治疗骨质疏松症药物研究进展（一）

骨质疏松症（Osteoporosis，OP）分为两类：（1）原发性骨质疏松痛包括Ⅰ型绝经后骨质疏松症和Ⅱ型老年性骨质疏松症：（2）继发性骨质疏松症由其他疾病或由药物等一些因素诱发。治疗骨质疏松症的药物主要有两大类：抑制骨吸收药物和促进骨形成药物。现对治疗骨质疏松症的药物作用机制及研究进展综述如下。     

锶抗骨质疏松的作用机制研究

目的:综述锶抗骨质疏松的作用机制,为其临床应用提供参考。方法:以"骨质疏松症机制""锶""骨细胞""雷奈酸锶""Osteoporosis""Strontium""Strontium Ranelate"等为关键词,组合查询2005-2018年中国知网、万方数据、PubMed等数据库中的相关文献,对锶抗骨质疏松的作用机制及含锶的药物进行归纳总结。结果与结论:共检索到相关文献978篇,其中有效文献38篇。锶抗骨质疏松的作用机制包括结合钙离子敏感受体、上调转化生长因子水平、调节成骨相关标志物表达等促进骨细胞形成;调节核因子κB受体活化因子/核因子κB受体活化因子配体/骨保护素(RANK/RANKL/OPG)信号通路、调节κB抑制蛋白α(IκBα)等抑制破骨细胞分化;诱导间充质干细胞(MSCs)表达成骨相关基因、激活Wnt/β-catenin信号通路促进MSCs成骨分化;改善骨的微观结构,增强骨强度。临床常用含锶药物为雷奈酸锶,其具有促进骨形成和抑制骨吸收的双重作用,与其他治疗骨质疏松症的药物相比,雷奈酸锶具有良好的治疗效果。     

骨持疏松症治疗药依普黄酮

依普黄酮为植物雌激素异黄酮衍生物，雌激素拮抗特性，通过抑制骨吸收和促进骨形成过程，维持骨代谢的动态平衡，可有效地预防骨质疏松症。     

染料木素抗骨质疏松研究进展

染料木素作为一种"植物雌激素",能促进成骨细胞增殖、分化和矿化骨形成功能,也能够抑制破骨细胞骨吸收过程,存在多种抗骨质疏松的分子机制。该文综述染料木素抗骨质疏松作用及其机制的研究进展,为研究与开发抗骨质疏松新药提供依据。     

葛根素防治骨质疏松症的作用机制研究进展

我国骨质疏松症的患病率高,是老年患者致残和致死的主要原因之一。葛根素是葛根中主要活性成分,可促进成骨细胞的增殖分化、抑制骨吸收和破骨细胞的分化形成、促进骨髓间充质干细胞向成骨分化、发挥雌激素样作用。综述了葛根素防治骨质疏松症的作用机制研究进展,为深入开展葛根素治疗骨质疏松症的基础研究和新药开发提供参考。     

抗骨质疏松药物的研究

目的寻求疗效好毒副作用小的抗骨质疏松新药。方法运用文献检索，分类归纳、综合分析的方法。结果骨质疏松症作为中老年多发的退行性疾病之一，倍受关注；抗骨质疏松药物主要为激素类、双磷酸盐类、抑钙素类、中药等。结论骨质疏松症不仅是老年人特有的疾病，实际上在儿童时期就已存在。目前尚无特效药物能够治愈此病，因此重在预防。抗骨质疏松药物中雌激素可抑制破骨细胞的骨吸收进而抑制绝经后骨的快速丢失。双磷酸盐类药物为防治以破骨细胞性骨吸收为主的各种代谢性骨病及高转化型骨质疏松症的主要药物。降钙素是中度以上骨痛患者的首选药物；中医药通过补肾增加肾脏对活性维生素D的转化，促进机体对钙的吸收；维持血钙的稳定。抗骨质疏松药物研究与开发前景广阔     

抗骨质疏松症药物的临床应用进展

近年来,随着社会老龄化的发展,骨质疏松症患者愈来愈多,作为一个社会问题已引起越来越多的关注.骨质疏松主要是由于骨吸收与骨形成之间的平衡被打破,骨吸收量大于骨形成量,从而引起骨量减少的一种疾病.一般认为,破骨细胞活性增强,导致骨吸收增加,是形成骨质疏松的重要原因.破骨细胞活性受多种激素和细胞因子影响,如降钙素、甲状旁腺激素、炎症因子、雌激素等.因此,目前普遍认为,治疗骨质疏松的药物应具有增强钙吸收、调节内分泌平衡及抑制骨吸收、增强骨形成的作用.本文通过对近年来有代表性的相关文献进行分析归纳,为临床合理选用提供参考.     

