Abstract
The experiment was performed to explore the pharmacologic effects and the dose-dependency of risedronate in adult rabbits. Groups of sexually mature Japanese female albino rabbits weighing 2.8-3.5 kg were dosed subcutaneosuly with risedronate at three graded dose levels for 14 days. A control group of 5 animals received 0.9% NaCl in the same manner. The rabbits were injected with calcein and oxytetracycline as bone growth indicators. On day 15, the animals were sacrificed, blood was collected, and the tibiae were removed. Bone mineral density (BMD) of the tibia was measured by the MD method, and a non-destructive tibial substantia spongirosa examination at 4.0mm below the growth plate was performed by microfocus CT. Subsequently, histologic examination of the proximal metaphysis was carried out on microslides prepared from resin-embedded tissue blocks, with a phase contrast and a fluorescent light. Blood samples were processed for determination of serum levels of Ca, P, alkaline phosphatase and tartarateresistant acid phosphatase. The results showed a dose-dependent increase in BMD of both the proximal and distal metaphysis, with significant differences especially in the proximal metaphysis betweeen the control groups vs. the 0.01 and 0.05 mgP/kg groups. Microfocus CT analysis revealed a marked increase in spongy bone trabeculae of the risedronate-treated groups. Histologic examination with a phase contrast source revealed increased trabeculae in the risedronate groups. A number of osteoclasts appearing as if clinging to the trabeculae were noted in the controls, whereas in the 0.01 and 0.05 mgP/ kg groups few or no osteoclasts were observed. The findings suggest that the risedronate acted upon osteoclasts to reduce their number and activity. Examination with a fluorescent light showed a reduced interval between the labeling lines, indicating suppression of long-axialtrabecular growth. The treatment with risedronate suppressed both boneformation and, more profoundly, bone resorption. Consequently, the treatment produced an increase in bone density. The effects of this risedronate proved to be more pronounced in the substantia spongiosa showing a faster turn over.
