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（破骨细胞）的速度远远大于骨形成（成骨细胞）的速度时，导致骨丢失，骨质量恶化，导致骨强度和骨脆性下降，易发生骨折。目前fda批准的药物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已经因疾病而丢失的骨质。此外，这些药物中的许多都有严重的副作用（例如，雌激素治疗引起的乳腺癌，颌骨骨坏死和双膦酸盐类药物的延迟愈合）。该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和黄酮/类黄酮的组合，FF)，这将是安全的，负担得起的和有效的预防和逆转骨质流失。初步数据显示，MZF-CaP制剂作为补充或注射，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。对于继续进行的研究，具体目标是：(1)制备(a) MZF-CaP（含低氟化物）和(b) MZ- CaP/FF（不含氟化物，与黄烷/类黄酮结合，FF，已知可抑制与骨吸收相关的细胞因子），并表征它们的特性（组成、离子释放、溶解）以及骨形成（成骨细胞）或骨吸收（破骨细胞）细胞引起的体外反应；(2)与钙+维生素D补充剂相比，评价选定的MZF-CaP和MZ-CaP/FF制剂作为补充剂在(a)预防和(b)恢复或逆转卵巢切除术或矿物质缺乏引起的骨质流失方面的效果；(3)在大型动物模型（羊）上评价MZF-CaP和MZ-CaP/FF对骨质流失的预防作用；(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)显微结构（骨皮质和骨小梁厚度、骨小梁孔隙率、各向异性）；(d)生物化学（基质矿物比、骨矿化程度）和生物矿物（骨矿物组成、结晶度和溶解性）。分析方法包括：x射线衍射，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：这些研究的结果可能会导致开发出安全、负担得起的治疗方法，以预防和逆转骨质疏松症和其他骨质缺乏症引起的骨质流失。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。

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.