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

描述（由申请人提供）：骨质疏松症是一种无声的使人衰弱的骨病，当骨吸收率（由破骨细胞）远大于骨形成率（由成骨细胞）时，就会导致骨质流失、骨质量恶化，导致骨强度下降、骨脆性降低以及容易发生骨折。目前 FDA 批准的药物已被证明可以防止进一步的骨质流失，但尚未被证明可以恢复因疾病而流失的骨质。此外，许多这些药物具有严重的副作用（例如，雌激素治疗引起的乳腺癌、颌骨坏死以及基于双膦酸盐的药物的延迟愈合）。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/黄酮类化合物 FF 的组合），它们对于预防和逆转骨质流失将是安全、实惠且有效的。初步数据表明，作为补充剂或注射给药的 MZF-CaP 制剂可预防大鼠因矿物质缺乏或雌激素缺乏（卵巢切除术）引起的骨质流失。对于后续研究，具体目标是：（1）制备（a）MZF-CaP（低氟）和（b）MZ-CaP/FF（不含氟化物与黄烷/类黄酮，FF，已知可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）以及由骨形成（成骨细胞）或骨吸收（破骨细胞）引起的体外反应细胞； (2) 与钙维生素 D 补充剂相比，评估选定的 MZF-CaP 和 MZ-CaP/FF 制剂作为补充剂对 (a) 预防和 (b) 恢复或逆转卵巢切除或矿物质缺乏引起的骨质流失的效果； (3)在较大动物模型(绵羊)中评价MZF-CaP和MZ-CaP/FF预防骨丢失的效果； (4) 确定 MZF-CaP 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（骨皮质和骨小梁厚度、骨小梁孔隙率、各向异性）； (d) 生物化学（基质/矿物质比例、骨矿化程度）和生物矿物质（骨矿物质成分、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、显微计算机断层扫描。意义：拟议研究的结果可能会导致安全且负担得起的疗法的开发，该疗法的目标是预防和逆转骨质疏松症和其他骨缺乏疾病引起的骨质流失。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。 公共卫生相关性：骨质疏松症是世界范围内的一个主要健康问题，对生活质量和医疗保健费用产生严重影响。当骨吸收速率远大于骨形成速率时，就会出现骨质疏松症，导致骨质流失、骨微结构紊乱，导致骨质疏松和易发生骨折。女性发生髋部骨折的风险等于其患乳腺癌、子宫癌和卵巢癌的风险之和，而男性发生骨质疏松性骨折的风险则高于患前列腺癌的风险。目前可用于骨质疏松症治疗的药物仅涉及抑制骨吸收，但确实可以恢复因疾病而损失的骨质。目前的这些药物还具有严重的副作用（例如癌症、心血管发病风险等）。最近，颌骨骨坏死和延迟愈合与基于双膦酸盐的药物（例如 Fosamax(R)）有关。这项研究将开发出一种安全、实惠的类似于骨矿物质的化合物，有助于预防骨质流失和逆转骨质流失。

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.