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.

总结 双磷酸盐（BPs）是治疗绝经后骨质疏松症的主要药物。它们是高度 有效防止骨吸收和流失。然而，长期使用BP和其他抗吸收药也是 已知对骨质有负面影响，具有长期后遗症，包括骨微损伤累积， 改变基质成分和异质性，在某些情况下导致非典型股骨骨折。这些 后遗症导致了“药物假期”的想法，即，暂停抗再吸收治疗以允许骨再生 重塑以再吸收和替换具有累积的微损伤或相关材料缺损的骨区域。 然而，目前尚不清楚是否有可能重新重塑长期受损的骨 组织.拟议的研究将解决这一关键的知识差距。在目标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损伤演变的影响 大鼠弯曲疲劳，并确定对骨细胞损失、局部骨成分、材料 性能和骨干抗断裂性。RNA原位杂交将用于研究剩余的 活骨细胞，重点是调节骨重建，矿物质和基质矿化的主要基因。在 作为一项配套研究，我们将确定小鼠长时间的骨质、抗骨折性和骨细胞变化 卵巢切除术后长期使用BP的骨骼-导致骨细胞丢失的挑战组合， 与骨微损伤无关。在目标2中，我们将进行第一次直接测试， 在药物假期期间，替换长期存在的微损伤或骨细胞缺陷的骨组织以恢复骨骼 质量.在第二个系列的研究中，我们将扩展令人兴奋的初步数据，这些数据表明， 药物假期可以触发骨干形状的其他机械有益的骨适应， 以独立于组织转换和骨质量方式改善抗骨折性。在所有研究中， 动物将用阿仑膦酸盐（ALN，高骨矿物质结合=长逆转时间）长期治疗， 利塞膦酸盐（RIS，中度骨矿物质结合=中间逆转时间）或快速可逆BP NE 58025（低骨矿物质结合=短逆转时间），以比较它们对骨的作用， 骨细胞（目标1），然后我们检查每种BP在恢复骨干生物力学完整性方面的功效 在药物假期期间（目标2）。一旦完成，这些研究的结果将提供第一个强大的 对基本临床生物力学问题的机械见解，即“药物假期”是否可以 有效修复长期使用双磷酸盐累积的骨质缺陷， 抗骨折性。