Glucocorticoids, Bone Strength and Angiogenesis

糖皮质激素、骨强度和血管生成

• 批准号: 7785356
• 负责人: ROBERT Stewart WEINSTEIN
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7785356
• 关键词: Accounting; Acid Phosphatase; Address; Adherence; Adult; Affect; Agreement; Alendronate; Angiogenic Factor; Angiogenic Peptides; Animal Model; Animals; Apoptosis; Area; Attenuated; Biological Assay; Biopsy; Biopsy Specimen; Blood Vessels; Blood flow; Bone Density; Bone Diseases; Bone remodeling; Breathing; Calcium; Cell Culture Techniques; Cells; Cessation of life; Chest wall structure; Chronic; Collagen; Data; Deterioration; Dexamethasone; Disease; Dose; Endothelial Cells; Enzymes; Estrogens; Exhibits; Fracture; Funding; Genes; Glucocorticoid Receptor; Glucocorticoids; Goals; Guidelines; HIF1A gene; Health; Healthcare; Hormones; Human; Hydroxysteroid Dehydrogenases; Hypoxia; Image; In Vitro; Intercellular Fluid; Investigation; Knowledge; Liquid substance; Lung diseases; Measurement; Messenger RNA; Metatarsal bone structure; Methodology; Minerals; Mission; Modeling; Molecular; Motivation; Mus; Osteoblasts; Osteocalcin; Osteoclasts; Osteocytes; Osteogenesis; Osteoid; Osteoporosis; Pain; Parathyroid gland; Pathogenesis; Patient Care; Patients; Perfusion; Pharmaceutical Preparations; Physical activity; Physicians; Plastics; Play; Postmenopausal Osteoporosis; Prevalence; Prevention; Process; Production; Proteins; Publishing; Raloxifene; Recruitment Activity; Research Design; Resistance; Respiratory physiology; Rib Fractures; Risk; Role; Site; Skeleton; Spinal Fractures; Splint Device; Staining method; Stains; Structure; Surface; System; Tartrates; Testing; Time; Tissues; Tracer; Transgenic Mice; Tube; Umbilical vein; Vascular Endothelial Growth Factors; Veterans; Vitamin D; Water; Weight; Woman; Work; abstracting; angiogenesis; base; bisphosphonate; bone; bone cell; bone loss; bone mass; bone strength; bone turnover; clinically significant; fetal; in vitro Assay; in vivo; innovation; insight; lead chromate; male; overexpression; prednisolone; prevent; promoter; public health relevance; research study; resilience; response; rib bone structure; skeletal; spine bone structure; tissue/cell culture; treatment strategy; vascular factor

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.

描述（由申请人提供）：