VITAMIN K AND SKELETAL HEALTH

拟议的计划将促进尼尔·宾克利的发展 华盛顿大学学术老年病学家和老年病学家 威斯康星州，一个有着悠久老年学研究历史的机构。 这将为进一步开发和应用BASIC提供机会 科学和临床技能到他感兴趣的重点领域， 骨质疏松症，通过保护他的时间和允许获得 作为一名独立研究人员，需要成熟的技能和经验。 骨骼脆性随着年龄的增加而变得普遍，最高可达40岁 患有骨质疏松性骨折的女性所占比例。因为至少 存在三种依赖维生素K的骨骼蛋白，这似乎是合理的 维生素K在维持骨骼健康方面起着重要作用。而当 维生素K缺乏的经典定义是 凝血异常(凝血酶原时间延长)， 最近人们认识到，对羧化不足的测量 其他蛋白质，特别是骨钙素，是一种更敏感的指标。 充分性。如果定义为血清中低羧化水平升高 骨钙素，一些报告发现大多数绝经后妇女 维生素K不足。因此，维生素K似乎有可能 不足是很常见的，也是导致 骨质疏松。然而，先前关于维生素K对健康的影响的研究 这一框架产生了相互矛盾的结果。一些报道发现， 维生素K缺乏与低骨量或骨骼有关 脆弱，而其他人则没有影响，甚至增加了骨骼 质量。这些数据导致了截然相反的建议，即， 维生素K缺乏可能导致骨质疏松症，反过来， 维生素K拮抗剂可能对治疗骨质疏松症有用。致信地址 这些不同的假设，是拟议研究的总体目标 是确定维生素K或维生素K拮抗剂华法林是否有 在确定骨骼健康方面的作用。在这方面，我们假设 即：1.治疗引起的维生素K缺乏 抗凝会导致骨质流失。2.不同的动物研究可能 是华法林对骨骼的未知毒性作用的结果。 3.维生素K缺乏和由此导致的骨钙素减少 含量可能会降低骨骼强度，从而导致骨骼脆性。 4.维生素K缺乏加重雌激素耗竭性骨丢失。 为了验证这些假设，我们将使用恒河猴作为模型。 以评估华法林治疗对患者的影响 骷髅。此外，利用成年老鼠，我们将评估 长期膳食维生素K缺乏和华法林的影响 对血清和骨钙素、骨转换标志物和骨代谢指标的影响 钙稳态、骨密度和生化强度。 随后，我们将评估预先存在和正在进行的 卵巢摘除后维生素K缺乏导致女性骨质丢失 老鼠。描述维生素K在骨骼健康中的作用(S)可能会 对骨质疏松症的预防和治疗具有重要意义。

The proposed program will facilitate the development of Neil Binkley as an academic geriatrician and gerontologist at the University of Wisconsin, an institution with a long history of gerontologic research. It will provide the opportunity to further develop and apply basic science and clinical skills to his focused area of interest, osteoporosis, by protecting his time and allowing the acquisition of skills and experience needed to mature as an independent researcher. Skeletal fragility becomes common with advancing age with up to 40 percent of females sustaining an osteoporotic fracture. As at least three vitamin K dependent skeletal proteins exist, it is plausible that vitamin K plays a role in the maintenance of skeletal health. While vitamin K insufficiency has classically been defined in terms of coagulation abnormalities (prolongation of the prothrombin time), it has recently become appreciated that measurement of undercarboxylation of other proteins, notably osteocalcin, is a much more sensitive measure of adequacy. If defined as elevated serum levels of undercarboxylated osteocalcin, some reports find the majority of postmenopausal women to be vitamin K insufficient. Thus it is plausible that vitamin K insufficiency is common and contributes to the development of osteoporosis. However, prior studies of the effect of vitamin K upon the skeleton have yielded contradictory results. Some reports find that vitamin K insufficiency is associated with low bone mass or skeletal fragility, while others find no effect, or even an increase in bone mass. These data have lead to diametrically opposed suggestions, i.e., that vitamin K insufficiency may cause osteoporosis and conversely, that vitamin K antagonists may be useful to treat osteoporosis. To address these divergent hypotheses, the overall goal of the proposed research is to determine if vitamin K or the vitamin K antagonist warfarin have a role in determining skeletal health. In this regard, we hypothesize that: 1. Vitamin K insufficiency produced by therapeutic anticoagulation leads to bone loss. 2. The disparate animal studies may be the result of unrecognized toxic effects of warfarin on the skeleton. 3. Vitamin K insufficiency and resultant reduced bone osteocalcin content may contribute to skeletal fragility by reducing bone strength. 4. Vitamin K insufficiency accentuates estrogen depletion bone loss. To test these hypotheses, we will utilize the rhesus monkey as a model in which to assess the effect of therapeutic warfarin treatment upon the skeleton. In addition, utilizing adult rats, we will evaluate the effect of long-term dietary vitamin K insufficiency and warfarin regimens on serum and bone osteocalcin, markers of skeletal turnover and calcium homeostasis, bone density and biochemical strength. Subsequently, we will assess the effect of pre-existing and ongoing vitamin K insufficiency upon ovariectomy induced bone loss in female rats. Delineation of the role(s) of vitamin K in skeletal health may have implications for osteoporosis prevention and treatment.