Actions of Endoxifen on the Skeleton

描述（由申请人提供）：目前还没有治愈骨质疏松症的方法，治疗方法的发展仍然有限。目前的治疗涉及抗再吸收剂，如二膦酸盐、雌激素类似物、雷洛昔芬和降钙素，其主要靶向骨再吸收破骨细胞，导致骨转换减少。然而，抗吸收疗法与骨量的显著增加无关，因此仅部分降低骨折风险并防止维持骨健康所需的正常骨重建。因此，非常需要开发另外的骨合成代谢剂来预防或治疗这种使人衰弱的疾病。本项目探讨内昔芬（一种他莫昔芬代谢物）对骨骼的作用及其在骨细胞中的作用机制。初步数据表明，内昔芬在骨质疏松症中所见的雌激素减少的情况下增加骨的质量和结构，并且可能比表现出显著有害骨骼效应的其他新一代乳腺癌疗法更有利。因此，中心假设是内昔芬，一种新的SERM，通过增加而不是减少骨形成来增强骨合成代谢效应，从而与其他SERM不同地发挥作用。本提案的目标是使用小鼠模型系统表征对骨骼的体内作用，并确定内昔芬与他莫昔芬和雷洛昔芬相比对培养的成骨细胞和破骨细胞发挥作用的分子机制。 公共卫生相关性：骨质疏松症和乳腺癌是社会的主要负担。Endoxifen是一种新发现的三苯氧胺的主要活性代谢产物，它是目前用于乳腺癌治疗的主要选择性雌激素受体调节剂之一。我的初步研究表明，内昔芬也是一种有效的合成代谢剂的骨骼。与雌激素对骨重建的作用类似，我的研究表明，Endoxifen通过增强重建维持/增强整体骨形成。这些研究有可能确定Endoxifen作为一种新型的，非常有益的，治疗骨质减少，骨质疏松症和其他骨相关疾病，以及乳腺癌治疗剂

DESCRIPTION (provided by applicant): Currently there is no cure for osteoporosis and the development of therapeutic treatments remains limited. Present day therapies involve anti-resorptive agents such as bisphosphonates, estrogen analogs, raloxifene and calcitonin which primarily target bone resorbing osteoclasts resulting in reduced bone turnover. However anti-resorptive therapies are not associated with significant increases in bone mass and therefore only partially reduce fracture risk and prevent the normal bone remodeling required to maintain bone health. Thus, a significant need exists for the development of additional bone anabolic agents to prevent or treat this debilitating disease. This project explores the actions of endoxifen, a tamoxifen metabolite, on the skeleton and its mechanism of action in bone cells. Preliminary data suggests that endoxifen increases quality and structure of bone in conditions of reduced estrogen as is seen in osteoporosis and may be more favorable than other new generation breast cancer therapies which exhibit significant deleterious skeletal effects. Therefore, the central hypothesis is that endoxifen, a novel SERM, elicits bone anabolic effects by increasing, rather than decreasing, bone formation thereby functioning differently than that of other SERMs. The goals of this proposal are to characterize in vivo effects on the skeleton using a mouse model system and to identify the molecular mechanisms by which endoxifen, as compared to tamoxifen and raloxifene, exerts its effects on cultured osteoblasts, and osteoclasts. PUBLIC HEALTH RELEVANCE: Osteoporosis and Breast Cancer are major burdens on society. Endoxifen is a newly identified as the primary active metabolite of Tamoxifen, one of the major therapeutic selective estrogen receptor modulators used in Breast Cancer therapy today. My preliminary studies have shown that Endoxifen is also a potent anabolic agent on the skeleton. Similar to Estrogen action on bone remodeling, my studies have indicated that Endoxifen maintains/enhances overall bone formation via enhanced remodeling. These studies have the potential to identify Endoxifen as a novel, highly beneficial, therapeutic agent for osteopenia, osteoporosis and other bone related disorders, as well as breast cancer therapy