning patient's osteoarthritic (OA) knees, from computerized measurements of minimum joint space width (JSW) and reproducibility in joint repositioning, during their training for the clinical trial., Methods: Technologists from 12 NA and 12 EU clinical radiology units received identical training, at one site on each continent, in performing the fluoroscopically assisted semiflexed knee examination and in quality control criteria (QCC) for film acceptance. Subjects recruited were 129 in NA and 70 in EU, with both knees radiographed for some subjects. Each technologist radiographed 5 OA knees and repeated the process on the same knees 2 to 7 days later. Minimum medial JSW was measured at a single center on digitized images with computer software that corrected for radiographic magnification. Technologists' reproducibility in joint repositioning and JSW measurement was determined from the difference between test and retest., Results: In all, only 3/50 technologists failed qualification criteria with a repeat-film JSW difference > 0.50 mm. The mean, standard deviation (SD) of the difference in JSW between test/retest for 146 NA film-pairs of -0.020 (0.16) mm was not statistically different from that in 120 EU film-pairs: -0.001 (0.18) mm. In NA and EU 45% of examinations achieved high quality, i.e., JSW difference between repeat films < 0.1 mm, and 92% achieved excellent to good quality with a difference between repeat films < 0.3 mm. NA and EU technologists' reproducibility was unaffected by subject's sex, age, and degree of JSW loss. Reproducibility in joint reposition for all technologists was excellent., Conclusion: Between-continent precision of JSW measurements from all accepted pairs of semiflexed views was excellent to very good and similar to the high technical quality achieved in the authors' original report. The value of training incorporating both test/retest radiographs and film QCC is essential for the high technical quality required for multinational clinical trials.

Objective: In knee osteoarthritis (OA) damage to meniscal cartilage is associated with the changes in articular cartilage. Using double-contrast macroradiographs we determined whether the degree of meniscal cartilage damage was similar to or different from that at the corresponding regions of the articular cartilage on the tibia and femur., Design: Double-contrast microfocal macroradiographs,x7-x9 magnification, were obtained of the tibio-femoral joint in 20 osteoarthritic knee patients with medial compartment disease (Kellgren and Lawrence grades I-III). The appearance of the meniscus and the femoral and tibial articular cartilage were graded separately using a 5-point scale., Results: In the medial diseased compartment, articular cartilage damage on the tibia was similar to that of the meniscus, which had significantly greater (P<0.02) degenerative changes than the cartilage on the femur. In the lateral compartment, meniscal damage was significantly worse than in either tibial (P<0.04) or femoral articular cartilages (P<0.01), respectively; none was as severe as that in the medial osteoarthritic compartment., Conclusion: Although the cross-sectional nature of this study precluded definite aetiological inferences, this study showed that degenerative changes in the meniscal and articular cartilages were not totally variable. Because of its larger articular surface, changes in the medial femoral cartilage were less marked than at the meniscal and tibial cartilages in the osteoarthritic compartment. In the lateral compartment, meniscal damage precedes tibial and femoral articular cartilage changes. In knees with medial compartment OA, combined meniscal and articular cartilage damage would account for detection of radiographic joint space loss and not meniscal extrusion only.

One method of Herbert screw insertion is to mobilize the scaphotrapezial joint and insert the screw through the articular surface of the distal scaphoid. Because of concern that this might predispose to osteoarthritis in the scaphotrapezial joint, we have investigated joint space width and the presence of osteophytes adjacent to the scaphotrapezial joint using high definition macroradiography.Twenty-eight patients with symptomatic primary osteoarthritis of their hands, 23 with a scaphoid fracture successfully treated conservatively and 18 treated with a Herbert screw were studied. The patients with primary osteoarthritis of their hands had more narrowing of the scaphotrapezial joint compared with the other two groups, but patients treated with a Herbert screw had a significantly higher incidence of osteophytosis on the distal scaphoid than the other two groups. With Herbert screw fixation, osteophytosis on the distal scaphoid may cause impingement and pain, and be a predictor of further degenerative joint changes., (Copyright 2000 The British Society for Surgery of the Hand.)

