Dose and Administration Schedule Effect of Tiludronate on Joint Damage in the Model of Complete Freund Adjuvant Induced Monoarthritis in Rats

The effects of dose and administration schedule of Tiludronate (TA) were assessed on joint lesions and hyperalgesia in a rat model of monoarthritis induced by injection of Complete Freund Adjuvant into the tibio tarsal joint of the hindpaw on day 0 (D0). Rats (n = 12/group) received subcutaneous injection of saline at D1, D4, D8 and D12; single dose (15 mg/kg; 60 mg/kg) at D1 or repeated doses (15 mg/kg) at D1, D4, D8 and D12 of TA; or daily injection of Meloxicam (1 mg/kg, from D1 to D12). Joint lesion severity, hindpaw volume and hyperalgesia were evaluated using radiography, plethysmometry and paw pressure, respectively. TA dose dependently reduced radiographic joint lesion (p < 0.001), including bone demineralisation and erosion, joint deformation and to a lesser extent, soft tissue and space articular narrowing. These results were supported by a significant limited increase of paw volume at the highest dose, independently of the administration schedule (60 mg/kg, 4 × 15 mg/kg) within D12-D28 (p < 0.01). In contrast, Meloxicam had no effect on radiographic joint lesion and significantly reduced paw volume only within D0-D12 (p < 0.01). Irrespective of dose and administration schedule, TA had a significant partial anti hyperalgesic effect (p < 0.05) within D0-D12 that was sustained until D28. In contrast, Meloxicam had a significant early anti hyperalgesic effect (p < 0.001) that was not sustained overtime. In conclusion, early TA administration showed a beneficial effect on joint lesion severity, with a partial anti hyperalgesic effect indicating that TA might be helpful for the management of arthritic pathologies with bone remodelling and osteolysis.