Effects of the NSAIDs meloxicam and indomethacin on cartilage proteoglycansynthesis and joint responses to calcium pyrophosphate crystals in dogs

NSAIDs are a major cause for concern for their propensity to cause joint de terioration in canine, as in human, patients receiving these drugs for trea tment of pain in osteoarthritis and other acute and chronic painful conditi ons. To determine the potential effects of the new NSAID meloxicam on carti lage integrity, the effects of this drug on proteoglycan biosynthesis in vi tro and ex vivo were compared with those of indomethacin, a known inhibitor of sulphated proteoglycans that accelerates joint injury in human osteoart hritis. In vitro cartilage proteoglycan synthesis from a radiosulphate precursor wa s unaffected by 0.5-10.0 mu mol/L meloxicam but was significantly inhibited by 50 mu mol/L indomethacin after 6 or 24 h incubation of femoral or tibia l cartilage explants in organ culture. This is in accord with previous obse rvations in human or porcine articular cartilage under the same culture con ditions. Studies were performed in vivo to establish the effects of the NSAIDs on jo int integrity. This involved determining cartilage proteoglycan synthesis e x vivo, leukocyte, fluid and protein accumulation, as well as pain relief T hus, meloxicam (0.2 mg/kg i.v. x 3 doses) or indomethacin (0.5 mg/kg i.v. x 3 doses) was given for 26 h and the effects were compared with a control ( 1.0 ml saline i.v. x 3 doses) in dogs in which acute inflammation had been induced by intra-articular (i.a.) injection of calcium pyrophosphate dihydr ate (CPPD) crystals into the right stifle joint, an equivalent Volume of sa line being injected into the left stifle joint as a control. No effects wer e observed of the treatment with the NSAIDs on ex vivo sulphated proteoglyc an synthesis. The lack of the expected inhibitory effects of indomethacin m ay be related to the relatively low plasma concentrations of this drug obta ined during the 26 h period of treatment. The pain response, which was elicited up to 6 h following i.a. injection of CPPD crystals, was totally prevented by the treatment with meloxicam and t o a lesser extent with indomethacin. There were no effects from the drug tr eatment on synovial inflammatory reactions (fluid and cell accumulation), a lthough the protein concentration of the exudate was reduced by meloxicam. This indicates that, at the doses given, it was possible to discriminate th e analgesic action from the anti-inflammatory action of the two NSAIDs, thi s being achieved at relatively low plasma concentrations of these drugs. In conclusion, while relatively high therapeutic concentrations of indometh acin inhibit cartilage proteoglycan synthesis, this is not an effect seen e ven at high concentrations of meloxicam. Furthermore, the lack of effects o n proteoglycan synthesis was evident when these two drugs were given in viv o to dogs. However, the signs of pain, but not the inflammation in the join t, were relieved by low plasma concentrations of the drugs. Meloxicam may t hus be safely employed for acute analgesia without the potential risks of j oint cartilage damage that occurs with indomethacin given at antiinflammato ry doses for long periods of time.