Objective: To determine, in a preliminary cross sectional study of patients with anterior cruciate ligament (ACL) ruptured knees, which of the radiographic features-subchondral cortical plate thickness, trabecular sclerosis, and osteophytosis-appears before or in association with changes in joint space width (JSW) as a surrogate for articular cartilage thickness in patients with ruptured knees., Methods: 19 patients (14 men), mean (95% CI) age 28.7 (23.6 to 33.8) years, had ACL rupture in one knee only, confirmed by arthroscopy. Anterior draw, Lachman's test, and pivot shift tests were performed and x5 posteroanterior macroradiographs of both knees in a standing semiflexed view were taken at a mean (95% CI) time from injury of 34. 3 (26.9 to 41.7) months. In each radiograph, computerised methods were used to measure minimum JSW and fractal signature analysis (FSA) to quantify the vertical and horizontal trabecular organisation, osteophyte area, and the subchondral cortical plate thickness, in the medial and lateral tibial compartments of all knees., Results: Physical examination confirmed the presence of joint laxity in the injured knees. No statistical difference in either medial or lateral JSW and subchondral cortical plate thickness was detected between ACL ruptured and uninjured knees. FSA showed a significant decrease in fractal dimension for the horizontal trabeculae (size 0.42 mm) in the medial compartment of the ACL ruptured knees compared with the uninjured knees (p<0.01, multivariate analysis of variance). There was an inverse correlation (R -0.74) between the time since knee injury and the difference in FSA values for ACL ruptured and uninjured knees in medial compartment horizontal trabeculae (size 0.4 mm). No significant changes were detected in the lateral compartment. Osteophytes were detected in the medial compartment of nine ACL injured knees., Conclusion: Compared with the uninjured knee, ACL rupture leads to thickening of subchondral horizontal trabeculae (decreased FSA) in the medial tibial compartment of all knees, reaching significance at about four years after injury. Osteophytes were present in the same compartment in 9/19 knees. No changes in JSW and subchondral cortical plate thickness were detected. Whether the bony changes detected in these ACL ruptured knees presage those of early osteoarthritis requires further study.

Objective: The different radiographic procedures and methods for reading films and assessing the status and progression of hand osteoarthritis (OA) were reviewed., Methods: The methods that relate to each of the above procedures were assigned to categories upon which there was or was not general agreement., Results: It was agreed that the radiographic method should use published standardized radiographic protocols; that X-ray features should be graded separately for determining the extent of the disease and that changes in osteophyte size was the most sensitive indicator of progression. For epidemiological studies films should be read blind and randomly, but for assessing progression films should be read in pairs and in sequence. No agreement was obtained on the value of the lateral radiographic view of the hand nor on which radiographic atlas would be best for long-term longitudinal studies., Conclusions: Further work was required to evaluate the role of MRI and scintigraphy in hand OA; radiographic atlases could be improved by incorporating diagrams to illustrate the change in grade for each feature; validation was required for methods of assessment in long-term trials.

