Alendronate reduces bone toughness of ribs without significantly increasing microdamage accumulation in dogs following 3 years of daily treatment

Abstract

Reduced bone toughness, the energy absorption capacity of the tissue, has been consistently documented in vertebrae of animals treated with a wide range of bisphosphonate doses. Data regarding toughness changes in the rib are conflicting, with one report showing no effect and another showing a significant reduction following treatment of beagle dogs with high doses of bisphosphonates. The goal of this study was to evaluate changes in bone toughness and various other tissue-level properties of the rib following 3 years of bisphosphonate treatment with doses at and above those used to treat osteoporosis. Skeletally mature intact beagle dogs were treated daily for 3 years with vehicle (VEH), alendronate 0.2 mg/kg (ALN0.2), or alendronate 1.0 mg/kg (ALN1.0). The lower ALN dose approximates, on a milligram per kilogram basis, that used for treatment of postmenopausal osteoporosis, with the higher dose being five times higher. Ribs were assessed for biomechanical properties, bone turnover rate, microdamage, density, and geometry. Toughness was significantly lower with ALN1.0 (-33%) but not ALN0.2 (-19%) compared to VEH, while neither ultimate stress nor modulus differed among the groups. Bone density, geometry, and structural biomechanical properties were similar among the three groups. There was no significant difference in overall microdamage accumulation among the groups. Intracortical bone formation rate was significantly lower than VEH in both ALN groups (-69% to -90%). These data show that while rib cortical bone experiences significant reductions in turnover following bisphosphonate treatment, it is only in animals treated with doses above those used to treat osteoporosis that toughness is significantly compromised.

Figure 1

Schematic of mechanical test plot from three-point bending test of dog rib. Load versus deformation data from tests are converted to stress and strain, respectively, using standard equations (see methods for equations). In these tests, the yield stress and ultimate stress are nearly identical, while there is a considerable amount of displacement (strain) between these points and the point of fracture. In the current study, toughness (the area under the stress/strain curve) was quantified fracture (total area under the curve). We also separated the area under the curve into pre-yield toughness (area of the curve to ultimate stress, lightly shaded region) and post-yield toughness (area under the curve between ultimate stress and fracture, darkly shaded region). Previous analyses by Komatsubara [6] assessed toughness only to the point of ultimate stress.

Figure 2

Bone remodeling, microdamage accumulation, and toughness of rib cortical bone following three years of treatment with vehicle or alendronate (ALN). (A) Intracortical bone formation rate was significantly lower than vehicle in both ALN-treated groups while there was no difference between the two ALN doses (ANOVA p = 0.008). (B) Crack surface density, an index of microdamage accumulation representing the product of crack number and crack length normalized to bone area, was not significantly different from VEH with either dose of ALN (ANOVA p = 0.157). (C) Toughness, the energy absorption capacity to fracture, was significantly lower than VEH with ALN1.0 (-33%), but not with ALN0.2 (-19%) (ANOVA p = 0.023). Data expressed as mean ± SE. *p < 0.05 versus vehicle.