Effects of long-term administration of clodronate on growing rat bone.

Bisphosphonates inhibit bone resorption. Short-term bisphosphonate treatment at therapeutical dosage has been shown to be safe, but there are only a few studies concerning the long-term effects of bisphosphonates on the non-osteoporotic skeleton. Here, we studied the bone effects of 32 weeks' treatment with clodronate on growing rats, using a therapeutical dose of 2 mg/kg and a high dose of 10 mg/kg. We used biomechanical, densitometrical, and, histomorphometrical analyses to examine the rat tibia, femur, and vertebra and also tested some hematological and biochemical parameters. Tibial length was significantly lower in the high clodronate group compared with the controls. No differences were found in tibial or vertebral ash weights. The L4 vertebra compression failure load was higher in the high clodronate group compared with the therapeutical clodronate group, but not compared with the controls. The mechanical strength of the femoral shaft or femoral neck was not affected by clodronate. Cortical BMD in the L4 vertebra was significantly higher in both clodronate groups compared with controls. Histomorphometrical analysis indicated that the trabecular number of vertebra was increased in the therapeutical clodronate group. The mineral apposition rate was not significantly affected by the treatment. Hematological analyses showed a decreased number of platelets at the high dosage. A slight increase in liver enzyme activity was seen in both groups. We conclude that long-term administration of clodronate has no harmful but rather some beneficial effects on bone at the therapeutical dosage. However, a fivefold dose of clodronate causes a slight decrease in the growth of tibial length.