RESTORING BONE IN OSTEOPENIC FEMALE SKELETON

恢复骨质疏松女性骨骼的骨骼

• 批准号: 3158497
• 负责人: WEBSTER S JEE
• 金额: $ 22.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3158497
• 关键词: aging; bone density; bone metabolism; diphosphonate; disease /disorder model; disease /disorder prevention /control; estrogens; female; histology; laboratory rat; osteoporosis; parathyroid hormones; physiologic bone resorption; prostaglandin E

Osteoporosis is mainly a disease of elderly women, who have low cancellous and cortical bone mass, poor bone structure, and fragility fractures. Though osteoporosis can be prevented by maintaining "peak" bone mass, treating it by substantially increasing bone strength is difficult. We propose using osteopenic, aged female rats to test a two-phase concept to treat established osteopenia. Since it has an anabolic phase to restore lost bone and a maintenance phase to preserve the new bone, it is named Activate->Restore->Maintain (A->R->M). We propose two experiments using aged female rats with established osteopenia originating from estrogen-depletion or chronic disuse, or a combination of the two. We will use either prostaglandin E2 (PGE2) or parathyroid hormone (hPTH) as anabolic agents to restore lost bone (+Phase). Past experience with both shows that their discontinuation is associated with rapid disappearance of the new bone they induce. When we stop +Phase, we will switch to an agent known chiefly for its ability to block bone loss (+Phase). We will use either 17-beta-estradiol (E2) or risedronate, a bisphosphonate. We will study animals at the beginning of +Phase, at the close of +Phase, and twice during +Phase, to establish both the permanence of the new bone and its incorporation into the adult skeleton by modeling and remodeling processes. A third experiment examines the ability of co-treatment with a resorption inhibitor and an anabolic agent, to add new bone, yet avoid an early transient phase of bone loss. For endpoints, we plan quantitative histologic studies of bone mass, structure, and turnover in the cancellous bone of the proximal and distal tibial metaphyses, and cortical bone of the tibio-fibular junction. We hypothesize that bone mass of the osteopenic skeleton improves during treatment with an anabolic agent, and then is permanently maintained by other routinely available agents. We hypothesize that differences in estrogen-depletion and disuse-related osteopenia exist, such that risedronate can, but E2 cannot, maintain new bone in the skeleton of an animal suffering chronic disuse osteopenia. We hypothesize that co- treating with a resorption inhibitor allows anabolic agents to work normally, while blocking the consequences of any early resorption phase. A->R->M, that limits the use of skeletal anabolic agents to the time when they are most effective, could hasten the application of such agents for treating osteoporosis.

骨质疏松症主要是老年妇女的疾病， 皮质骨质量、骨结构差和脆性骨折。 虽然骨质疏松症可以通过保持“峰值”骨量来预防， 通过显著增加骨强度来治疗是困难的。 我们 建议使用骨质减少的老年雌性大鼠来测试两阶段概念， 治疗骨质疏松症。 因为它有一个合成代谢阶段， 失去的骨头和维护阶段，以保存新的骨头，它被命名为 激活->恢复->维护（A->R->M）。 我们提出了两个实验，使用老年雌性大鼠与建立 源于雌激素耗竭或慢性废用的骨质减少，或 两者的结合。 我们将使用前列腺素E2（PGE 2）或 甲状旁腺激素（hPTH）作为合成代谢剂来恢复丢失的骨骼 （+相位）。 过去的经验表明，这两个国家的停止是 与它们诱导的新骨快速消失有关。 当我们 停止+阶段，我们将切换到一个主要以其能力而闻名的代理， 阻断骨丢失（+阶段）。 我们将使用17-β-雌二醇（E2）或 利塞膦酸盐，一种双磷酸盐。 我们将在一开始就研究动物 +阶段，在+阶段结束时，在+阶段期间两次，以建立 新骨的持久性及其与成人骨的结合 骨架的建模和重塑过程。 第三个实验考察了 再吸收抑制剂和合成代谢抑制剂共同治疗能力 添加新骨，但避免早期短暂的骨丢失。 对于终点，我们计划对骨量进行定量组织学研究， 近端和远端松质骨的结构和周转 胫骨干骺端和胫腓骨连接处的皮质骨。 我们假设骨质减少骨骼的骨量在治疗过程中得到改善， 用合成代谢剂治疗，然后通过 其他常规可用的药物。 我们假设， 存在雌激素耗竭和废用相关骨质减少， 利塞膦酸钠可以，但E2不能，维持新骨的骨骼， 患有慢性废用性骨质减少症的动物。 我们假设- 用再吸收抑制剂治疗允许合成代谢剂起作用 正常情况下，同时阻断任何早期再吸收阶段的后果。 A->R->M，这限制了骨骼合成代谢剂的使用， 它们是最有效的，可以加速这种药物的应用， 治疗骨质疏松症