Remodeling Suppression--Damage and bone toughness

描述（由申请人提供）：我们最近表明，抑制 使用双膦酸盐的重塑与2-3倍的增加有关， 损伤累积，肋骨韧性降低20%， 腰椎目前尚不清楚微损伤累积速率是否 会随着重塑的持续抑制而加速，或者它是否会 达到一个渐近线，标志着重塑和损伤之间的新平衡。 也不是重塑抑制和有效之间的适当平衡 修复已知的损坏。我们假设微损伤的累积是 自限性，并将在1-3年内接近渐近线 二磷酸盐治疗。我们还假设，如果激活频率 对于重塑被抑制低于50%，将不会有 显著的微损伤累积，也不会降低组织韧性。 将成年雌性比格犬（n = 120）伪随机分配至10只 体重匹配的剂量和时间组。对照组中的狗将被给予 安慰剂，由与药物溶液体积相当的糖水组成。 其余组的狗将每天用阿仑膦酸钠（Merck和 有限公司、公司）以0.2、0.5或1.0 mg/kg/天的剂量经口给药，持续12、24或36天 个月处死后，将进行标准组织形态计量学测量。 在右侧第九肋骨和L2的一部分上微损伤分析将是 对右侧第9根肋骨的剩余部分、L3和右侧股骨进行了检查 脖子将在左侧第9肋骨、L4和L4上进行生物力学测试。 左股骨颈L1将用于使用DXA进行骨矿物质测量。 PQCT将用于测量L1-L4椎骨、肋骨和股骨颈的BMC/BMD。 将使用Micro-CT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，以及多久，而不会导致增加， 微损伤累积，或骨的机械强度显著降低， 特性.

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.