Biomaterials (Mf/Zn/F-BCPs) for osteoporosis therapy

用于骨质疏松症治疗的生物材料（Mf/Zn/F-BCP）

• 批准号: 7921968
• 负责人: Racquel Zapanta LeGeros
• 金额: $ 67.12万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-19 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921968
• 关键词: Adverse effects; Animal Model; Animals; Anisotropy; Bees; Biochemical; Biocompatible Materials; Biological Factors; Biomechanics; Bone Density; Bone Diseases; Bone Formation Stimulation; Bone Resorption; Bone Resorption Inhibition; Bone necrosis; Breast; Calcium; Calcium ion; Cardiovascular system; Cells; Data; Deterioration; Development; Disease; Drug Formulations; Economic Burden; Equilibrium; Estrogen Therapy; Estrogens; FDA approved; Flavonoids; Fluorides; Fosamax; Fracture; Funding; Gene Expression; Goals; Health; Health Care Costs; Hip Fractures; Human; Impaired wound healing; In Vitro; Injection of therapeutic agent; Intervention; Ions; Jaw; Lead; Magnesium; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Minerals; Modeling; Molecular; Morbidity - disease rate; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Osteoporosis prevention; Ovariectomy; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiologic calcification; Porosity; Predisposition; Preparation; Prevention; Prevention therapy; Property; Prostaglandin Receptor; Public Health; Quality of life; Rattus; Recurrent Malignant Neoplasm; Research; Resistance; Risk; Scanning Electron Microscopy; Sheep; Spectrum Analysis; Testing; Thermogravimetry; Thick; Vitamin D; Woman; X-Ray Computed Tomography; Zinc; abstracting; analytical method; base; biomineralization; bisphosphonate; bone; bone cell; bone loss; bone mass; bone quality; bone strength; calcium phosphate; cytokine; density; dietary supplements; improved; innovation; inorganic phosphate; malignant breast neoplasm; man; mineralization; novel; osteoporosis with pathological fracture; prevent; repaired; response; restoration; socioeconomics; substantia spongiosa

DESCRIPTION (provided by applicant): Osteoporosis, a silent debilitating bone disease, results when the rate of bone resorption (by osteoclasts) is much greater than the rate of bone formation (by osteoblasts) causing bone loss, deterioration of bone quality, leading to decreased bone strength and bone fragility and susceptibility to bone fracture. Current FDA-approved drugs are shown to prevent further bone loss but have not been shown to restore bone already lost to the disease. Furthermore, many of these drugs have serious side effects (e.g., breast cancer from estrogen therapy, osteonecrosis of the jaw and delayed healing from bisphosphonate-based drugs). The over-all objective of the study is to develop novel innovative compounds, MZF-CaP and MZ- CaP/FF (a combination of MZ-CaP and flavan/flavonoids, FF), that will be safe, affordable and effective for prevention and reversal of bone loss. Preliminary data showed that MZF-CaP formulations administered as a supplement or by injection prevented bone loss induced by mineral deficiency or estrogen deficiency (ovariectomy) in rats. For the continuing study, the specific aims are to: (1) prepare (a) MZF-CaP (with low fluoride) and (b) MZ- CaP/FF (without fluoride combined with flavan/flavonoids, FF, known to inhibit cytokines associated with bone resorption) and characterize their properties (composition, ion release, dissolution) and the in vitro response elicited from bone-forming (osteoblasts) or bone-resorbing (osteoclasts) cells; (2) evaluate the effect of selected MZF-CaP and MZ-CaP/FF preparations as supplement on the (a) prevention and (b) restoration or reversal of bone loss induced by ovariectomy or mineral deficiency, compared with calcium + vitamin D supplement; (3) evaluate the effect of MZF-CaP and MZ-CaP/FF on prevention of bone loss in a larger animal model (sheep); and (4) determine the effects of MZF-CaPs and MZ-CaP/FF on the following levels: (a) molecular (gene expression) and cellular (osteocyte density); (b) biomechanical (bone strength, bone density); (c) microstructural (cortical and trabecular bone thickness, trabecular bone porosities, anisotropy); (d) biochemical (matrix/mineral ratio, degree of bone mineralization)' and biomineral (bone mineral composition, crystallinity and dissolution properties). Analytical methods will include: x-ray diffraction, FT-IR spectroscopy, thermogravimetry, scanning electron microscopy, micro- computed tomography. Significance: Results from the proposed studies could lead to the development of safe and affordable therapy that will target both prevention and reversal of bone loss due to osteoporosis and other bone- deficient diseases. These results will greatly impact public health and alleviate the tremendous socio- economic burden associated with osteoporosis. PUBLIC HEALTH RELEVANCE: Osteoporosis, a major health problem worldwide, has a severe impact on the quality of life and health care cost. Osteoporosis results when the rate of bone resorption is much greater than the rate of bone formation, causing bone loss, disorganization of bone microarchitecture leading to bone weakness and susceptibility to fracture. A woman's risk of hip fracture is equal to her combined risk of breast, uterine, and ovarian cancer and a man's risk of osteoporotic fracture is more than his risk of prostate cancer. Current drugs available for osteoporosis therapy are concerned only with suppressing bone resorption but does recover bone already lost to the disease. These current drugs also have serious side effects (e.g.risk of cancer, cardiovascular morbidity, etc). Recently, osteonecrosis of the jaw bone and delayed healing has bee associated with bisphosphonate-based drugs (e.g., Fosamax(R)). This study will result in the development of a safe, affordable compound similar to bone mineral that will help in preventing bone loss and reversing bone loss.

