Glucocorticoids, Bone Strength and Angiogenesis

描述(由申请人提供)： 糖皮质激素引起的骨质疏松症是最常见的药物引起的骨质疏松形式。接受慢性糖皮质激素治疗的患者中有30%到50%可能发生骨折，但骨密度测量低估了这种疾病中的骨折风险，至少部分原因是对这种疾病的认识不足和治疗不足。脊椎和肋骨骨折对退伍军人管理局患者的护理任务特别重要，因为它们除了会引起疼痛和减少体力活动外，还会导致胸壁夹板，从而减少呼吸能力，从而显著降低肺部疾病患者的呼吸功能。糖皮质激素治疗导致的骨强度下降超过了骨密度的下降，但人们对这种现象背后的机制知之甚少。虽然人们普遍认识到骨骼是由细胞、矿物质和胶原蛋白组成的，但很少有人意识到水是另一个主要成分，占骨骼湿重的四分之一以上。硬组织的抗折性在没有水的情况下是有缺陷的，而水赋予了骨骼许多其独特的强度和弹性。这项建议的长期目标是确定药物引起的骨水和血管的恶化是否可能是糖皮质激素引起的骨质疏松症典型的骨强度下降不成比例地大于骨量的原因，以及糖皮质激素对骨细胞的直接作用是否可能损害骨强度和血管。研究激素性骨质疏松症骨强度丧失的细胞和分子机制，探讨目前治疗效果有限的原因，将增强在骨密度下降之前尽早保护骨骼的动力。为了实现这一目标，将研究糖皮质激素过量对骨细胞血管蛋白表达的直接影响。接下来，在糖皮质激素诱导性骨质疏松症的动物模型中，将检测骨水和血管对骨强度丧失的贡献，以及预防糖皮质激素诱导性骨质疏松症的各种治疗策略的额外影响。这些骨血管因子变化的临床意义将通过从绝经后骨质疏松症或糖皮质激素性骨质疏松症患者的档案骨活检标本在人类中阐明。本申请中提出的研究是及时的，通过利用现代概念和创新方法，提供了预防和治疗糖皮质激素性骨病迫切需要的新见解的机会，因此，与退伍军人管理局的医疗保健任务直接相关和至关重要。 公共卫生相关性： 与退伍军人健康相关：脊椎或肋骨骨折通常是糖皮质激素引起的骨质疏松症(GIO)的主要表现。这种骨折对退伍军人管理局的病人护理任务特别重要，因为除了引起疼痛和减少活动外，它们还会显著降低呼吸功能。在一个中心，对已公布的GIO管理指南的遵守程度非常低，只有8%的男性退伍军人得到了足够的钙和维生素D，只有不到20%的人得到了特定的治疗。这种不坚持的原因包括：1)医生低估了给予糖皮质激素的时间，并淡化了GIO的风险；2)许多医生认为骨质疏松症是女性的疾病；3)骨密度测试低估了GIO的骨折风险。因此，对GIO的了解不足在疾病的管理不善中起着重要作用。这项针对GIO中骨骼强度丧失机制的拟议研究应该会提供新的见解，这些见解是退伍军人迫切需要的，而且对退伍军人的医疗保健至关重要。

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Glucocorticoid-induced osteoporosis is the most common drug-induced form of osteoporosis. Fractures may occur in 30 to 50% of patients receiving chronic glucocorticoid therapy but bone density measurements underestimate the risk of fracture in this disorder and account for, at least in part, the under- recognition and under-treatment of the disease. Vertebral and rib fractures are of particular importance to the VA patient care mission because in addition to causing pain and reducing physical activity, they can markedly decrease respiratory function in patients with pulmonary disease by causing splinting of the chest wall, thereby reducing the capacity to breathe. Glucocorticoid therapy causes a decline in bone strength that surpasses the decline in bone density, but little is known of the mechanism behind this phenomenon. Although it is widely appreciated that bone is composed of cells, mineral and collagen, it is seldom realized that water is another major component accounting for more than one fourth of the wet weight of bone. Fracture resistance of hard tissues is defective without water and water confers to bone much of its unique strength and resilience. The long-term objective of this proposal is to determine whether drug-induced deterioration of bone water and vascularity may account for the disproportionately greater decline in bone strength than in bone mass typical of glucocorticoid- induced osteoporosis and whether the bone strength and vascularity may be compromised through direct actions of glucocorticoids on bone cells. Studies aimed at the cellular and molecular mechanisms of the pathogenesis of the loss of bone strength in glucocorticoid-induced osteoporosis and investigation of the reasons for the limited response to current therapy would increase motivation to protect the skeleton as early as possible, before there are decreases in bone density. To achieve this goal, the direct effects of glucocorticoid excess on the expression of vascular proteins from bone cells will be investigated. Next, determination of the contribution of bone water and vascularity to the loss of bone strength in an animal model of glucocorticoid-induced osteoporosis and the additional impact of various treatment strategies to prevent glucocorticoid-induced osteoporosis will be examined. The clinical significance of these changes in bone vascular factors will be elucidated in humans using archival bone biopsy specimens obtained from patients with postmenopausal osteoporosis or glucocorticoid-induced osteoporosis. The studies proposed in this application are timely and by capitalizing on modern concepts and innovative methodology offer the opportunity for new insights that are sorely needed for the prevention and treatment of glucocorticoid-induced bone disease and are, therefore, immediately relevant and vital to the VA health care mission. PUBLIC HEALTH RELEVANCE: Relevance to Veterans Health: Fractures of the vertebrae or ribs are often the presenting manifestations of glucocorticoid-induced osteoporosis (GIO). Such fractures are of particular importance to the VA patient care mission because in addition to causing pain and reducing activity, they can markedly decrease respiratory function. In one center, adherence to published guidelines for the management of GIO was so low that only 8% of male veterans were given adequate calcium and vitamin D and less than 20% were given specific therapy. Reasons for this nonadherence include: 1) physicians underestimate the time glucocorticoids will be given and downplay the risk of GIO, 2) many physicians think osteoporosis is a disorder of women, and 3) bone density tests underestimate fracture risk in GIO. Thus, inadequate knowledge about GIO plays an important role in the mismanagement of the disease. The proposed studies aimed at the mechanisms of the loss of bone strength in GIO should provide new insights that are sorely needed and immediately vital to veterans health care.