Maintenance of bone mineral density of femoral cortex in ovariectomized rats after withdrawal of concurrent administration of human parathyroid hormone (1–34) and incardronate disodium (YM175)

The aim of this study was to evaluate the potential use of a combination of human parathyroid hormone (1–34) [hPTH(1–34)] and bisphosphonate (incadronate disodium cycloheptylaminomethylenedisphosphonate monohydrate, YM175) as a therapy for osteoporosis. We examined the effects of concurrent administration of PTH and YM175 or single administration and the persistence of their therapeutic effect after withdrawal on bone mineral density (BMD) of the femur in ovariectomized rats with established osteopenia. One hundred and two 11-week-old Sprague-Dawley rats were divided into sham operation and ovariectomy (OVX) groups. OVX rats were untreated for the first 4 weeks post ovariectomy to allow for the development of moderate ovariectomy to allow for the development of moderate osteopenia. These animals were then subjected to various treatment regimens with either PTH, YM175, or both for 4 weeks. The animals were then killed at 4 or 12 weeks, after withdrawal of the treatment and the bone mineral density (BMD) of distal, middle, proximal part, and total area of the femur were determined by dual-energy X-ray absorptiometry (DXA). In the distal femur (cancellous bone-rich region), treatment with YM failed to restore BMD in OVX rats, while treatment with PTH alone (P<.01) or PTH + YM175 (P<.01) reversed BMD in OVX rats after 4 weeks of treatments. The restored distal BMD by PTH or PTH + YM175 treatments could be maintained thereafter until 12 weeks withdrawal. In midshaft of the femur (cortical bone-rich region), treatment with PTH (P<.05), YM175 (P<.05), and PTH + YM175 (P<.01) all could increase BMD after 4 weeks of treatments in the OVX rats, but only concurrent treatment with PTH + YM175 maintained the BMD of femoral midshaft for 12 weeks after withdrawal of the treatment. These results suggest that (1) concurrent treatment with PTH and YM175 could result in a bone gain not only in cancellous bone but also in cortical bone of the femur, and (2) the restored BMD could be maintained for 12 weeks after cessation of the treatment in cortical bone only by concurrent use of PTH + YM175 in immature ovariectomized rats