Prevention of Bone Loss by Bisphosphonate YM175 in Ovariectomized Dogs with Dietary Calcium Restriction.

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  • Motoie Hiroyuki
    Endocrinology and Metabolic Disease Research Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Kanoh Hiroyuki
    Endocrinology and Metabolic Disease Research Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Ogata Stig
    Endocrinology and Metabolic Disease Research Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Kawamuki Kosei
    Endocrinology and Metabolic Disease Research Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Shikama Hisataka
    Endocrinology and Metabolic Disease Research Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
  • Fujikura Takashi
    Endocrinology and Metabolic Disease Research Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

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  • Preservation of bone loss by bisphosphonate YM175 in ovariectomized dogs with dietary calcium restriction

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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 YM 175 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. YM 175 reduced hydroxyproline excretion but not osteocalcin levels. These results indicate that YM 175 prevents bone loss induced by calcium restriction and ovariectomy through partially normalizing high bone turnover.

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