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 micrograms/kg/day, and (4) PGE2 + ALN at the respective doses. The sixth group served as nonovariectomized untreated controls. Histomorphometric analysis of 6-10 microns thick tibial sections after in vivo fluorochrome double labeling showed that treatment with PGE2 alone increased endocortical 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).(ABSTRACT TRUNCATED AT 250 WORDS)

Low levels of plasma IGF-1 inhibit intracortical bone remodeling during aging

“…Our results are in agreement with a previous study of 29 inbred mouse lines showing that genes affecting strength by varying BMD are different than those that affect strength by altering cross-sectional geometry (Wergedal et al 2005) and likely from those altering intracortical remodeling. Cortical porosity has been reported in several earlier studies and seems to differ greatly among animal models, with low values for rodents (Bagi et al 1997;Lauritzen et al 1993) and higher values for sheep (Chavassieux et al 2001) and dogs (Sietsema 1995;Wilson et al 1998). In agreement with the μCT data, showing increased intracortical porosity, we demonstrated an increase in intracortical calcein labeling and TRAP staining and a lack of new lamellar bone, indicating increased intracortical bone remodeling/turnover in WT mice that favors resorption over formation.…”

In vivo effects of two novel ALN-EP4a conjugate drugs on bone in the ovariectomized rat model for reversing postmenopausal bone loss

“…Unfortunately, systemic administration of exogenous PGE 2 has been associated with a number of adverse effects including headache, gastrointestinal problems, lethargy, flushing, and uterine contraction. Furthermore, PGE 2 requires daily administration as well as a fairly high dose of around 1 to 3 mg in order to achieve robust anabolic bone effects on rats [23,24]. As a result, its therapeutic use in humans may be limited.…”

Effects of a new conjugate drug in a rat model of postmenopausal osteoporosis

“…than that of PGE 2 alone. This was true for both dynamic bone formation parameters in trabecular bone and bone volume in the proximal tibial metaphysis 349 . In contrast, the conjugate drug in the current study demonstrates strong anabolic effects in both the proximal tibial metaphysis and the lumbar vertebrae, and appears to show both anti--resorptive and anabolic effects.…”