Remodeling Suppression--Damage and bone toughness

描述(由申请人提供)：我们最近显示被抑制 使用双膦酸盐的重塑与2-3倍的增加有关 肋骨的损伤累积和韧性降低20% 腰椎。目前尚不清楚微损伤累积的速度 是否会随着重塑的持续抑制而加速，或者是否会 达到一条渐近线，标志着重建和破坏之间的新平衡。 在抑制重塑和有效重塑之间也没有适当的平衡 已知的损坏修复。我们假设微损伤的累积是 自我限制，并将在1-3年内接近渐近线 双膦酸类治疗。我们还假设，如果激活频率 因为重塑被抑制了不到50%，就不会有 显著的微损伤积累，组织韧性也不会降低。 成年母比格犬(n=120)将被伪随机分配到10只 体重匹配的剂量和时间组。对照组的狗将被给予一种 由糖水组成的安慰剂，其体积相当于药物溶液。 其余组的狗将每天接受阿伦磷酸钠(默克公司和 公司)口服剂量为0.2、0.5或1.0毫克/公斤/天，共12、24或36次 月份。在牺牲之后，标准的组织形态测量将是 在右侧第9根肋骨和L2的一部分上制作的。微损伤分析将会是 在右侧第9根肋骨的剩余部分、L3和右侧股骨上执行手术 脖子。生物力学测试将在左9肋骨、L4肋骨和L4肋骨 左股骨颈。L1将用于使用DXA进行骨矿测量。 PQCT将用于测量L1-L4椎体、肋骨和股骨颈的BMC/BMD。 将使用Micro-CT来评估L1的横截面积和骨体积。我们 预计这些实验将使我们能够确定 重塑可以被抑制多长时间，而不会导致 微损伤堆积，或骨骼机械性能显著下降 属性。

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.