Remodeling Suppression--Damage and bone toughness

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DESCRIPTION (provided by applicant): We recently showed that suppressed remodeling using bisphosphonates is associated with a 2-3 fold increase in damage accumulation and a 20 percent reduction in toughness in the rib and lumbar vertebrae. It is not known whether the rate of microdamage accumulation will accelerate with continued suppression of remodeling, or whether it will reach an asymptote that signals a new balance between remodeling and damage. Nor is the appropriate balance between remodeling suppression and effective repair of damage known. We hypothesize that microdamage accumulation is self-limiting and will approach an asymptote between 1-3 years of bisphosphonate treatment. We also hypothesize that if the activation frequency for remodeling is suppressed by less than 50 percent, there will not be significant microdamage accumulation, nor will tissue toughness be reduced. Mature female beagle dogs (n = 120) will be pseudo-randomly assigned to 10 weight-matched dose and time groups. Dogs in the control group will be given a placebo consisting of sugar water at a volume equivalent to the drug solution. The remaining groups of dogs will be treated daily with alendronate (Merck and Co., Inc.) orally at doses of 0.2, 0.5 or 1.0 mg/kg/day for 12, 24 or 36 months. Following sacrifice, standard histomorphometric measurements will be made on a portion of the right 9th rib and L2. Microdamage analysis will be performed on the remainder of the right 9th rib, L3 and on the right femoral neck. Biomechanical tests will be performed on the left 9th rib, on L4, and on the left femoral neck. L1 will be used for bone mineral measurement using DXA. PQCT will be used to measure BMC/BMD in L1-L4 vertebrae, rib and femoral neck. Micro-CT will be used to assess cross-sectional area and bone volume in L1. We anticipate that these experiments will allow us to determine how much remodeling can be suppressed, and for how long, without causing an increase in microdamage accumulation, or a significant decrease in bone's mechanical properties.