Effects of 4-amino-1-hydroxybutylidene bisphosphonate on bone biomechanics in rats

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Abstract
Bisphosphonates inhibit osteoclast‐mediated bone resorption, but their effects on the mechanical behavior of bone remain uncertain. This study investigated the effects of 4‐amino‐1‐hydroxybutylidene bisphosphonate (AHBuBP) on the biomechanical and morphologic properties of bone in ovariectomized rats. Sprague‐Dawley rats (four groups, n = 6) were ovariectomized at 3 months of age. From 7 to 13 months, the groups received vehicle or 0.28, 2.8, or 28 μg/kg of AHBuBP twice weekly through subcutaneous injection. An additional group of control animals (n = 6) received neither surgery nor drug. We determined the stiffness, yield, and ultimate loads of the femoral midshaft, the sixth lumbar (L6) vertebra, and the femoral neck. Geometric properties of the cortical bone were measured from digitized images of the tibial diaphysis at the level of the synostosis. The area fraction of trabecular bone was determined through the midsagittal plane of the fifth lumbar (L5) vertebra. There were no significant differences in the structural properties of the femoral neck and midshaft, with the exception that the medium‐dose group had a greater ultimate load than the vehicle group for the femoral midshaft in bending. Cross‐sectional analysis of the tibia did not show significant differences in the inertial properties or area. Ovariectomy caused a significant reduction in the stiffness and ultimate load of L6 and in the area fraction of trabecular bone of L5. Using the Tukey method of pairwise comparisons, the mean ultimate load ± standard deviation of the L6 vertebrae from the ovariectomized vehicle group was 30% lower than that from the nonovariectomized control group (276 ± 35 versus 396 ± 63 N, p < 0.05). The mean stiffness was 46% lower (723 ± 206 versus 1327 ± 336 N/mm, p < 0.05), and the area fraction was 41% lower (17.8 ± 5.2 versus 30.0 ± 7.9%, p < 0.05). The high dose of AHBuBP maintained the structural properties of the vertebral bone; the ultimate load (424 ± 55 N), stiffness (1149 ± 145 N/mm), and area fraction (33.7 ± 5.5%) in the high‐dose group were all significantly greater than those in the vehicle group but did not differ significantly from those in the control group. We conclude that long‐term administration of AHBuBP in rats (started 4 months after ovariectomy) preserves the strength and area fraction of trabecular bone in the lumbar spine in a dose‐dependent manner, without evidence of detrimental effects upon the biomechanical or morphologic properties of cortical bone.
Funding Information
  • Merck Sharp & Dohme Research Laboratories
  • National Research Service Award-Academic Training in Trauma and Burns (GM-07806-11)