Responses of trabecular and cortical bone turnover and bone mass and strength to bisphosphonate YH529 in ovariohysterectomized beagles with calcium restriction.
Thirty-six beagles, 18 months of age, underwent ovariohysterectomy (OHX) or a sham operation. Sham-operated animals were given a diet with standard calcium (1.4%) (group 1, n = 6) or a restricted calcium diet (0.14%) (group 2, n = 6). The OHX animals were given the restricted calcium diet and YH529 orally with respective daily doses of 0, 0.02, 0.1, and 0.5 mg/kg of body weight (groups 3-6, n = 6 each) for 12 months. At the end of this period, the lumbar bone mineral densities (BMDs) in groups 2 and 3 and the load values for group 3 were significantly smaller than those for group 1. The midfemur BMD did not differ among the groups. The urinary deoxypyridinoline (U-Dpy) and bone formation rates (BFR/BS, BFR/BV) in groups 2 and 3 and the osteonal BFR/BS and trabecular osteoclast number (Oc.N/BS) in group 3 were significantly larger than the respective values for group 1. However, these parameters did not significantly differ between groups 2 and 3. The serum osteocalcin (OC) level, wall thickness (W.Th), and mineral apposition rate values for group 3 were significantly larger than those for group 2. In group 2, the trabecular activation frequency (Ac.F) increased by 3.11 times, and the percent values of the number of labeled osteons (L-Ot.N/T-Ot.N, %) in the tibia by 3.28 times over those for group 1. In group 3, the Ac.F increased by 3.20 times and the number of labeled osteons by 3.77 times over those for group 1. In groups 4-6, the U-Dpy and Oc.N/BS values were smaller, but their OC levels did not significantly differ from the level for group 3. The lumbar BMD, the load, and W.Th were dose-dependently significantly larger than those for group 3. The Ac.F values were significantly smaller, and the respective value in groups 4-6 was 67.9, 25.5, and 10.2% of that in group 3. The BMDs of the midfemur in groups 4-6 were significantly larger than those in group 3, but the ultimate load values did not significantly differ. The L-Ot.N/T-Ot.N values were also significantly smaller, and the respective value in groups 4-6 was 82.0, 48.5, and 55.2% of that in group 3. The tibial endocortical and periosteal BFR/BSs did not differ significantly. These data demonstrate that the effects of OHX on bone mass and turnover were small in the beagles fed a restricted calcium diet. YH529 maintained the mass and strength of the lumbar bone by reducing the bone resorption. The cortical bone appeared to be less sensitive to the agent than the trabecular bone in this animal model.
Yoshida
Y
Y
Discovery Research Laboratories, Hoechst Marion Roussel Ltd., Saitama, Japan.
Moriya
A
A
Kitamura
K
K
Inazu
M
M
Okimoto
N
N
Okazaki
Y
Y
Nakamura
T
T
D000284:Administration, Oral; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects*; D002118:Calcium / Q000172:deficiency*; D002136:Calcium, Dietary / Q000378:metabolism*; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005269:Femur / Q000187:drug effects*; D006801:Humans; D007044:Hysterectomy; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008159:Lumbar Vertebrae / Q000187:drug effects*; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000187:drug effects; D010052:Ovariectomy; D013977:Tibia / Q000187:drug effects*
D002136:Calcium, Dietary; D004164:Diphosphonates; D007093:Imidazoles; D015675:Osteocalcin; C087958:YM 529; D002118:Calcium