Effects of the bisphosphonate YM175 on bone mineral density, strength, structure, and turnover in ovariectomized beagles on concomitant dietary calcium restriction

Abstract

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.

Suppressed Bone Turnover by Bisphosphonates Increases Microdamage Accumulation and Reduces Some Biomechanical Properties in Dog Rib

“…Histologically, bisphosphonates reduce resorption depth and reduce activation frequency (17–20) . Depending on dosage, activation frequency with the newer generation bisphosphonates can be reduced as much as 93%, but the effect can be titrated by lower doses and shorter treatment periods (20–23) . Although earlier bisphosphonates such as etidronate inhibited mineralization of new bone and led to spontaneous fractures of ribs and spinous processes in animal models, the newer more potent bisphosphonates have an antiresorptive effect at lower doses without preventing normal mineralization (15,20,22–26) .…”

“…(20 -23) Although earlier bisphosphonates such as etidronate inhibited mineralization of new bone and led to spontaneous fractures of ribs and spinous processes in animal models, the newer more potent bisphosphonates have an antiresorptive effect at lower doses without preventing normal mineralization. (15,20,(22)(23)(24)(25)(26) In this study, we evaluated the effects of suppressed bone turnover on microdamage accumulation and mechanical properties in the rib of dogs. We used RIS or ALN only as agents to suppress bone turnover without impairment of mineralization and not to evaluate their safety or efficacy, both of which have been shown previously.…”

Computational Insights into Binding of Bisphosphates to Farnesyl Pyrophosphate Synthase

“…The SAR of activity in inhibiting bone resorption was therefore the only information for medicinal chemists, and the structure-based drug design (SBDD) approach using the three dimensional structure of the target enzyme and SAR analysis using direct in vitro activity of enzyme inhibition could not be applied. Table 3 shows our previously published data on the structures of our heterocyclic series of minodronate derivatives [1,43], their clogP values of the side chain, and their experimental antiresorptive activities. Our early research found that the bulkiness and lipophilicity of the side chain of N-BPs were important determinants of their antiresoptive activity [43].…”

“…Table 3 shows our previously published data on the structures of our heterocyclic series of minodronate derivatives [1,43], their clogP values of the side chain, and their experimental antiresorptive activities. Our early research found that the bulkiness and lipophilicity of the side chain of N-BPs were important determinants of their antiresoptive activity [43]. However, compound 1, having an equivalent clogP value, an index of lipophilicity as minodronate, and the compounds 2 and 3, having clogP values greater than that of minodronate, showed remarkably decreased potency, whereas compound 4, having clogP values below that of minodronate, showed almost the same level of activity as minodronate.…”

Inhibitory effects of YM175, a bisphosphonate, on the progression of experimental periodontitis in beagle dogs

“…by neurectomy, and in experimental hypercalcaemia induced by either an MBT-2 tumour or parathyroid hormone administration (9-1 1 ). In addition, the treatment of YM175 for 18 months preserved bone mass and strength of the lumbar spine and forelimbs without disturbing mineralization in ovariectomized calcium-restricted beagle dogs (12,13).…”