Effects of combined prostaglandin and alendronate treatment on the histomorphometry and biomechanical properties of bone in ovariectomized rats

Abstract

Prostaglandin E₂ (PGE₂) has been shown to stimulate both bone resorption and formation in experimental animals, leading to augmentation of trabecular and cortical bone. The amino bisphosphonate alendronate (ALN) is a potent inhibitor of bone resorption. The objectives of this study were to examine if PGE₂ stimulation of bone formation was dependent on bone resorption and if the bone accrued as a result of PGE₂ treatment contributed to bone strength. The 48 female Sprague‐Dawley rats were assigned to six groups as follows: five groups (8/group) were ovariectomized at the age of 6 months. One group was sacrificed 2 months later to establish baseline conditions, and four groups were treated for 25 days with (1) vehicle, (2) PGE₂ at 3 mg/kg/day, (3) ALN sc at 0.8 μg/kg/day, and (4) PGE₂ + ALN at the respective doses. The sixth group served as nonovariectomized untreated controls. Histomorphometric analysis of 6–10 μm thick tibial sections after in vivo fluorochrome double labeling showed that treatment with PGE₂ alone increased endo‐cortical mineral apposition rate and bone formation rate, stimulated production of bone trabeculae in the marrow cavity, and increased cortical porosity. Combined ALN + PGE₂ treatment prevented the resorption induced by PGE₂ but not the stimulation of bone formation on endocortical and periosteal surfaces and resulted in a significant increase in cortical thickness. Consistent with these observations, the femoral midshaft tested to failure in three‐point bending showed a significant increase in strength in the PGE₂ + ALN group (181 ± 15 N) compared to time 0 controls (145 ± 23 N) or to the ovariectomized vehicle‐treated group (141 ± 28 N). Similarly, there was a statistically significant increase in femoral midshaft stiffness. There was also a statistically significant increase in the ash content of bones from animals treated with PGE₂ + ALN relative to vehicle‐treated animals. No statistically significant differences among groups were observed in femoral neck or vertebral strength or stiffness. These findings show that PGE₂ stimulation of bone formation is not blocked by inhibition of bone resorption and that combined treatment with PGE₂ and the bone resorption inhibitor ALN increased the mechanical strength of ovariectomized rat femoral shaft compared to nonovariectomized animals.