骨质疏松症的雌激素疗法

高龄化社会的到来,骨质疏松症成为医学上一大问题。特别是妇女闭经后骨质量急剧下降。约30％60岁以上妇女患有骨质疏松症。为了改善中高龄妇女的生活质量,必须对此采取对策。妇女骨质疏松症是一种不可逆的病理变化,治疗是非常困难的。所以,骨质疏松症的预防是非常重要的。雌激素能提高具有抑制骨吸收作用的降钙素的活性。雌激素还能促使肠道对钙的吸收,促使骨形成,抑制骨吸收。雌激素对闭经后骨质疏松症有良好的预防     

骨质疏松症的药物治疗

骨质疏松症（osteoprosis）是以低骨量及骨组织微结构退变为特征的一种全身性骨骼疾病，伴有骨脆性增加,易发生骨折。骨质疏松症可分为原发性和继发性两类，其中原发性骨质疏松症占骨质疏松症的90％，它又分为2种亚型,即Ⅰ型和Ⅱ型。Ⅰ型又称绝经骨质疏松症，Ⅱ型为老年型骨质疏松症。继发性骨质疏松症可继发于其他疾病或由药物引起。骨质疏松症治疗药物中，大部分是骨吸收抑制剂，通过减少破骨细胞的生成（如雌激素）或减少破骨细胞活性（如双膦酸盐）来抑制骨的吸收，防止骨量过多丢失。     

药源性骨质疏松症

骨质疏松症是以骨强度下降、骨折风险增加为特征的全身骨代谢障碍性疾病。导致药源性骨质疏松症的常见药物包括抗凝药、质子泵抑制剂、噻唑烷二酮类降糖药、强效利尿药、芳香化酶抑制剂、抗癫痫药、促性腺激素释放激素类药物和糖皮质激素等。上述药物主要通过促进骨吸收、抑制骨形成、阻碍骨矿化而影响骨代谢,导致骨质疏松。治疗药源性骨质疏松症的有效措施包括停药和减少致病药物剂量,同时给予患者钙剂、维生素D制剂、双膦酸盐、选择性雌激素受体调节剂、降钙素等抗骨质疏松药物的治疗。     

Advances in the treatment of osteoporosis

Drugs used to treat osteoporosis act either by inhibiting bone resorption or stimulating bone formation. Osteoclast formation and bone resorption require cell-to-cell contact between osteoblasts and osteoclast precursors and osteoclasts in the marrow. Interaction between the receptor for activation of nuclear factor kappa B (RANK) on the surface of preosteoclasts and osteoclasts and RANK ligand on the surface of osteoblasts is required to stimulate osteoclast formation and activation. Binding of the RANK ligand to its receptor and osteoclastogenesis are prevented by osteoprotegerin (OPG), a decoy receptor produced by osteoblasts and marrow stromal cells. Thus, interference in binding of the RANK ligand to RANK by OPG determines the rate of bone resorption. Antiresorptive drugs such as estrogen, raloxifene, bisphosphonates, salmon calcitonin, and osteoprotegerin increase bone mass by inhibiting osteoclast function and bone resorption. Osteoprotegerin is more potent since it also inhibits osteoclast formation. Raloxifene, a selective estrogen receptor modulator (SERM), is a member of a class of compounds that act through estrogen receptors and are agonists for bone, antagonists for breast and uterine tissue and may be cardioprotective. The drug was shown to prevent vertebral fractures. Alendronate and bisphosphonates are the only antiresorptive drugs that have been shown to decrease fracture rates for the hip in addition to spine and other sites. Bone morphogenetic proteins stimulate bone formation at local sites and are being developed to stimulate fracture healing. Parathyroid hormone (1-34) stimulates osteoblastic bone formation, markedly increases bone mass, prevents vertebral fractures and is under development to treat osteoporosis.     

