bay-12-9566 and Osteoarthritis--Knee

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.. 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.. 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.. 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.

Topics: Arthrography; Biphenyl Compounds; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Knee Joint; Male; Middle Aged; Organic Chemicals; Osteoarthritis, Knee; Phenylbutyrates; Posture; Reproducibility of Results

To determine the effect of BAY 12-9566, a matrix metalloproteinase inhibitor, on articular cartilage metabolism in patients with osteoarthritis (OA).. Thirty-five patients with OA were randomized to receive oral daily dosing of BAY 12-9566 (25, 100, or 400 mg) or placebo for 3 weeks prior to knee surgery. Cartilage samples were obtained at surgery and examined for markers of proteoglycan aggrecan turnover (846 epitope, a putative synthesis marker, and keratan sulfate epitope content) and type II collagen synthesis (C-propeptide content), cleavage by collagenase (COL 2-3/4C short), denaturation, and content (COL2-3/4m epitope). BAY 12-9566 concentrations were measured by HPLC in serum, synovial fluid, and cartilage.. Comparisons between study drug and placebo treatments revealed that at the 100 mg dose there was a significant increase in the 846 epitope (p = 0.012). Total type II collagen content was also higher at this dosage (p = 0.012). Alterations in collagen degradation and synthesis were not detected.. BAY 12-9566 at daily doses of 100 mg significantly altered proteoglycan turnover, resulting in a cartilage composition reflected by the content of the 846 epitope that is more characteristic of a young growing individual. The increase in this epitope may signify increased matrix synthesis. The increase in type II collagen content was unexpected, since there was no other evidence for altered collagen turnover. However, increased matrix assembly would also be indicated by this increased content.

Topics: Administration, Oral; Aged; Aggrecans; Antineoplastic Agents; Biphenyl Compounds; Cartilage, Articular; Collagen Type II; Enzyme Inhibitors; Extracellular Matrix Proteins; Female; Humans; Lectins, C-Type; Male; Matrix Metalloproteinase Inhibitors; Middle Aged; Organic Chemicals; Osteoarthritis, Knee; Phenylbutyrates; Proteoglycans; Synovial Fluid; Treatment Outcome