NOVEL THERAPEUTICS FOR POSTMENOPAUSAL OSTEOPOROSIS

描述（由申请人提供）：绝经后骨质疏松症是一种比以前认为的更危险的疾病，是老年妇女最常见的疾病之一。每两个50岁以上的女性中就有一个会在她们的一生中发生骨质疏松相关的骨折，而绝经后女性的骨折是导致残疾、死亡和经济负担的主要原因。虽然骨质疏松性骨折在很大程度上是可以预防的，但不幸的是，目前的药理学预防药物在安全性和/或有效性方面存在一定的局限性。显然，我们非常需要新的、更安全、更有效的药物，毫无疑问，这些药物将能够占领骨质疏松治疗药物的全球市场份额。最近，我们的实验室已经开发出有希望的候选治疗方法，在绝经后骨质疏松症动物模型中显示出无毒迹象和更有效的防止骨量丢失和微结构恶化的能力。值得注意的是，这些候选治疗药物作用于新的疾病靶点，能够抑制骨吸收，并可能刺激骨形成，作为预防骨质流失的双重功能药物。这些药物最近受到美国专利的保护，该专利将授权给资助申请人，用于进一步开发各种治疗用途。本I期研究的目的是进一步明确候选物在上述动物模型中系统保护骨骼免受骨质疏松的能力，为后续的II期研究奠定具体基础。为了达到这一目的：首先，将根据我们建立的方法制备候选药物，并对其化学结构和纯度进行表征；其次，将获得绝经后骨质疏松动物模型，并使用这些药物，以及雌激素和双膦酸盐进行比较，使用我们实验室已经使用的标准手术和治疗方案；第三，在治疗后收集动物的不同骨骼样本（如股骨，肱骨，下颌骨，胫骨和椎骨），并使用各种先进技术评估治疗效果，包括电子顺磁共振，微型计算机断层扫描和骨组织形态测量技术，这些技术已经在我们的实验室开发和/或常规使用。我们的多学科团队拥有完成该项目所需的所有专业知识，是唯一从事这种新型药物开发的团队。我们相信，对治疗疗效的系统定义和候选药物的进一步开发，将带来新的、更安全、更有效的治疗药物，从而对骨质疏松症的预防和治疗产生深远的影响，并赢得相当大的全球市场份额。

DESCRIPTION (provided by applicant): Postmenopausal osteoporosis is a more dangerous disease than previously thought and is one of the most common diseases in older women. One in two women over age 50 will have an osteoporosis-related fracture during their lives, and fractures in postmenopausal women are a major cause of disability, mortality and economic burden. Although osteoporotic fractures are largely preventable, unfortunately, current pharmacological preventive drugs have certain limitations regarding their safety and/or efficacy. Obviously, there is a great need for new, safer and more effective drugs, which will, no doubt, be capable of capturing the global market share for osteoporotic therapeutics. Recently, promising candidates of such therapeutics have been developed in our laboratories, which show non-toxic signs and more efficacious ability to prevent bone mass loss and microstructural deterioration in a postmenopausal osteoporotic animal model. Significantly, these therapeutic candidates act on new disease targets and are able to inhibit bone resorption and possibly to stimulate bone formation as dual functional agents for preventing bone loss. These agents have been recently protected by a US patent, which will be licensed to the grant applicant for further development towards various therapeutic uses. The aim of this phase I study is to further define the candidates' ability to systematically protect bones from osteoporosis in the aforementioned animal model, thus laying a concrete foundation for the following phase II study. To reach this aim: First, the candidate agents will be prepared and their chemical structures and purity will be characterized based on our established methods; second, the postmenopausal osteoporotic animal model will be obtained and treated with the agents, as well as estrogen and bisphosphonates for comparison, using standard operative and treatment protocols already used in our laboratories; third, different bone samples (e.g. femur, humerus, mandible, tibia and vertebra) in the animals will be collected after treatment and the treatment efficacy will be evaluated using various advanced techniques, including electron paramagnetic resonance, micro-computed tomography and bone histomorphometric technologies, which have been developed and/or routinely used in our laboratories. Our multidisciplinary team with all the expertise necessary to accomplish this project is the only one working on this new kind of drug development. We believe that systematic definition of the therapeutic efficacy and further development of the candidate agents will lead to new, safer and more efficacious therapeutics, thus providing profound impacts on osteoporotic prevention and treatment and winning the considerable global market share. PUBLIC HEALTH RELEVANCE: There is a greatly unmet need for developing new osteoporotic therapeutics because of raising concerns over the current drugs' efficacy and their long-term safety. Additionally, the large number of current patients with postmenopausal osteoporosis and the worldwide growth in elderly population provide new safer and more efficacious drugs with ample opportunities to capture considerable share in the global markets for osteoporotic therapeutics. Currently, our studies have found a new kind of agent that may be the suitable candidates of such therapeutics. The agents act on new disease targets, and more effectively prevent bone loss without toxic signs. The mechanism underlying the bone protection of the agents is due to reducing bone resorption and perhaps increasing bone formation. We believe that further defining and developing these agents will lead to new dual action drugs with safer and more efficacious profiles for osteoporotic prevention and treatment.