Objective: To improve the radiographic assessment of cartilage loss, as measured by joint space width (JSW) in patients with osteoarthritis (OA) of the knees required to detect the effect of structure modifying drugs in OA trials. This was achieved by determining which of 3 nonfluoroscopic radiographic views--standing extended, semiflexed, and schuss--produced the most accurate radioanatomic positioning of the joint and greater reproducibility in joint repositioning and JSW measurement., Methods: Knees from 74 patients with OA of the knees who had medial tibiofemoral compartment JSW > or =2 mm in all views were studied. For all 3 radiographic views, accuracy in the radioanatomic positioning of the knee was determined for both joint rotation and flexion. Reproducibility in joint repositioning and JSW measurement were determined from the difference between repeat examinations taken within 2 h., Results: About 86% of knees in the 3 views had accurate rotational position of the joint at each visit. Radioanatomically, knees in the semiflexed view were significantly more accurately positioned in regard to knee flexion (p<0.0005) than in the schuss view, which in turn was better (p<0.014) than in the extended knee view. Joint repositioning was significantly more reproducible in the semiflexed (p<0.0001) than in the extended knee, which was better (p<0.013) than in the schuss position. JSW measurement was significantly more reproducible in the semiflexed (p<0.014) than both schuss and extended knee positions, which were not significantly different from each other., Conclusion: Protocols defining the nonfluoroscopic radiographic procedures for the semiflexed view provide the most accurate radioanatomic joint positioning, and the most reproducible joint repositioning and JSW measurement. Using this method significantly fewer knees would be required to detect significant JSW changes in a structure modifying drug trial compared to the schuss and the extended knee positions.

Objective: To estimate the reproducibility of computerized measurements of minimum joint space width (JSW) in the medial tibiofemoral compartment in knee radiographs (semiflexed AP view) obtained from clinical radiology units., Methods: Technologists from 5 clinical radiology units were trained in the performance of the fluoroscopically assisted semiflexed AP knee examination. Each of 44 subjects (34 with knee osteoarthritis, OA, 10 with bilaterally normal knees) were examined within 7 days in 2 of the 5 units. The examination in each unit was repeated 1 week later. Minimum JSW was measured on digitized radiographic images with computer software that corrected for radiographic magnification., Results: Despite ongoing quality control by technologists, 11% of radiographs were flawed with respect to the protocol standard for knee rotation and 36% with respect to the standard for knee flexion. The standard error of measurement (SEm) of JSW in 174 knees that were examined twice in the same unit was 0.32 mm (SEm = 0.25 mm for the subset of 76 paired radiographs with uniformly high quality). The overall between-unit SEm was 0.45 mm. Within-unit, but not between-unit, precision was related to the technical quality of the radiographs. Precision was unrelated to subject age, sex, race, weight, and radiographic severity of knee OA., Conclusion: The within-unit precision of JSW measurements from all pairs of semiflexed views (irrespective of technical quality) represented a notable improvement over that observed in radiographs with flawed knee rotation or flexion (as would be the case in conventional extended knee views). In future applications of this technique, assurance of technical quality by an independent observer should result in a level of measurement precision that will permit the design of clinical trials of disease modifying OA drugs with fewer subjects and/or shorter duration of treatment than is possible with conventional knee radiography.

Microfocal radiography records, with unusually good resolution, the detailed structural organization of cancellous bone. A textural imaging method, fractal signature analysis (FSA), was used to quantify the horizontal and vertical trabecular organization recorded within macroradiographic images of the spine of post-menopausal women and the tibia in osteoarthritic knees, and the analysis of variance method was applied to the wrist and hand of rheumatoid patients. Changes in trabecular structure were found to correlate with (i) body weight, age and bone mineral density in the lumbar spine of post-menopausal women; (ii) the degree of cartilage loss and age in the tibia of patients with knee OA; and (iii) analysis of variance quantified the extent of 'normal', osteopaenic and eroded bone in rheumatoid joints. Quantitation of cancellous bone organization can add significantly to our understanding of disease processes and effect of therapy in diseased joints.

