Enhancing bone strength using combination drug therapy

使用联合药物疗法增强骨强度

• 批准号: 9012010
• 负责人: Matthew R Allen
• 金额: $ 32.27万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9012010
• 关键词: Adverse effects; Affect; Alendronate; Animal Model; Animals; Antibodies; Assessment tool; Biomechanics; Bone Density; Canis familiaris; Clinic; Clinical; Combination Drug Therapy; Combined Modality Therapy; Data; Detection; Dose; FDA approved; Femur; Fracture; Goals; Histology; Human; Measures; Mechanics; Modeling; Mono-S; Oral; Osteoporosis; Osteoporosis prevention; Osteoporotic; Outcome Measure; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Postmenopausal Osteoporosis; Property; Raloxifene; Rattus; Risk; Safety; Saline; Selective Estrogen Receptor Modulators; Techniques; Testing; Therapeutic; Tissues; Translating; bisphosphonate; bone; bone mass; bone strength; density; humanized monoclonal antibodies; improved; in vivo; mineralization; novel; preclinical study; research study; rib bone structure; skeletal; spine bone structure

DESCRIPTION (provided by applicant): Pharmaceutical agents used to treat osteoporosis significantly reduce fracture risk via different mechanisms that ultimately enhance either structural or material biomechanical properties. Bisphosphonates such as Alendronate (ALN) increase structural bone strength almost entirely by promoting increased bone volume and density, but at the expense of impaired material properties. Raloxifene (RAL) minimally affects bone mass yet significantly improves material properties leading to an enhancement in overall bone strength. These two distinct pathways for improving bone strength suggest that combination treatment could significantly reduce fracture risk more than either ALN or RAL monotherapy. The goal of this proposal is to determine if the combination of ALN and RAL will have a greater positive effect on bone structural mechanical properties compared to either agent alone by combining their positive effects on BMD (from ALN) and material properties (from RAL). A second goal of this project is to determine if a lower dose of ALN can be used when given in combination with RAL, to achieve at least equivalent BMD and bone strength as ALN alone at higher doses. Demonstrating efficacy for enhancing bone strength with a reduced dose of ALN could improve safety by reducing negative side effects that accompany treatment with oral BPs. The third goal is to determine if combination treatment with RAL is effective as a combination therapy with non-bisphosphonate anti- resorptives such as Denosumab, the newest FDA-approved anti-remodeling agent. The human antibody denosumab cannot be given to animals, yet other mechanisms of inhibiting the RANK-L pathway such as by using osteoprotogerin fusion compound (OPG-Fc) have been shown in pre-clinical studies to mimic the skeletal effects of denosumab. Specifically, the experiments in this project will test the hypotheses that 1) the combination of ALN and RAL at current clinical doses will improve bone's mechanical properties more than each drug alone, 2) lower doses of ALN used in combination with the clinical dose of RAL will produce at least equivalent effects on bone strength as mono-therapy with ALN at the current therapeutic dose, and 3) The combination of a OPG-Fc and RAL will improve bone's mechanical properties more than each drug alone. We will test these hypotheses using both traditional outcome measures (ex vivo bone density, histology, mechanics) as well as a novel in vivo assessment tool (BioDent) to longitudinally track changes in bone material properties in animals. The data generated in this proposal will be highly translatable as our analyses will establish the relationship between changes in mechanical properties assessed in vivo to more traditional measures that can only be only made on excised bone. Additionally, as all drugs in these studies are already FDA approved for treatment of osteoporosis, combination treatment could be rapidly translated to the clinic.

描述（由申请人提供）：用于治疗骨质疏松症的药物通过不同的机制显着降低断裂风险，这些机制最终增强了结构性或材料生物力学特性。双膦酸盐（例如丙膦酸盐（ALN））几乎完全通过促进骨体积和密度增加而增加了结构骨强度，但牺牲了材料特性受损。 rAxifene（Ral）最小影响骨骼质量，但显着提高了材料特性，从而增强了整体骨强度。这两种不同的改善骨骼强度的途径表明，组合治疗可以显着降低骨折风险，而不是ALN或RAL单一疗法。该提案的目的是确定ALN和RAL的组合是否通过结合其对BMD（来自ALN）和材料特性（来自RAL）的积极作用（来自RAL）的积极作用来对骨结构机械性能产生更大的积极作用。该项目的第二个目标是确定与RAL结合给出时是否可以使用较低剂量的ALN，以达到至少等效的BMD和骨骼强度，而单独使用ALN的ALN在较高剂量下。通过降低ALN剂量，可以通过减少口服BPS治疗的负面副作用来提高骨骼强度的功效，从而提高安全性。第三个目标是确定与RAL的组合治疗是否有效，作为与非双膦酸盐抗吸收剂（如Denosumab）（例如FDA最新的FDA批准的抗新型剂）的联合疗法。人类抗体非洲蛋白酶单抗无法给予动物，但在临床前研究中已经显示了抑制秩-1途径（例如使用骨蛋白毒素融合化合物（OPG-FC））的其他机制，以模仿denosumab的骨骼效应。具体而言，该项目的实验将测试以下假设：1）ALN和RAL在当前临床剂量下的组合将比单独使用每种药物更大的骨骼机械性能，2）较低剂量的ALN与临床剂量的RAL剂量结合使用，将至少在骨骼强度上产生与ALN的骨骼强度以及在当前的剂量相结合，并在当前的剂量中产生剂量的结合，以及3）。骨的机械性能比单独的每种药物都多。我们将使用传统的结果指标（离体骨密度，组织学，力学）以及一种新型的体内评估工具（Biodent）来检验这些假设，以纵向跟踪动物骨骼材料特性的变化。本提案中产生的数据将是高度翻译的，因为我们的分析将在体内评估的机械性能变化与更传统的措施之间的关系，而这些措施只能仅在切除的骨头上进行。此外，由于这些研究中的所有药物已经批准用于治疗骨质疏松症的治疗，因此联合治疗可以迅速转化为诊所。

项目成果

Foreword: Calcified Tissue International and Musculoskeletal Research Special Issue: Bone Material Properties and Skeletal Fragility.

前言：钙化组织国际和肌肉骨骼研究特刊：骨材料特性和骨骼脆弱性。

• DOI: 10.1007/s00223-015-0012-7
• 发表时间: 2015
• 期刊: Calcified tissue international
• 影响因子: 4.2
• 作者: Burr,DavidB;Allen,MatthewR
• 通讯作者: Allen,MatthewR

True Gold or Pyrite: A Review of Reference Point Indentation for Assessing Bone Mechanical Properties In Vivo.

• DOI: 10.1002/jbmr.2603
• 发表时间: 2015-09
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Allen MR;McNerny EM;Organ JM;Wallace JM
• 通讯作者: Wallace JM

In vivo reference point indentation reveals positive effects of raloxifene on mechanical properties following 6 months of treatment in skeletally mature beagle dogs.

• DOI: 10.1016/j.bone.2013.07.009
• 发表时间: 2013-10
• 期刊: BONE
• 影响因子: 4.1
• 作者: Aref, Mohammad;Gallant, Maxime A.;Organ, Jason M.;Wallace, Joseph M.;Newman, Christopher L.;Burr, David B.;Brown, Drew M.;Allen, Matthew R.
• 通讯作者: Allen, Matthew R.