Effects of the bisphosphonate YM175 on bone mineral density, strength, structure, and turnover in ovariectomized beagles on concomitant dietary calcium restriction.
We evaluated the effect of YM175 on bone in ovariectomized beagles fed a calcium-restricted diet for 18 months. Groups 1 (n = 6) and 2 (n = 6) underwent sham operation, and groups 3-6 were ovariectomized at the age of 21 months. Group 1 was fed standard dog chow (calcium: 1.4%), and groups 2-6 were given a low calcium diet (0.14%). Groups 3 (n = 7), 4 (n = 7), 5 (n = 7), and 6 (n = 7) were given YM175 orally at doses of 0, 0.01, 0.1, and 1.0 mg/kg/day, respectively. At the end of the experimental period, bone mineral density values measured in the lumbar (L2) vertebra, the femoral neck, and the midfemur, were reduced in groups 2 and 3. Bone strength, measured by compression tests on L2 body and L3 cancellous core specimens and by bending tests on the femoral neck, also decreased. YM175 treatment dose-dependently increased the values of these parameters. However, the reduction in torsional stiffness in the midfemur was not completely prevented. In the L4 body, trabecular thickness decreased in group 2 and trabecular separation increased in group 3. YM175 treatment prevented these changes, and the values in group 6 were maintained at the same levels as those in group 1. Bone formation rates were increased in groups 2 and 3. YM175 treatment decreased these indices, but the reduction was incomplete even with the highest dose (group 6). These results demonstrate that, in our model, YM175 maintained the mass, structure, and mechanical properties of cancellous bone. Increased bone turnover was not completely prevented by the doses employed, but the balance between net resorption and formation in one remodeling cycle would have been equilibrated by YM175.
Motoie
H
H
Endocrinology and Metabolic Disease Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Nakamura
T
T
O'uchi
N
N
Nishikawa
H
H
Kanoh
H
H
Abe
T
T
Kawashima
H
H
D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001696:Biomechanical Phenomena; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects*; D001846:Bone Development / Q000187:drug effects*; D001862:Bone Resorption / Q000188:drug therapy; D002118:Calcium / Q000097:blood / Q000172:deficiency*; D004100:Dihydroxycholecalciferols / Q000097:blood; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005269:Femur / Q000187:drug effects / Q000502:physiology; D005272:Femur Neck / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000502:physiology; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy / Q000503:physiopathology; D010052:Ovariectomy; D011897:Random Allocation; D012044:Regression Analysis
D004100:Dihydroxycholecalciferols; D004164:Diphosphonates; C071542:cimadronate; D000469:Alkaline Phosphatase; D002118:Calcium