Effects of long-term clodronate administration on bone and on fracture healing in rat, with special reference to methodological aspects

Abstract

<div lang="en" class="abs"><p class="abs_header">Abstract</p><p>Bisphosphonates (BPs) are used in the treatment of osteoporosis. However, their effects, especially long-term effects, on bone and bone healing are not fully known. Clodronate (dichloromethylene bisphosphonic acid) is a first-generation BP.</p><p>The thesis was based on two animal experiments. The first, with 199 rats on long-term clodronate treatment, was divided into four separate substudies. The effects of long-term administration of clodronate to rats were investigated after 32 weeks of treatment. The effects on the femoral shaft, femoral neck and vertebra in normal, non-osteoporotic skeleton were described in two publications. The evaluations were made by biomechanical, densitometric, histological, hematological and electron-microscopic investigations. Fracture healing was investigated in rats after 24 weeks of clodronate treatment. The tibia was fractured, and the effects of treatments were evaluated at 4 and 8 weeks after the fracture. Radiographs and densitometric pQCT in the evaluation of experimental fracture healing were compared. In the other experiment with 30 mice, a mouse immobilisation osteoporosis model for further studies was investigated.</p><p>Long-term administration of clodronate at therapeutic dosage had no harmful impacts but rather some beneficial effects on normal, non-osteoporotic bone. However, long-term high-dose clodronate treatment resulted in a decrement of tibial length but did not have any other significant or adverse effects. In the evaluation of fracture healing, pQCT proved to be better than radiographs in differentiating the total mineralised cross-sectional area of callus and the area of compact bone. Clodronate treatment does not seem to prolong the fracture healing process, even when administered on a long-term basis before the fracture. Clodronate increased the size of callus, but had only a minor effect on its biomechanical properties. Three weeks of hind limb immobilization caused local osteopenia in the tibia when compared to its contralateral leg.</p><p>In conclusion, this thesis suggests that long-term administration of clodronate at therapeutic dosage has no harmful, but rather some beneficial effects on normal, non-osteoporotic bone. However, a fivefold dose of clodronate causes a slight decrease in the growth of tibial length. Healing of fractures during or after clodronate treatment is not inhibited.</p></div>