Objective: To determine whether fractal signature analysis (FSA) of digitised macroradiographs of knees quantifies alterations in trabecular structure in the tibial cancellous bone of osteoarthritic patients with either early or definite joint space narrowing compared with non-arthritic subjects., Methods: 90 osteoarthritic knees had macroradiographs at x5 magnification. Joint space width and FSA of horizontal and vertical trabecular organisation in the tibial subarticular cancellous bone were measured in the medial and lateral tibio-femoral compartments and compared to reference values obtained from the knees of 14 healthy non-arthritic volunteers, and to the subject's age and weight., Results: Compared to the non-arthritic joints, FSA of the trabecular structure of the medial diseased compartment of the tibia was significantly different and correlated with the degree of joint space narrowing (P < 0.003); FSA of horizontal trabecular structures decreased (P < 0.001) in knees with early osteoarthritis (joint space > 3 mm) and vertical trabecular FSA increased in knees with marked joint space narrowing (joint space < 3 mm). In the lateral compartment of the tibia, FSA did not show a difference between any of the categories. With increasing age of all subjects, the changes in FSA indicated a significant increase in the number of fine horizontal and vertical trabeculae. No correlation was found between the subjects' body weight and changes in the subarticular cancellous bone organisation., Conclusions: FSA quantifies changes in cancellous bone organisation in knee osteoarthritis. In the diseased compartment, increased horizontal trabecular thickness occurred early and preceded the later changes in the vertical structures.

Quantitative macroradiography of patients with hand and knee OA, employing standardized radiographic and mensural procedures, permit: accurate and reproducible measurements of all radiographic features. significant changes in JSW and osteophyte number and size to be detected within as short a period as 18 months. therapeutic effects upon articular cartilage to be determined from changes in JSW. a better understanding of the disease process from an evaluation of the relative changes in the different radiographic features of OA.

Objectives: To improve the reproducibility and accuracy of joint space width (JSW) measurement as an assessment of cartilage loss in patients with osteoarthritis (OA) of the knee by determining how precision and accuracy of JSW measurement were altered by a computerised method of measurement, correction for radiographic magnification, radiography of the knee in the standing semiflexed view, and high definition macroradiography of the knee in the semiflexed view--taking JSW measurements from standard radiographs of OA knees in the extended view as the standard for comparison., Methods: Twenty five OA and 10 nonarthritic knees were radiographed in the extended view and minimum JSW was measured manually. Conventional and x5 macroradiographs were taken in the semiflexed view. All radiographs were taken twice on the same day and repeated two weeks later. Automated computerised measurement of minimum JSW was obtained from digitally stored images of all radiographs., Results: For medial compartment JSW measurements, computerised was more accurate than manual, correction for radiographic magnification improved precision and accuracy, measurements in the semiflexed view were more precise and accurate, and macroradiography increased measurement precision. For the lateral compartment JSW measurements, correction for radiographic magnification improved precision and accuracy, and the semiflexed view improved precision only., Conclusions: Protocols defining radiographic and mensural procedures are essential for quality control of knee radiography in the semiflexed view to permit accurate and reproducible measurement of JSW. Macroradiography provides greater precision of JSW measurement.

We undertook to determine which of the radiographic features most reliably detected the presence and disease progression in osteoarthritis in the hand; and which of the radiographic features corresponded with the radionuclide bone scan images. 32 patients with osteoarthritis had X 5 macroradiographs taken of their wrists and hands at 6 monthly intervals over an 18 month period. The high magnification and resolution of microfocal radiography permitted quantitative detection of the extent and change in joint space width, subchondral sclerosis, osteophytosis and juxtaarticular radiolucencies. 4-hour technetium 99m methylene bisphosphonate bone scans were taken at 0 and 12 months and the activity of the tracer uptake at each joint scored. The latter was compared with the radiographic features at each visit and the changes between visits analysed. In hand OA the most sensitive radiographic parameters for detecting disease were osteophytes, subchondral sclerosis and juxtaarticular radiolucencies, with radionuclide imaging demonstrating the increased activity in bone formation associated with the growth and remodelling of osteophytes. Changes in the number and size of osteophytes and joint space narrowing were the only reliable and sensitive parameters for assessing disease progression. We conclude that in osteoarthritis, the bony changes progress significantly before the occurrence of radiographically evident joint space narrowing indicative of cartilage thinning.

