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

The aim of the study was to assess the long-term anabolic effect of the par athyroid hormone (PTH) analog SDZ PTS 893 in a dose-response manner, and to determine the ability of the antiresorptive agents estradiol and alendrona te to maintain bone mass after withdrawal of SDZ PTS 893. One hundred thirt y retired breeder Wistar rats were distributed into 13 groups with 10 rats in each group: 1 baseline group, 2 sham groups, and 10 ovariectomized group s. Treatment was initiated 12 weeks after ovariectomy. SDZ PTS 893 treatmen t was administered daily subcutaneously (Monday to Friday) for 36 weeks. Tr eatment 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 mu g/kg/day (36 weeks); (6) SDZ PTS 893 25 mu g/kg/day (36 weeks); (7) SDZ PTS 893 50 mu g/kg/day (36 weeks); (8) SDZ PTS 893 100 mu g/kg/day (36 weeks); for the maintenance part of the study: (9) sham (48 weeks); ovx an imals treated with SDZ PTS 893, 50 mu g/kg/day for 36 weeks followed by 12 weeks of treatment regimens: (10) placebo; (11) SDZ PTS 893 50 mu g/kg/day; (12) estradiol 10 mu g/kg/day; or (13) alendronate 28 mu g/kg (2 injection s/week). The effects of ovx, SDZ PTS 893 treatment, and maintenance regimens were me asured at four skeletal sites: lumbar vertebra; femoral diaphysis; distal f emoral 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-depen dent 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. Stati c histomorphometry showed increased bone area due to a decreased marrow are a (endosteal net bone gain) but also due to increased tissue area (perioste al 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 an alog 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. (C) 1999 by Elsevier Science Inc, All rights reserved.