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

描述(申请人提供)：骨质疏松症是一种无声的衰弱的骨骼疾病，当(破骨细胞)的骨吸收速度远远大于(成骨细胞)的骨形成速度时，会导致骨丢失，骨质量恶化，导致骨强度和骨脆性降低，并容易骨折。目前FDA批准的药物被证明可以防止进一步的骨丢失，但还没有证明可以恢复已经因这种疾病失去的骨。此外，这些药物中的许多都有严重的副作用(例如，雌激素治疗导致的乳腺癌、颌骨骨坏死和双膦酸类药物的延迟愈合)。这项研究的总体目标是开发新的创新化合物，MZF-CAP和MZ-CAP/FF(MZ-CAP和黄烷/黄酮类化合物的组合，FF)，将是安全的，负担得起的，并有效地预防和逆转骨丢失。初步数据显示，MZF-CAP制剂作为补充剂或注射给药，可防止因矿物质缺乏或雌激素缺乏(卵巢切除)而导致的大鼠骨质丢失。在继续的研究中，具体目标是：(A)制备(A)MZF-Cap(低氟)和(B)MZ-Cap/FF(不含氟和黄烷类/黄酮类化合物，FF，已知可抑制与骨吸收相关的细胞因子)，并表征它们的性质(组成、离子释放、溶解)以及成骨细胞(成骨细胞)或骨吸收细胞(破骨细胞)的体外反应；(2)与钙+维生素D补充剂相比，评价选定的MZF-CAP和MZ-CAP/FF制剂在(A)预防和(B)恢复或逆转卵巢切除或矿物质缺乏引起的骨丢失方面的效果；(3)在更大的动物模型(绵羊)上评价MZF-CAP和MZ-CAP/FF预防骨丢失的效果；以及(4)确定MZF-CAPS和MZ-CAP/FF对以下水平的影响：(A)分子(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(皮质骨和松质骨厚度、骨小梁疏松、各向异性)；(D)生化(基质/矿物比率、骨矿化程度)和生物矿物(骨矿物成分、结晶度和溶解性能)。分析方法将包括：X射线衍射法、傅里叶变换红外光谱、热重法、扫描电子显微镜、微型计算机断层扫描。意义：拟议的研究结果可能导致安全和负担得起的疗法的开发，该疗法将以预防和逆转骨质疏松症和其他骨缺乏性疾病造成的骨丢失为目标。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。 公共卫生相关性：骨质疏松症是一个世界性的主要健康问题，严重影响着人们的生活质量和医疗费用。骨质疏松症是指骨吸收的速度远远大于骨形成的速度，导致骨丢失、骨微结构紊乱，导致骨无力和易骨折。女性髋部骨折的风险相当于她患乳腺癌、子宫癌和卵巢癌的风险总和，而男性患骨质疏松性骨折的风险高于他患前列腺癌的风险。目前治疗骨质疏松症的药物只涉及抑制骨吸收，但确实可以恢复已经因这种疾病失去的骨骼。这些目前的药物也有严重的副作用(如癌症风险、心血管发病率等)。最近，颌骨的骨坏死和愈合延迟与以双膦酸盐为基础的药物(例如，Fosamax(R))有关。这项研究将导致开发一种安全、负担得起的类似骨矿物质的化合物，有助于预防骨丢失和逆转骨丢失。

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.