Long-term therapy of ovariectomy-induced osteopenia with parathyroid hormone analog SDZ PTS 893 and bone maintenance in retired breeder rats

Abstract

The aim of the study was to assess the long-term anabolic effect of the parathyroid hormone (PTH) analog SDZ PTS 893 in a dose-response manner, and to determine the ability of the antiresorptive agents estradiol and alendronate to maintain bone mass after withdrawal of SDZ PTS 893. One hundred thirty retired breeder Wistar rats were distributed into 13 groups with 10 rats in each group: 1 baseline group, 2 sham groups, and 10 ovariectomized groups. Treatment was initiated 12 weeks after ovariectomy. SDZ PTS 893 treatment was administered daily subcutaneously (Monday to Friday) for 36 weeks. Treatment regimens were as follows: (1) baseline (−12 weeks); (2) ovariectomy (ovx) (0 weeks); (3) sham (36 weeks); (4) ovx (36 weeks); (5) SDZ PTS 893 12.5 μg/kg/day (36 weeks); (6) SDZ PTS 893 25 μg/kg/day (36 weeks); (7) SDZ PTS 893 50 μg/kg/day (36 weeks); (8) SDZ PTS 893 100 μg/kg/day (36 weeks); for the maintenance part of the study: (9) sham (48 weeks); ovx animals treated with SDZ PTS 893, 50 μg/kg/day for 36 weeks followed by 12 weeks of treatment regimens: (10) placebo; (11) SDZ PTS 893 50 μg/kg/day; (12) estradiol 10 μg/kg/day; or (13) alendronate 28 μg/kg (2 injections/week). The effects of ovx, SDZ PTS 893 treatment, and maintenance regimens were measured at four skeletal sites: lumbar vertebra; femoral diaphysis; distal femoral metaphysis; and proximal femoral metaphysis (femoral neck). At these sites, bone density and bone strength were measured as treatment endpoints. Furthermore, bone dimensions were measured at the midpoint of the femur. The results showed that SDZ PTS 893 increased bone strength in a dose-dependent manner at all skeletal sites tested. At the vertebral body and distal femoral metaphysis, apparent ash density increased in a similar way. There was a slight decrease in cortical density at the mid-diaphyseal site. Static histomorphometry showed increased bone area due to a decreased marrow area (endosteal net bone gain) but also due to increased tissue area (periosteal net bone gain). For maintenance, continuous SDZ PTS 893 therapy was most efficient, followed by alendronate and estradiol treatment with regard to preservation of bone mass and strength. It is concluded that the new PTH analog SDZ PTS 893 has a highly anabolic, dose- and time-dependent effect on all skeletal sites tested. Bone formation is induced at both endosteal and periosteal surfaces.