Objective: To assess the usefulness of, and define the time course of changes in the features of osteoarthritic (OA) knees measurable using microfocal radiography, and to determine whether it differs in patients taking a nonsteroidal antiinflammatory drug (NSAID)., Methods: Forty-five patients with knee OA were randomly allocated to receive either diclofenac sodium or placebo for 18 months; 33 (17 NSAID, 16 placebo) completed the study. Clinical and 5 x high definition macroradiographic assessments of both knees in standing semiflexed views were carried out at 6-monthly intervals. Precise measurements were taken of the tibial and femoral subchondral thickness and osteophyte size, and of joint space width (JSW) across the narrowest part of the medial and lateral tibiofemoral compartments., Results: In all knees as a group, there was no statistically significant difference in JSW between treatment groups. However, changes in JSW were significantly different (p < 0.04, multivariate analysis of variance) between treatments in 51 knees with early disease, i.e., those with initially > 50% JSW (22 active, 29 placebo), but not in 15 knees with severe disease, i.e., initially < 50% JSW (10 active, 5 placebo). During the study, osteophyte size in all knees and in those with > 50% JSW increased significantly (p < 0.016; p < 0.008) in the placebo group but remained unchanged in the treatment group. No significant changes were detected in subchondral cortical thickness., Conclusion: Using microfocal radiography the time course of changes in JSW and osteophyte size of knees with early, but not late OA, was found to differ in both pattern and magnitude in patients receiving NSAID: In knees with late stage OA the JSW progressively decreased irrespective of treatment. The observations may prove useful for the design of future therapeutic trials.

Objective: To test reliability of joint space width (JSW) measurements as a predictor of cartilage thickness in knees of patients with osteoarthritis (OA), using high definition microfocal radiography., Method: JSW was measured from weight bearing plain film macroradiographs taken in the tunnel view and compared with the sum of femoral and tibial cartilage thicknesses measured from double contrast macroarthrograms of the same regions of the same knees obtained in the non-weight bearing lateral position., Results: All knees had medial compartment OA. Comparison of the JSW with the sum of the tibial and femoral cartilage thicknesses revealed a highly significant correlation (p < 0.0001) between the two measurements in the medial but not the lateral compartment. In the middle region of both compartments, JSW was smaller than the cartilage thickness, indicating that, on standing, the curvature of the femoral condyles compressed the cartilage in this region., Conclusions: JSW reliably measured cartilage thickness in the medial but not the lateral compartment of knees with medial compartment OA. Depending upon the stage of OA disease, JSW reliably reflects cartilage thinning and compression.

Stereoscopic macroradiography was used to study the pattern of union of scaphoid fractures. Of 21 patients who had partial union of a scaphoid fracture, 13 united on the ulnar side and five on the radial side only. In three it was on both sides but delayed in the centre. Where there was initial union on the ulnar side, all progressed to complete union, including two patients with displaced fractures. Four out of five patients with initial union on the radial side had displaced fractures, and three of these went on to non-union. We conclude that in those patients with partial union of a scaphoid fracture, if union is seen on the ulnar side, the fracture is likely to unite completely, whereas if there is partial union on the radial side, there is a high risk of non-union.

Objective: Joint space width (JSW) in osteoarthritis (OA) knee radiography is reported to be optimally assessed from semiflexed standing and tunnel views although no detailed assessment of tunnel view radiography of OA knees has been done. The primary objective of our study was to determine the incidence of joint space narrowing (JSN) in semiflexed standing vs weight bearing tunnel views. The data were also analyzed to examined the degree and relationship of JSN and bony features of OA in the 2 views., Methods: Ninety OA knees had macroradiographs at 5 times magnification taken in weight bearing standing semiflexed and weight bearing tunnel views. JSW and OA related bony features were measured and compared with reference values obtained from the knees of 14 healthy volunteers without arthritis., Results: Comparison of JSW between the 2 radiographic views identified 3 locations of cartilage loss: JSN recorded in the tunnel only (22%), that in standing view only (8%), and that in both the views (30%). Subchondral sclerosis and osteophytes were significantly larger in 40% of OA knees despite a normal JSW. The tunnel view also enabled better visualization and measurement of osteophytes., Conclusion: Standing semiflexed view radiography alone failed to detect JSN in 22% of OA knees. Combined standing and tunnel radiographic views detected JSN more frequently than either view alone. Bony changes were radiographically evident without the presence of JSN indicative of cartilage thinning in as many as 40% of the patients with OA studied.