Quercetin suppresses bone resorption by inhibiting the differentiation and activation of osteoclasts

Although quercetin has suppressed bone resorption in several animal studies, its target cells and the mechanism of its action related to bone resorption has not been fully elucidated. We investigated the effect of quercetin on the differentiation and activation of osteoclasts. We used cocultures of mouse spleen cells and ST2 cells, and cultures of osteoclast progenitor cells [M-CSF-dependent (MD) cells from mouse bone marrow and murine monocytic RAW 264 (RAW) cells]. Quercetin dose-dependently inhibited osteoclast-like (OCL) cell formation at 2-5 microM concentration in both the coculture and MD cell culture. Quercetin inhibited the increase of tartrate-resistant acid phosphatase (TRAP) activity of mononuclear preosteoclasts (pOCs) induced by receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) in both MD and RAW cell cultures. Quercetin reversely induced the disruption of actin rings in OCLs. Quercetin also suppressed both pit formation induced by osteoclasts on dentine slices and PTH-stimulated (45)Ca release in mouse long bone cultures. These results suggest that osteoclast progenitors as well as mature osteoclasts, are quercetin's target cells in relation to bone resorption, and that quercetin's suppressive effect on bone resorption results from both its inhibitory effect on the differentiation of osteoclast progenitor cells into pOCs and from its disruptive effect on actin rings in mature osteoclasts.     

Oral administration of quercetin inhibits bone loss in rat model of diabetic osteopenia

Diabetic osteopenia can result in an increased incidence of bone fracture and a delay in fracture healing. Quercetin, one of the most widely distributed flavonoids in plants, possesses antioxidant property and beneficial effect on osteoporosis in ovariectomized mice. All these properties make quercetin a potential candidate for controlling the development of diabetic osteopenia. Therefore, the present study was designed to investigate the putative beneficial effect of quercetin on diabetic osteopenia in rats. Diabetes mellitus was induced by streptozotocin. The diabetic rats received daily oral administration of quercetin (5 mg/kg, 30 mg/kg and 50 mg/kg) for 8 weeks, which was started at 4 weeks after streptozotocin injection. Quercetin at 5 mg/kg showed little effect on diabetic osteopenia, while quercetin at 30 mg/kg and 50 mg/kg could increase the decreased serum osteocalcin, serum alkaline phosphatase activity, and urinary deoxypyridinoline in diabetic rats. In addition, quercetin (30 mg/kg and 50 mg/kg) could partially reverse the decreased biomechanical quality and the impaired micro-architecture of the femurs in diabetic rats. Histomorphometric analysis showed that both decreased bone formation and resorption were observed in diabetic rats, which was partially restored by quercetin (30 mg/kg and 50 mg/kg). Further investigations showed that quercetin significantly lowered the oxidative DNA damage level, up-regulated the total serum antioxidant capability and the activity of serum antioxidants in diabetic rats. All those findings indicate the beneficial effect of quercetin on diabetic osteopenia in rats, and raise the possibility of developing quercetin as potential drugs or an ingredient in diet for controlling diabetic osteopenia.     

Protective estrogen-like properties and mechanism of quercetin in rat cerebral cortex neurons

OBJECTIVE To investigate the effect of quercetin on primary cultured newborn rat cortex neuron cell which is estrogen depletion,and discuss the possible mechanism,to provide new ideas and strategies for developing a drug of neurodegenerative disease.METHODS Rat cortex neurons were isolated from one day old Sprague Dawley rats and treated with estrogen,quercetin and estrogen receptor antagonists(ICI182,780).Cell viability was determined by MTT assay,neurite outgrowth was measured by fluorescent microsope and estrogen receptors were determine by Western blot.RESULTS Quercetin functions like estrogen to increase cortex neuronal cell viability,the Que(50,100μmol·L~(-1))group compared with the control group could significantly improve the activity of the cortical neurons(P<0.05).It can also increase neurite out growth,the Que(50,100μmol·L~(-1))group significantly promoted the formation of synapse,most of the neurons were full,and the synapses of neurons became thick,growth,and connect to a dense neural network.And in the Western blot experiments,Que(50,100μmol·L~(-1))group could obviously increase the expression of estrogen receptor alpha protein,in addition,the neural protective effect of quercetin can be inhibited by ICI182,780.CONCLUSION Quercetin like estrogen can protected cortex neuronal and the effect of quercetin on cortex neuronal cells was mediated by estrogen receptor alpha.     

