Responses of Trabecular and Cortical Bone Turnover and Bone Mass and Strength to Bisphosphonate YH529 in Ovariohysterectomized Beagles with Calcium Restriction

Abstract

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. (J Bone Miner Res 1998;13:1011-1022)

Differences in Skeletal Kinetics Between Vertebral and Humeral Bone Measured by 18F-Fluoride Positron Emission Tomography in Postmenopausal Women

“…(25) Skeletal metabolic heterogeneities are of interest in the study of the pathophysiology of metabolic bone disorders including osteoporosis and also may help us to understand the different treatment responses observed with regard to bone mass and fracture risk at different skeletal sites. (6,9,11,14) Whyte et al found that it was not possible to predict regional heterogeneity in postmenopausal osteoporotic skeletal dynamics without histomorphometric analysis but predicted that radionuclide methods might allow these measurements in the future. (26) Unlike histomorphometry, which essentially is limited to the iliac crest, 18 F-fluoride PET has the potential to measure kinetics at any skeletal site although to date there is only limited experience in the spine.…”

“…(10) Studies on regional turnover or regional blood flow are possible in animal models but in man histomorphometry is used to infer information on regional metabolism. (11)(12)(13) However, this is a relatively invasive technique that generally is limited to the iliac crest and is not always practical in a clinical setting.…”

Bisphosphonate effects on bone turnover, microdamage, and mechanical properties: What we think we know and what we know that we don't know

“…Pre-clinical studies in larger animals (dogs and mini pigs) consistently show absence of a BP effect on periosteal bone formation [18,19,[36][37][38][39]. More detailed studies have been conducted in rats and mice, although in these species conflicting results exist.…”

Reductions in Bone Mass, Structure, and Strength in Axial and Appendicular Skeletons Associated With Increased Turnover After Ovariectomy in Mature Cynomolgus Monkeys and Preventive Effects of Clodronate

“…(14) Ultimate load (UL) to failure at the time of bone fracture, stiffness, maximum deformation, and energy were determined from the test charts. The value of the bending moment to failure (BMF, N⅐mm) was then calculated from the following equation: BMF ϭ 1/4 ϫ UL (N) ϫ L (40 mm).…”