Quantitative microfocal radiography was used to assess the degree of symmetry in radiological features between the dominant and non-dominant wrist and hands of 51 patients with early to moderately advanced RA. With few exceptions, erosion size and joint space width were bilaterally symmetrical between the dominant and non-dominant side in: total erosion area and total joint space width; area at each of the separate sites of erosion formation, and width at each joint space; and the change in these X-ray features over an 18-month study period. Asymmetry in the number and size of erosions and joint space occurred in a small number of patients within either extremity; these differences were not sustained over the study period. In view of this degree of bilateral symmetry, the extent and progression of the radiographic features in RA can be assessed from a single macroradiograph of either the left or right wrist and hand.

High definition macroradiography was used to provide an image of the detailed structural organization of the cancellous bone in human lumbar vertebrae. The fractal signature analysis (FSA) method was used to quantify the horizontal and vertical trabecular organization recorded within the image. Comparison of the FSA of the postero-anterior and lateral macroradiographs in postmortem lumbar vertebrae showed that neither the superimposition of the neural arch nor the radiographic angle affected the trabecular measurement within the vertebral body. FSA analysis of the trabecular structure measured from the macroradiographs of lumbar vertebrae in two groups of postmenopausal women, with high and low bone mineral density (BMD), showed that the large vertical trabecular structures correlated with the women's body weight (P < 0.01-0.03) and body mass index (P < 0.005-0.05), the fine horizontal structures correlated with the women's age (P < 0.005-0.05), and fine vertical trabecular structures were significantly greater (P < 0.005-0.05) in the low compared with the high BMD group.

Thirty-five patients with OA of the hands had an early and late phase isotope bone scan performed at entry and 1 yr later. Simultaneous assessment of symptoms was made by a visual analogue pain score (VAS) and a tender joint articular index (AI) and comparisons were made between the clinical and scintigraphic findings. Sixty-five percent of joints were classed as positive in the late phase compared to 17% in the early phase scan. Thirteen per cent of joints were positive only in the early phase and 49% only in the late phase. There was no significant overall change in either phase of the scan in 1 yr. The pattern of positive joints showed considerable symmetry and wrist involvement. There was a high degree of correlation between AI and the late phase scan but none with the early phase scan. VAS showed no correlation with the late phase scan but did correlate significantly with the early phase scan at 1 yr.

The precision of joint space width (JSW) measurements from plain film radiographs of the knee is limited by poor radio-anatomical positioning of the joint and/or insensitive methods of measurement. These limitations were overcome by establishing a precise radio-anatomical position for standing loaded and weight-bearing tunnel views of the knee, using the advantages of high definition macroradiography and a new computerized method for automatic JSW measurement from digitized macroradiographs of the knee. Reproducibility of JSW measurements was obtained from macroradiographs of knees of five post-mortem subjects and 12 patients with osteoarthritis (OA). JSW measurements were altered more by vertical than by horizontal misalignment of the X-ray beam relative to the joint space. In OA knees with medial compartment involvement, JSW measurements were more reproducible in the medial than lateral compartments in both radiographic views. In the medial compartment, the coefficient of variation for joint repositioning was 1% for minimum and 2% for average JSW, and for inter- and intraobserver errors, it was < 1% for both JSW measurements. The precision of this method will permit quantification of changes in JSW associated with disease progression and the treatment of OA.

