One year of alendronate treatment lowers microstructural stresses associated with trabecular microdamage initiation

Abstract

Alendronate, an anti-remodeling agent, is commonly used to treat patients suffering from osteoporosis by increasing bone mineral density. Though fracture risk is lowered, an increase in microdamage accumulation has been documented in patients receiving alendronate, leading to questions about the potentially detrimental effects of remodeling suppression on the local tissue (material) properties. In this study, trabecular bone cores from the distal femur of beagle dogs treated for one year with alendronate, at doses scaled by weight to approximate osteoporotic and Paget's disease treatment doses in humans, were subjected to uniaxial compression to induce microdamage. Tissue level von Mises stresses were computed for alendronate-treated and non-treated controls using finite element analysis and correlated to microdamage morphology. Using a modified version of the Moore and Gibson classification for damage morphology, we determined that the von Mises stress for trabeculae exhibiting severe and linear microcrack patterns was decreased by approximately 25% in samples treated with alendronate compared with non-treated controls (p<0.01), whereas there was no reduction in the von Mises stress state for diffuse microdamage formation. Furthermore, an examination of the architectural and structural characteristics of damaged trabeculae demonstrated that severely damaged trabeculae were thinner, more aligned with the loading axis, and less mineralized than undamaged trabeculae in alendronate-treated samples (p<0.01). Similar relationships with damage morphology were found only with trabecular orientation in vehicle-treated control dogs. These results indicate that changes in bone's architecture and matrix properties associated with one year of alendronate administration reduce trabecular bone's ability to resist the formation of loading-induced severe and linear microcracks, both of which dissipate less energy prior to fracture than does diffuse damage.

Figure 1

Microdamage description and classification, with FEA von Mises stress predictions. i. Linear damage including a) single crack and b) parallel cracks, ii. Diffuse (crosshatch) damage including c) equal crosshatching and d) large area distribution, iii. Severe damage including e) one primary crack with minor secondary cracks and f) through-thickness cracks.

Figure 2

Total damage quantified based on fluorescence and plotted by treatment group. An increased amount of damage occurred due to the mechanical test in the control group. The total damage columns are created by totaling damage counted in the three previous columns for each treatment group, and no significant differences were found. Bars represent significant differences. p<0.05, mean ± SE. is plotted

Figure 3

Von Mises stress plotted by treatment group and damage morphology. The stress state of trabeculae exhibiting severe and linear damage was decreased in both treatment groups compared with controls. In the control group, severe damage was associated with the greatest stress compared with all other damage groups. In both treatment groups, the stress state of severely damaged trabeculae was significantly increased compared with linear and undamaged trabeculae. Bars between damage morphologies within the same treatment group indicate significant differences. p<0.01 indicates significance, mean + SE is plotted.

Figure 4

Trabecular mineralization and architectural characteristics plotted by treatment group and damage morphology. There were no differences due to treatment dose, so the two samples were combined. 4a. Trabecular mineralization is plotted with respect to damage morphology and treatment; severely damaged trabeculae were less mineralized than undamaged trabeculae in the treated group. 4b. Trabecular thickness is plotted with respect to treatment and damage morphology; severely damaged trabeculae were significantly thinner than other trabeculae in the treated group. 4c. Structural model index is plotted with respect to damage morphology and treatment; severely damaged trabeculae are more rod-like than diffusely damaged trabeculae. 4d. The angle between the principal material axis and the loading axis is plotted; undamaged trabeculae were generally aligned perpendicular to the loading axis in both treatment and control groups*indicates a significantly increased angle compared with all other damage morphologies in the same group. Bars indicate significant differences between damage morphologies within the same group. p<0.01 indicates significance, mean + SE plotted