Actions of Endoxifen on the Skeleton

描述(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。目前的治疗方法包括抗吸收药物，如双膦酸盐、雌激素类似物、雷洛昔芬和降钙素，这些药物主要针对骨吸收破骨细胞，导致骨转换减少。然而，抗吸收治疗与骨量的显着增加无关，因此只能部分降低骨折风险，并防止维持骨骼健康所需的正常骨重建。因此，有必要开发更多的骨合成代谢药物来预防或治疗这种衰弱的疾病。该项目探索他莫昔芬代谢物endoxifen对骨骼的作用及其在骨细胞中的作用机制。初步数据表明，在雌激素减少的情况下，Enoxifen可以改善骨骼的质量和结构，就像在骨质疏松症中看到的那样，而且可能比其他对骨骼产生显著有害影响的新一代乳腺癌疗法更有利。因此，中心假说是Enoxifen，一种新的SERM，通过增加而不是减少骨形成而引起骨合成代谢效应，从而发挥与其他SERM不同的功能。这项建议的目的是利用小鼠模型系统表征体内对骨骼的影响，并确定与他莫昔芬和雷洛昔芬相比，依多昔芬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。Enoxifen是一种新发现的他莫昔芬的主要活性代谢物，他莫昔芬是目前用于乳腺癌治疗的主要治疗选择性雌激素受体调节剂之一。我的初步研究表明，依多昔芬也是骨骼上的一种有效的合成代谢剂。与雌激素对骨重建的作用类似，我的研究表明，依多昔芬通过促进骨重建维持/增强整体骨形成。这些研究有可能确定艾多昔芬是一种新的、非常有益的治疗药物，用于骨量减少、骨质疏松症和其他骨相关疾病，以及乳腺癌的治疗。

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