Patients with early rheumatoid arthritis (RA) were randomly divided into those receiving gold early (n = 13) or 6 months later (n = 10). They were followed 6 monthly over 18 months. Mean erosion area in gold and delayed gold, measured from macroradiographs, was comparable at baseline and increased significantly over the first 6 months. In the second 6 months, gold showed no increase and delayed gold an insignificant increase. By the third 6 months both groups showed a decrease. On comparing the second 6 months of gold therapy in gold and delayed gold with a group of patients with RA of similar disease duration (n = 34) not receiving gold, a lower proportion (p < 0.005) had erosion area progression and a higher proportion (p < 0.001) erosion repair.

Measurement of joint space width and subchondral sclerosis from x 5 macroradiographic examination of 32 patients with osteoarthritis (OA) of the hand over an 18-month period showed that joint space loss was symmetrical in both hands. Its change showed that over a period of time narrowing progressed proximally from distal interphalangeal to proximal interphalangeal, metacarpalphalangeal and wrist joints. Sclerosis was greatest in those joints at which the largest forces were exerted across the hand in precision, power and pulp-pinch grip, respectively. Our findings suggest that constitutional factors determine the onset of cartilage changes in OA which in turn result in subchondral sclerosis, the extent of which is determined by the pattern of normal forces within the hand.

Quantitative microfocal radiographic assessment of osteophytes in osteoarthritic hands showed that their number and area were greatest at joint margins, in the dominant hand, in the second and third compared with fourth and fifth phalanges, in the third phalanx, and in the second distal interphalangeal joint respectively. These sites correspond with those for the largest forces exerted in the hand: the dominant side, the finger tripod used in the precision grip, power grip, and pulp-pinch respectively. The greater osteophytosis on the trapezium of the nondominant first carpometacarpal joint was probably related to forces exerted during power grip. Osteophytes increased significantly in number and area during the 18 month study period.

Simultaneous clinical, scintigraphic, and macroradiographic assessments were carried out on 32 patients with hand osteoarthritis and the results at entry and one year reported. The presence and growth of osteophyte correlated with symptoms and a positive scan. The scan did not detect the radiographic features of juxta-articular radiolucencies, subchondral sclerosis, or cartilage thinning. Osteophytes, particularly when fast growing, produce pain, a 'hot' scan, and may predict disintegration of joint architecture.

Texture of regions of macroradiographs (x5) of six normal and five osteoarthritic knee joints, taken on a high resolution microfocal x-ray unit, are examined using mathematical morphology. Radiographs of bones are two-dimensional projections of attenuation coefficient through the three-dimensional (3D) joint structure. Visible texture represents the summation of the attenuation from numerous thin plates of bone. Where there is no organization in the trabeculae, resultant radiographs approximate a fractal surface. Varying structuring element size in mathematical morphology allows estimation of fractal dimension over a range of resolution. Variation of fractal dimension with resolution, the fractal signature, indicates how images deviate from fractal surfaces. By correct choice of structuring element, a texture analysis method using the fractal signature has been developed, tolerant to changes in image acquisition and digitization. Texture in regions of radiographs of normal tibia approximates a fractal surface with dimension 2.8 as does vertical structure in arthritic patients. In osteoarthritic knee joints, horizontal tibial trabeculae thicken. Horizontal structure in the tibia on radiographs of arthritic patients deviates from the fractal model. This is indicated by peaks in the fractal signature whose height and position match a visual assessment of the degree of arthritic change.

In osteoarthritis of the knee, horizontal trabeculae in the tibia thicken, leading to the appearance of horizontal striations on radiographs. Any attempt to understand and monitor the disease process must examine these changes. We have previously described a method of analysing the texture in these images that uses the mathematical morphology operations of dilation and erosion to calculate how image fractal dimension varies with resolution. This variation with resolution is the fractal signature. Calculation of fractal dimension should be independent of linear transformations in image values, and it is shown that careful choice of morphological structuring element is required for this. In this paper we describe the dependence of our method of calculating the fractal signature on image acquisition and digitization parameters. Errors due to variations in pixel size, X-ray exposure, and patient repositioning are small compared to the changes seen in the signature due to osteoarthritic change. Using pairs of orthogonal structuring elements, one tuned to calculate the signature due to horizontal image structure and the other for vertical image structure, texture directionality is examined. The difference between the two resulting signatures in individual knees is shown to be a measure of the change in texture seen in osteoarthritis.

