Hiroyuki Motoie, Hiroyuki Kanoh, Stig Ogata, Kosei Kawamuki, Hisataka Shikama (*) and Takashi Fujikura
Endocrinology and Metabolic Disease Research Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 2I Miyukigaoka, Tsukuba, Ibaraki 305, Japan (*) To whom correspondence should be addressed
Abstract: We have evaluated the effects of YM175 {disodium dihydrogen (cycloheptylamino) methylenebisphosphonate monohydrate}, a novel bisphosphonate, on bone mineral densities (BMD) at the lumbar spine and forelimb in ovariectomized beagles with dietary calcium restriction. Groups 1 and 2 were given a sham operation and Groups 3 - 6 were ovariectomized. One month later (month 0), a low calcium diet was given to Groups 2 - 6. Groups 4 - 6 were orally treated with YM175 at doses of 0.01, 0.1 and 1.0 mg/kg, respectively, for 18 months. Changes in BMD at the lumbar spine and left forelimb were determined serially by dual energy X-ray absorptiometry. Calcium restriction decreased lumbar BMD by 19% at month 2 and by up to 30% at month 17 compared to its baseline value, but ovariectomy itself had a minimal effect on bone mass in dogs with restricted calcium intake. YM175 (1 mg/kg) prevented the bone loss at month 2 and YM175 at 0.1 mg/kg or more inhibited the BMD reduction at month 17. The magnitude of BMD reduction of the forelimb was less remarkable as compared to that of the lumbar spine. Urinary hydroxyproline excretion and plasma osteocalcin levels were increased by calcium restriction, indicating a high turnover of bone. YM175 reduced hydroxyproline excretion but not osteocalcin levels. These results indicate that YM175 prevents bone loss induced by calcium restriction and ovariectomy through partially normalizing high bone turnover.
Keywords:
Bisphosphonate, YM175, Bone mineral density, Dietary calcium restriction, Ovariectomy