SKELETAL GROWTH AND BONE-DENSITY AS SENSITIVE PARAMETERS IN EXPERIMENTAL ARTHRITIS - EFFECT OF CYCLOSPORINE-A

Osteopenia and retarded skeletal growth are consistent features of juvenile polyarthritis. Although the former has also been described in the experimental animal, the consequences of induced joint inflammation on skeletal growth have not yet been documented. In order to investigate the effect of experimental arthritis on these parameters, we studied female rats with adjuvant arthritis (AA) subjected to chronic treatment with cyclosporin A (CsA, Sandimmun(R)). This compound has been found to prevent the development of articular swelling and also repair joint and skeletal lesions in AA rats. Five groups of 8 animals each received oral CsA, 2.5, 5, 10, 20, or 30 mg/kg daily for 30 days. Eight normal and eight diseased, untreated rats served as placebo controls. The parameters studied were (a) measurement of hindpaw swelling, (b) radiometric assessment of vertebral growth, (c) vertebral trabecular density, (d) weight control and nutritional status. At the end of the investigational period, AA-rats on no therapy had severe osteopenia and growth retardation. Treatment with CsA, 2.5 mg/kg, was ineffective, but doses between 5 and 20 mg/kg prevented the development of articular and osseous lesions and normalized growth. A catch-up phenomenon was also observed. The 20 mg/kg dose showed no better effect than 10 mg/kg, and 30 mg/kg produced a significant reduction in bone density and skeletal growth, an effect thought to be toxic in nature. Body weight paralleled growth profiles, and average food consumption was stable in all groups with the exception of somewhat low records in the animals receiving 30 mg/kg. A comparison with classical features of human juvenile arthritis indicated that the clinical and radiological profiles concerning joint swelling, osteopenia, skeletal growth, and response to treatment, occur in a similar fashion, although it cannot be inferred that the operating mechanisms are common to both situations. It is concluded that skeletal growth measurements may represent a sensitive additional parameter in the evaluation of experimental arthritis and its response to potential therapeutic agents.