The addition of a raloxifene analog (LY117018) allows for reduced PTH(1-34) dosing during reversal of osteopenia in ovariectomized rats

To test the hypothesis that an antiresorptive agent might reduce the dosing requirement for an anabolic drug during reversal of osteopenia due to estr ogen deficiency, the following experiment was conducted in 6-month-old fema le rats, Ovariectomy or sham surgery was performed and the following six ex perimental groups were studied, Untreated (SHAM) or ovariectomized (OVX) an imals served as control groups. Four weeks post-OVX, osteopenic rats (now 7 months old), were treated in one of four experimental protocols: human par athyroid hormone (hPTH(1-34)), 80 mu g/kg/day, given by subcutaneous inject ion 5 days/week; a selective estrogen receptor modulator (SERM), raloxifene analog LY117018 (RA), 3 mg/kg/day, given by gavage 5 days/week; and two co mbinations of LY117018 at the same dose and frequency with hPTH(1-34) (same dose, 5 times/week) and a reduced dosing interval of hPTH(1-34) (same dose , 2 times/week), After 12 weeks of treatment, the four experimental groups were sacrificed at age 10 months, SHAM and OVX controls were also studied a t 7 and 10 months of age. Bone mineral density (BMD) was measured by dual-e nergy X-ray absorptiometry at four skeletal sites: two mixed cortical/trabe cular sites (femur and tibia) and two predominantly trabecular sites (lumba r spine and pelvis), The differences in BMD were consistent at all four sit es. RA alone maintained BMD at all skeletal sites, but the results were not significantly improved over OVX controls, at age 10 months. hPTH(1-34) inj ections given 5 days/week resulted in BMD increments significantly higher t han in either OVX or SHAM controls (p < 0.001),,While the RA did not enhanc e the anabolic effects of full doses of hPTH(1-34), the addition of RA trea tment to twice-weekly hPTH(1-34) dosing resulted in BMD increments at all f our skeletal sites that were similar to the more intensive anabolic regimen of hPTH(1-34) therapy given 5 times/week, Therefore, an antiresorptive age nt such as SERMs may potentially reduce the pharmacologic doses of PTH need ed to reverse estrogen deficiency-induced osteopenia.