The role of chloride channels in osteoclasts: ClC-7 as a target for osteoporosis treatment

Chloride ions play a major role in osteoclast biology and bone homeostasis. In addition to its general cellular roles, chloride is involved in the specific bone resorption activity of osteoclasts. The chloride channel ClC-7 has been shown to be mandatory for bone resorption. It is necessary for the acidification of the resorption lacunae. In addition to ClC-7, other chloride channels and exchangers have been identified in osteoclasts. The bicarbonate-chloride exchanger at the plasma membrane of osteoclasts is important for regulating the cytoplasmic pH during bone resorption. The role of the additional chloride channels or putative chloride channels identified in osteoclasts, volume-regulated anion channel, Chlor.62 and CLIC1 has not been established. To date, ClC-7 is the only known chloride channel whose disruption or mutation leads to a bone disease: osteopetrosis, which is characterized by an increased bone mass. Inhibition of ClC-7 constitutes a new potential way to treat osteoporosis. The expression of ClC-7 is restricted to few tissues with very high expression in the osteoclasts in bone. Pharmacologically, inhibitors of acidification of the resorption lacunae have proved to be unique, as inhibition leads to a decrease in bone resorption without affecting bone formation, suggesting that the coupling principle has been challenged. Thus, ClC-7 inhibitors may prove to be potent for prevention and treatment of osteoporosis.     

Quercetin, a flavonoid, inhibits proliferation and increases osteogenic differentiation in human adipose stromal cells

Flavonoids, which have been detected in a variety of foods, have been repeatedly reported to affect bone metabolism. However, the effects of flavonoids on osteoblastogenesis remain a matter of some controversy. In this study, the effects of quercetin on the differentiation and proliferation of human adipose tissue-derived stromal cells (hADSC) were determined. Quercetin was found to increase osteogenic differentiation in a dose-dependent manner. Other flavonoids, chrysin and kaempferol, were also shown to increase the osteogenic differentiation of hADSC, but this stimulatory effect was weaker than that associated with quercetin. Quercetin pretreatment administered prior to the induction of differentiation also exerted stimulatory effects on the osteogenic differentiation of hADSC. RT-PCR and real time PCR analysis showed that quercetin treatment induced an increase in the expression of osteopontin, BMP2, alkaline phosphatase and Runx2. Quercetin inhibited the proliferation of hADSC, but did not affect their survival. The pretreatment of quercetin increased ERK phosphorylation during osteogenic differentiation, although it did not increase ERK activity in control culture condition. ICI182780, an specific estrogen receptor antagonist, failed to inhibit the effects of quercetin on osteogenic differentiation. Quercetin-pretreated hADSC showed better bone regenerating ability in skull defect model of nude mice than naive cells. Our findings indicate that quercetin enhances osteogenic differentiation via an independent mechanism from estrogen receptor (ER) activation, and prove useful for in vivo bone engineering, using human mesencymal stem cells (hMSC).     

Isoflavones extracted from<Emphasis Type="Italic">sophorae fructus</Emphasis> upregulate IGF-I and TGF-β and inhibit osteoclastogenesis in rat born marrow cells

Isoflavones have been a central subject in research on the natural phytoestrogens found in Leguminosae. Their effects on bone formation and remodeling are important in that they can act like estrogen by binding on estrogen receptors on the target cell surface. We, therefore, believed that isoflavones may help in the treatment of patients with estrogen deficiency disease such as estrogen replacement therapy (ERT) for osteoporosis. As commonly known, osteoporosis is one of the hormonal deficiency diseases, especially in menopausal women. When estrogen is no longer produced in the body a remarkable bone remodeling process occurs, and the associated events are regulated by growth factors in the osteoblast lineage. In the present study, we investigated whether isoflavones (Isocal) extracted from Sophorae fructus affect the growth factors IGF-I and TGF-beta that have been known to be related with bone formation. In the study, we found that the active control (PIII) effectively enhanced the level of nitric oxide (NO) and growth factors, and thereby inhibited osteoclastogenesis. The most efficient concentration was 10(-8)% within five days, whereas the comparative control (soybean isoflavone) was not as effective even at a lower concentration. In conclusion, the products which contain enriched glucosidic isoflavone and nutrient supplements such as shark cartilage and calcium can be used for osteoporosis therapy by enhancing the production of IGF-I and TGF-beta. Furthermore, the NO produced through endothelial constitutive NO synthase (ecNOS) may play a role in inhibiting bone reabsorption.     