描述（由申请人提供）：骨质疏松症是一种无症状的使人衰弱的骨疾病，当骨吸收（通过破骨细胞）的速率远大于骨形成（通过成骨细胞）的速率时，导致骨丢失、骨质量恶化，导致骨强度和骨脆性降低以及对骨折的易感性。目前FDA批准的药物显示可以防止进一步的骨质流失，但尚未显示可以恢复已经因疾病而流失的骨。此外，这些药物中的许多具有严重的副作用（例如，雌激素治疗导致的乳腺癌、颌骨骨坏死和双膦酸盐类药物导致的延迟愈合）。该研究的总体目标是开发新型创新化合物MZF-CaP和MZ-CaP/FF（MZ-CaP和黄烷/类黄酮，FF的组合），其将安全、可负担且有效地预防和逆转骨丢失。初步数据显示，MZF-CaP制剂作为补充剂或通过注射给药可预防大鼠中矿物质缺乏或雌激素缺乏（卵巢切除术）诱导的骨丢失。对于继续研究，具体目标是：（1）制备（a）MZF-CaP（低氟化物）和（B）MZ-CaP/FF（不含氟与黄烷/类黄酮，FF，已知抑制与骨吸收相关的细胞因子），并表征其特性（组成、离子释放、溶解）和由骨形成引起的体外反应（成骨细胞）或骨吸收（2）评价与钙+维生素D补充剂相比，所选MZF-CaP和MZ-CaP/FF制剂作为补充剂对（a）预防和（B）恢复或逆转由卵巢切除术或矿物质缺乏诱导的骨丢失的作用;（3）评估MZF-CaP和MZ-CaP/FF在较大动物模型（绵羊）中对预防骨损失的作用;和（4）确定MZF-CaP和MZ-CaP/FF对以下水平的作用：（基因表达）和细胞（骨细胞密度）;（B）生物力学（骨强度、骨密度）;（c）微观结构（皮质骨和骨小梁厚度、骨小梁孔隙度、各向异性）;（d）生物化学（基质/矿物质比率、骨矿化程度）和生物矿物（骨矿物组成、结晶度和溶解特性）。分析方法包括：X射线衍射、FT-IR光谱、热重分析、扫描电子显微镜、微型计算机断层扫描。重要性：拟议研究的结果可能导致开发安全和负担得起的治疗方法，这些方法将针对预防和逆转由于骨质疏松症和其他骨缺陷疾病引起的骨丢失。这些结果将极大地影响公众健康，并减轻与骨质疏松症相关的巨大社会经济负担。 与公共卫生的相关性：骨质疏松症是一个全球性的主要健康问题，对生活质量和医疗保健费用产生严重影响。当骨吸收的速率远大于骨形成的速率时，导致骨质疏松症，引起骨丢失、骨微结构的紊乱，导致骨虚弱和对骨折的易感性。女性髋部骨折的风险等于她患乳腺癌、子宫癌和卵巢癌的风险之和，而男性髋部骨折的风险大于前列腺癌的风险。目前可用于骨质疏松症治疗的药物仅涉及抑制骨吸收，但确实恢复了因疾病而丢失的骨。这些目前的药物也有严重的副作用（例如癌症风险，心血管发病率等）。最近，颌骨的骨坏死和延迟愈合与基于双膦酸盐的药物（例如，福善美（R））。这项研究将导致开发一种安全，负担得起的化合物，类似于骨矿物质，这将有助于防止骨质流失和逆转骨质流失。