Effects of cyclosporin-a on rat skeletal biomechanical properties

BACKGROUND Cyclosprin A (CsA) has been widely used clinically to treat the patients who have undergone organ transplantation or acquired autoimmune disease. The purpose of this study is to determine the effects of three different doses of CsA (1.5, 7.5, 15 mg/kg body weight) on the skeletal biomechanical proprieties at different anatomic sites in rats. METHODS Fifty-six male 3-month-old Wistar rats were divided into five groups. Eight rats were randomly chosen as the basal group, while the others were randomly distributed into four groups of 12 animals each. One group was used as controls and received daily subcutaneous injection of 1 ml of saline solution; another three experimental groups were injected subcutaneously with CsA in a daily dose of 1.5, 7.5, and 15 mg/kg body weight respectively for 60 days. The bone biomechanical proprieties, the bone mineral density, as well as the trabecular bone architecture were measured at different anatomic sites, i.e. the lumbar vertebra, the middle femur shaft, and the proximal femur. RESULTS CsA therapy at 7.5 and 1.5 mg/kg can significantly reduce the ultimate force, the ultimate stress and the energy absorption per unit of bone volume of the lumbar vertebra, with no effect on the middle femur. CsA therapy at 7.5 mg/kg can significantly reduce the ultimate force, the ultimate stress and the Young's modulus of the femoral neck, but not CsA at 1.5 mg/kg. Furthermore, CsA therapy at 7.5 and 1.5 mg/kg can significantly reduce the bone mineral density of the lumber vertebra and the proximal femur, but have no effect on the middle femur. CsA therapy at 7.5 and 1.5 mg/kg can also significantly reduce the bone volume fraction of the proximal tibia and the lumber vertebra, but has no effect on the cortical thickness of the middle femoral shaft. In the 15 mg/kg CsA group only one rat survived, and the kidney and liver histology of the survived rat showed extensive tissue necrosis. CONCLUSION Long-term use of CsA can weaken the biomechanical properties and thus increase the fracture rate of the lumbar vertebra and the proximal femur. However, CsA therapy has less effect on the middle femur shaft. The effects of CsA on skeleton are site-specific.