Optimising antiresorptive therapies in postmenopausal women: why do we need to give due consideration to the degree of suppression?

Accelerated bone turnover with bone resorption exceeding bone formation is a major mechanism underlying postmenopausal bone loss and hence the development of osteoporosis. Accordingly, inhibition of bone resorption is a rational approach for the prevention of osteoporosis. In this context, the most logical option, hormone replacement therapy, reverses the rate of bone turnover to premenopausal levels, whereas the magnitude of inhibition by amino-bisphosphonates and the recently introduced anti-receptor activator of NFkappaB ligand (RANKL) antibody often exceeds this. As bone turnover has crucial implications for the continuous renewal of bone tissue, the over-suppression of bone turnover has potential consequences for bone quality and strength. Long-term treatment with potent bisphosphonates has recently been associated with osteonecrosis of the jaw and dose-dependent increases in micro-crack accumulation in animals. Although these observations are the subject of ongoing discussions, it is timely to discuss whether the over-suppression of bone turnover below premenopausal levels is really our ultimate goal when defining the success criteria for antiresorptive agents. In this review, the implications of high and excessively low bone turnover of endogenous origin for bone quality, fracture risk and integrity of the jaw are discussed. In addition, animal and clinical research revealing initial findings regarding the potential adverse effects of drug-induced suppression of bone remodeling are summarised. The inhibition of bone resorption, which is either transient between doses (e.g. with calcitonin) or does not exceed premenopausal levels (with hormone replacement therapy or selective estrogen receptor modulators), is preferable because it not only provides similar antifracture efficacy but can also assist in the maintenance of the dynamic repair of micro-cracks/micro-fractures.     

槲皮素防治急性肝损伤作用机制的研究进展

急性肝损伤是一种严重的疾病，其发病机制和影响因素多种多样，其中药物治疗是目前急性肝损伤的主要治疗方法。槲皮素为黄酮醇类化合物，可通过抗炎、抗氧化应激反应、抗肝纤维化、抗细胞凋亡、增强细胞自噬、抑制转运体NTCP的表达降低胆汁酸重吸收、调节肝脏脂质代谢，多途径减轻肝损伤，发挥肝保护作用。总结了槲皮素防治急性肝损伤的作用机制，为急性肝损伤治疗提供参考。     

Mechanism of osteoclast mediated bone resorption--rationale for the design of new therapeutics

Bone resorption is an important cellular function in the development and physiology of the skeleton. Pathophysiology of several skeletal diseases includes either increased (for instance osteoporosis, metastatic bone disease and Paget's disease of bone) or decreased (various syndromes of osteopetrosis) bone resorption rate. Thus there is a genuine need to regulate, especially inhibit, bone resorption rate in several diseases. Bone resorption can be inhibited by several strategies. One can prevent osteoclast formation, inhibit their action or induce premature cell death. All these strategies have been used in pharmacology to inhibit bone resorption and there are also physiological regulators for each of these three different phases of in osteoclast life. Many present resorption inhibitors inhibit osteoclast formation via osteoblastic cells since they are producing a number of factors that are essential for osteoclast differentiation. Best characterized of these factors are macrophage colony stimulating factor (M-CSF) and receptor activator of NFêB ligand (RANKL). For instance sex steroids, parathyroid hormone and some interleukins are known to exert their positive or negative effects on osteoclast differentiation via the RANK/RANKL/osteoprotegrin pathway. It is not yet clear enough how specific intervention to osteoclast formation is since also other cell lineages derived from hematopoetic precursors use similar signalling pathways. An effective inhibition of bone resorption can also be achieved by inhibiting osteoclast activity to resorb bone. Examples of this category of physiological and pharmacological inhibitors are calcitonin and aminobisphosphonates, respectively. Finally one can reduce bone resorption by shortening osteoclast lifespan with substances that induce apoptosis in osteoclasts. A good example of these substances is a first generation bisphosphonate, clodronate. Several new potential molecular targets have been revealed during recent years since many individual molecules in osteoclast differentiation, function and apoptosis have been identified and their physiological functions revealed. Thus we are expecting several new bone inhibitors to be developed in following years both for experimental studies and finally also for clinical use.