Renewed bone remodeling after pausing long-term bisphosphonate use: Does it replace regions of impaired bone quality and restore mechanical integrity?

暂停长期使用双膦酸盐后重新进行骨重塑：它是否可以替代骨质量受损的区域并恢复机械完整性？

• 批准号: 10656954
• 负责人: MITCHELL B SCHAFFLER
• 金额: $ 50.74万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-05 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656954
• 关键词: Acute; Affect; Alendronate; Animals; Apoptosis; Apoptotic; Area; Automobile Driving; Binding; Biomechanics; Bone Resorption; Bone Tissue; Bone necrosis; Bone remodeling; Clinical; Companions; Data; Defect; Diaphyses; Effectiveness; Estrogens; Evolution; Failure; Fatigue; Femoral Fractures; Fracture; Functional disorder; Genes; Grant; Growth; Heterogeneity; Holidays; Impairment; In Situ; In Situ Hybridization; Jaw; Knowledge; Lead; Measurable; Measurement; Mechanics; Microscopy; Minerals; Modeling; Molecular; Mus; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Ovariectomy; Pathogenesis; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Postmenopausal Osteoporosis; Property; RNA; Rattus; Research; Residual state; Resistance; Risedronate; Series; Shapes; Signal Transduction; System; TNFSF11 gene; Testing; Time; Tissues; United States National Institutes of Health; bisphosphonate; bone; bone fragility; bone health; bone loss; bone quality; bone repair; bone strength; bone turnover; clinically relevant; cortical bone; design; efficacy evaluation; geometric structure; improved; in vivo; insight; interest; long bone; long-term sequelae; mechanical properties; mineralization; nanoindentation; novel; prevent; recruit; response; tool

SUMMARY Bisphosphonates (BPs) are the mainstay for treatment of postmenopausal osteoporosis. They are highly effective at preventing bone resorption and loss. However, long-term use of BPs and other antiresorptives is also known to negatively impact bone quality, with long-term sequelae including bone microdamage accumulation, altered matrix composition and heterogeneity, leading in some case to Atypical Femur Fractures. These sequelae have led to the idea of a “drug holiday,” i.e., pausing anti-resorptive treatment to allow renewed bone remodeling to resorb and replace bone areas with accumulated microdamage or associated material defects. However, it is not known if it is possible for renewed remodeling to target long-standing compromised bone tissue. The proposed research will address this critical knowledge gap. In Aim 1, we will first establish consequences of long-term BP use on evolution of controlled bone microdamage introduced in vivo by ulnar bending fatigue in rats and determine associated effects on osteocyte loss, local bone composition, material properties and diaphyseal fracture resistance. RNA in-situ hybridization will be used to investigate remaining viable osteocytes, focusing on major genes that regulate bone remodeling, mineral and matrix mineralization. In a companion study, we will determine bone quality, fracture resistance and osteocyte changes in mouse long bones with long-term BP use after ovariectomy – a combination of challenges that leads to osteocyte loss, that is not related to bone microdamage. In Aim 2, we will perform the first direct test of whether renewed remodeling during a drug holiday replaces long-standing microdamaged- or osteocyte-deficient bone tissue to restore bone quality. In a second series of studies, we will expand upon exciting preliminary data which suggests that a BP drug holiday can trigger other mechanically beneficial bone adaptations in diaphyseal shape that can potentially improve fracture resistance in a manner which is independent of tissue turnover and bone quality. In all studies, animals will be treated long-term with either Alendronate (ALN, high bone mineral binding = long-reversal time), Risedronate (RIS, moderate bone mineral binding = intermediate reversal time) or a rapidly reversible BP NE58025 (low bone mineral binding = short reversal time) in order to compare their effects on bone and osteocytes (Aim 1), and then we examine the efficacy of each BP in restoring diaphyseal biomechanical integrity during a drug holiday (Aim 2). Once completed, the results of these studies will provide the first robust mechanistic insights into the essential clinical-biomechanical question of whether a “drug holiday” can be effective in repairing the bone quality defects that accumulate with long-term bisphosphonate use and improving bone fracture resistance.

概括 双膦酸盐（BPS）是治疗绝经后骨质疏松症的主要手段。他们很高 有效防止骨骼分辨率和损失。但是，长期使用BP和其他抗吸收剂也是 已知会对骨骼质量产生负面影响，长期后遗症包括骨微斑的积累， 基质组成和异质性改变，在某些情况下导致非典型股骨骨折。这些 后遗症导致了“毒品假期”的想法，即暂停反应治疗以允许重新骨头 用累积的微型或相关的材料缺陷来重塑和替换骨骼区域。 但是，尚不清楚是否有可能更新重塑以瞄准长期妥协的骨头 组织。拟议的研究将解决这一关键知识差距。在AIM 1中，我们将首先建立 长期使用BP对尺骨在体内引入的受控骨微罕见的进化的后果 大鼠疲劳并确定对骨细胞损失，局部骨组成，物质的相关影响 性质和dia骨断裂性。 RNA的原位杂交将用于研究剩余 可行的骨细胞，重点是调节骨重塑，矿物质和基质矿化的主要基因。在 一项伴侣研究，我们将确定小鼠长的骨质质量，抗断裂性和骨细胞变化 卵巢切除术后长期使用BP的骨骼 - 挑战的组合，导致骨细胞损失，这是 与骨微宏无关。在AIM 2中，我们将对是否更新重塑进行首次直接测试 在药物假期期间，替代长期存在的微型塑料或骨细胞缺乏骨组织以恢复骨骼 质量。在第二个研究中，我们将扩展令人兴奋的初步数据，这表明BP 毒品假期可以触发其他机械有益的骨骼适应性diaphyseal形状，这可能会有可能 以独立于组织更新和骨质质量的方式改善断裂性。在所有研究中， 动物将以任何一种阿兰德膦酸盐（Aln，高骨矿物结合=长反转时间）长期治疗， risdronate（RIS，中等骨矿物结合=中间反转时间）或快速可逆的BP NE58025（低骨矿物结合=短反转时间），以比较它们对骨骼的影响 骨细胞（AIM 1），然后我们检查每个BP在恢复diaphyseal生物力学完整性方面的效率 在毒品假期期间（AIM 2）。完成后，这些研究的结果将提供第一个强大的 关于“毒品假期”是否可以是的基本临床生物力学问题的机械洞察力 有效地修复长期双膦酸盐使用并改善的骨质缺陷 骨断裂性。