Gastrointestinal intolerance has been associated with amino bisphosphonate therapy in the clinic. The objective of this study was to develop a model for assessing bisphosphonate-induced gastric damage that may aid in the development of future bisphosphonate therapies. Rats were dosed concomitantly with indomethacin (40 mg/kg, subcutaneously) and an amino or pyridinyl bisphosphonate (orally at. 150, 225 or 300 mg/kg). The bisphosphonates studied were pamidronate and alendronate (primary amino bisphosphonates) and risedronate and NE-97221 (pyridinyl bisphosphonates). Macroscopically, alendronate induced significantly (P < 0.05) more antral damage (both lesion length and number) than pamidronate and risedronate at 225 and 300 mg/kg, and more than NE-97221 at 300 mg/kg. NE-97221 induced significantly more antral damage (lesion length) than risedronate at 225 mg/kg and a greater number of lesions compared to pamidronate and risedronate at 225 and 300 mg/kg. The model was validated histologically, and macroscopic findings correlated with histologic evidence of antral mucosal necrosis and inflammatory infiltration of the lamina propria. The calcium chelators EGTA and EDTA did not induce gastric damage in this model when dosed according to the same protocol as the nitrogen-containing bisphosphonates. This suggests that calcium chelation does not account for the gastric effects in this model. The fasted, indomethacin-treated rat provides a novel nonclinical model to assess gastric effects of bisphosphonates, which may aid in the development of future bisphosphonate therapies. These data suggest that when expressed on an actual or anticipated clinical dose basis for osteoporosis (pamidronate, 150 mg; alendronate, 5-10 mg; risedronate and NE-97221, 5 mg), primary amino bisphosphonates may have a greater potential for inducing gastric damage than do pyridinyl bisphosphonates.

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[4-14C]Cholesterol side chain cleavage, progesterone synthesis, and cytochrome oxidase activities were measured in mitochondria from unincubated and short term incubated large (8-10 mm) follicles isolated from porcine ovaries. Compared to the activity of mitochondria from unincubated follicles, specific [4-14C]cholesterol side chain cleavage activity in mitochondria from follicles incubated with LH (0.05 microgrogram/ml) did not change significantly after 12 h, but increased almost 2-fold after 18 h and 5-fold after 24 h. Also, specific mitochondrial progesterone synthesis activity increased dramatically after incubation of follicles for 24 h with LH. In comparison, mitochondria prepared from follicles incubated without LH showed no significant change in specific [4-14C]cholesterol side chain cleavage or progesterone synthesis activities after 18 h of incubation. While both of these activities increased after incubating follicles 24 h without LH, the values were significantly lower than those observed for preparations from follicles incubated with LH. In contrast to these changes in mitochondrial steroidogenesis, specific cytochrome oxidase activity in mitochondria did not change after incubation of follicles without or with LH. It is concluded that incubation of follicles with LH stimulates the development of mitochondrial steroidogenesis but initially does not affect some components of the respiratory chain.

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