To test the hypothesis that an
antiresorptive agent might reduce the dosing requirement for an anabolic
drug during reversal of
osteopenia due to
estrogen deficiency, the following experiment was conducted in 6-month-old female rats.
Ovariectomy or
sham surgery was performed and the following six experimental groups were studied. Untreated (
SHAM) or ovariectomized (OVX) animals served as control groups. Four weeks post-OVX, osteopenic rats (now 7 months old), were treated in one of four experimental protocols: human
parathyroid hormone (hPTH(1-34)), 80 microg/kg/day, given by
subcutaneous injection 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 combinations 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 at 7 and 10 months of age. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at four skeletal sites: two mixed cortical/trabecular sites (femur and tibia) and two predominantly trabecular sites (lumbar spine and pelvis). The differences in BMD were consistent at all four sites. 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)
injections given 5 days/week resulted in BMD increments significantly higher than in either OVX or
SHAM controls (p < 0.001). While the RA did not enhance the
anabolic effects of full doses of hPTH(1-34), the addition of RA treatment to twice-weekly hPTH(1-34) dosing resulted in BMD increments at all four skeletal sites that were similar to the more intensive anabolic regimen of hPTH(1-34)
therapy given 5 times/week. Therefore, an
antiresorptive agent such as
SERMs may potentially reduce the pharmacologic doses of PTH needed to reverse
estrogen deficiency-induced
osteopenia.