In this prospective study, the radiological features characteristic of osteoarthritis of the hand were compared with the radionuclide bone scan images. A total of 32 patients was assessed at 6-monthly intervals for 18 months. Microfocal radiographs were taken at each visit. The high magnification and resolution of this technique permitted direct measurement of joint space width, subchondral sclerosis, osteophyte number and area and juxta-articular radiolucency area for each joint in the hand. Four-hour technetium 99m methylene diphosphonate bone scans were taken at 0 and 12 months and the activity of tracer uptake at each joint scored. The latter was compared with each X-radiographic feature at every visit and the changes between visits analysed. The scan scores did not correlate with any of the X-radiographic features other than osteophyte size. During the study the size of growing and remodelling osteophytes increased significantly at joints with raised or increased isotope uptake.

High definition microfocal radiography permitted the quantitative assessment of the radiographic features of renal osteodystrophy in the phalanges of 11 children in stable chronic renal failure, treated with phosphate binders for 1 year. The most consistent feature was subperiosteal cortical resorption, expressed as a ratio total length of resorbed subperiosteal bone/total length subperiosteal bone x 100. It was found that the extent of resorbed bone was significantly greater in the middle phalanx and on the ulnar surface of the phalanges. The radiological findings over the duration of the disease were compared with laboratory assessments and bone histomorphometry. The extent of the percentage of subperiosteal resorption at base line and its change during the study period correlated significantly with the level of serum parathyroid hormone levels and its change over the same period. No other significant correlations were found between radiographic features and laboratory assessments or with bone histomorphometry.

We studied 32 patients with osteoarthritis who had 5x macroradiographs taken of their wrists and hands at 6-month intervals over an 18-month period. The higher magnification and resolution of microfocal radiography permitted the quantitative detection of progressive changes in 4 different features: subchondral sclerosis, the number and size of osteophytes, juxtaarticular radiolucencies, and joint space narrowing. Compared with normal control subjects, subchondral cortical thickness was greater in all patients at entry and showed a variable degree of change over the study period. Osteophytes and juxtaarticular radiolucencies were present in all patients at study entry; by the end of the study, osteophytes had increased in number and area, and juxtaarticular radiolucencies had increased in area, but not in number. At entry, 44% of the patients had joint space narrowing significantly greater than that in the control subjects; by 18 months, this proportion increased to 65%. No correlation was found between subchondral sclerosis, osteophytes, juxtaarticular radiolucencies, and joint space narrowing. We conclude that in osteoarthritis of the hand, the bony changes have progressed significantly before the occurrence of radiographically evident joint space narrowing indicative of cartilage thinning.

Standard radiographic assessment of changes in rheumatoid joints is limited by factors within the radiographic process, i.e. the performance of the X-ray equipment, recording medium and X-ray assessment. The development of microfocal X-ray units overcomes many of the limitations of conventional radiology. The radiographs of high magnification and resolution produced by this system permit early diagnosis and direct quantitative evaluation of disease progress, providing a more effective assessment in therapeutic trials. Advances in other imaging techniques such as computed tomography (CT), nuclear magnetic resonance (NMR) and emission tomography are evaluated in terms of their potential value in assessing disease activity.

This review paper examines the limitations of X-ray techniques, and describes the results of the different methods of assessing disease progression including joint involvement in relation to the duration of the disease, and the different methods for scoring joint destruction. The application of the new X-ray technique of microfocal radiography, which produces radiographs of high magnification (x5-x10) and resolution (2 x 10(-5)m object diameter), is described. The techniques, developed by the author, provide the most accurate method of qualitative and quantitative assessment of disease progression in the wrist and hands of rheumatoid patients.