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Keywords:

  • bisphosphonates;
  • remodeling;
  • toughness;
  • biomechanics;
  • osteoporosis

Abstract

Three years of daily alendronate treatment increases microdamage in vertebral bone but does not significantly increase it beyond levels of microdamage found after 1 yr of treatment. This suggests microdamage accumulation peaks during the early period of bisphosphonate treatment and does not continue to accumulate with longer periods of treatment.

Introduction: Clinically relevant doses of alendronate increase vertebral microdamage by 4- to 5-fold in skeletally mature beagles after 1 yr of treatment. The goal of this study was to determine whether microdamage would continue to accumulate with 3 yr of alendronate treatment in an intact beagle dog model.

Materials and Methods: One-year-old female beagles were treated with daily oral doses of vehicle (VEH, 1 ml/kg/d) or alendronate (ALN, 0.2 or 1.0 mg/kg/d) for 3 yr. These ALN doses were chosen to approximate, on a milligram per kilogram basis, those used to treat osteoporosis (ALN0.2) and Paget's disease (ALN1.0). Microdamage accumulation, static and dynamic histomorphometry, densitometry, and mechanical properties of lumbar vertebrae were assessed. Comparisons were made among the three groups treated for 3 yr and also within each treatment group to animals treated under the same conditions for 1 yr.

Results: Overall microdamage accumulation (crack surface density) was not significantly higher in animals treated for 3 yr with either dose of ALN, whereas crack density increased significantly (100%; p < 0.05) with the higher dose of ALN compared with VEH. Both ALN doses significantly suppressed the rate of bone turnover (−60% versus VEH). There was no difference among groups for any of the structural biomechanical properties-ultimate load, stiffness, or energy absorption. However, when adjusted for areal BMD, ALN-treated animals had significantly lower energy absorption (−20%) compared with VEH. Toughness, the energy absorption capacity of the bone tissue, was significantly lower than VEH for both ALN0.2 (−27%) and ALN1.0 (−33%). Compared with animals treated for 1 yr, there was no significant difference in microdamage accumulation for either ALN dose. VEH-treated animals had significantly lower bone turnover (−58%) and significantly higher levels of microdamage (+300%) compared with values in 1-yr animals. Toughness was significantly lower in animals treated for 3 yr with ALN1.0 (−18%) compared with animals treated for 1 yr, whereas there was no difference in toughness between the two treatment durations for either VEH or ALN0.2.

Conclusions: Although 3 yr of ALN treatment resulted in higher microcrack density in vertebral trabecular bone compared with control dogs, the amount of microdamage was not significantly higher than animals treated for 1 yr with similar doses. This suggests that bisphosphonate-associated increases in microdamage occur early in treatment. Because toughness continued to decline significantly over 3 yr of treatment at the higher ALN dose, decreases in toughness are probably not dependent on damage accumulation.