骨质疏松性骨折药物治疗的研究进展

骨质疏松症(osteoporosis,OP)是一种以低骨量和骨组织微结构破坏为特征,导致骨质脆性增加和易于骨折的全身性骨代谢性疾病。骨质疏松症患者最终结局常常是脆性骨折。骨质疏松症不利于骨折愈合,主要是由于骨质疏松症导致患者的骨吸收作用增强、新骨形成能力下降造成的。为了缩短骨质疏松症个体的骨折愈合时间、提高愈合质量,抑制骨吸收或促进骨形成的药物成为研究热点。而抗骨质疏松的治疗药物主要是通过抑制骨吸收或促进骨形成促进骨质疏松性骨折的愈合。所以现在已有大量的实验探讨了抗骨质疏松治疗药物对骨质疏松性骨折愈合的影响。同时还有关于抗骨质疏松药对骨修复影响的研究。这些研究的结果总结来说,指出了抗骨质疏松药可能对骨质疏松性骨折治疗有一定的作用。同时现在还没有明确的证据证明抗骨质疏松治疗不利于骨修复,故抗骨质疏松药在骨质疏松性骨折上有很大的应用前景。本文回顾综述了当下骨质疏松性骨折治疗的研究进展,总结了双膦酸盐、地诺单抗、雌激素、雷洛昔芬、特立帕肽、雷尼酸锶、他汀类药物以及一些正在研究中的抗骨质疏松药物对骨折愈合的影响及其作用机制。     

骨质疏松药物治疗率和依从性

骨质疏松症(osteoporosis,OP)是一种以骨量低下、骨微结构损坏,导致骨脆性增加,易发生骨折为特征的全身性骨代谢性疾病。骨质疏松性骨折是骨质疏松常见的并发症,多见于老年人,但在其他年龄段也有可能发病。脆性骨折好发部位多集中在髋关节、脊柱及腕关节。目前有多种现成的及有效的药物治疗骨质疏松症,如双膦酸盐、降钙素等。但由于医师及患者对骨质疏松知识不够熟悉、患者过度担心药物不良反应、抗骨质疏松药价格过高等因素的影响,骨质疏松症的患者接受药物治疗率与依从性仍较低,这导致了骨密度增加减慢,骨折发生率增加,很大程度的加重了临床和经济负担。因此,提高骨质疏松患者的药物治疗率及依从性变得至关重要,早期的抗骨质疏松治疗和长期坚持服药可以缓解骨量流失甚至提升骨量,显著降低患者骨折风险。本文主要回顾综述了骨质疏松药物治疗率及依从性现状,影响药物治疗率和依从性的原因,以及提出改善骨质疏松药物治疗率和依从性的措施。     

异位骨化治疗研究进展

异位骨化(HO)一旦形成,可导致病变组织周围肿胀、疼痛,神经受压,关节活动障碍等一系列并发症。目前认为HO发病机制为机体局部炎症反应导致骨生成诱导因子释放,在局部微环境的作用下,成骨前体细胞增殖分化,从而形成异位骨。目前临床上HO的防治主要有非甾体类抗炎药(NSAID)、双膦酸盐等药物治疗,小剂量局部放射疗法及手术切除等。基于HO发病机制的靶向治疗有骨形态发生蛋白(BMP)受体抑制剂、维甲酸受体(RAR)γ激动剂等药物治疗和基因治疗等,但目前尚处于研究阶段。该文就HO发病机制及其防治研究进展作一综述。     

微小RNA在骨质疏松症治疗中的作用及机制的研究进展

骨质疏松症是以骨量减少、骨强度下降、骨折危险性增加为特征,受遗传因素和环境因素共同影响的一种全身骨代谢障碍的疾病。骨质疏松是骨折的重要原因之一,它影响骨折的处理及其预后。原发性骨质疏松症的防治主要包括物理治疗和药物治疗两个方面,物理治疗包括运动疗法和物理因子疗法;药物治疗包括雌激素代替疗法、降钙素、选择性雌激素受体调节剂以及双膦酸盐等,这些药物可以阻止骨吸收但对骨形成的作用影响较小。微小RNA(miRNA)是一种由高等真核生物基因组编码,在进化上十分保守的非编码小分子RNA,具有调控基因表达的能力。miRNA主要通过和靶基因mRNA碱基配对,引导沉默复合体降解mRNA或抑制其翻译。基于miRNA的作用机制,通过人工合成miRNA拟似物和miRNA抑制剂调节miRNA相关通路,或人工构建miRNA介导RNA干扰途径,进行基因和分子治疗,从而在分子水平上为研究新一代基因药物和生物治疗手段提供新的切入点。关于骨质疏松,目前研究发现miRNA主要通过影响Runx2和Osterix信号通路发挥调控成骨信号作用,因此,干预miRNA可通过影响干细胞骨再生延缓骨质疏松进程,促进骨折修复。本文重点对微小RNA在骨分化和骨再生的分子机制及治疗应用做一综述,旨在为骨质疏松的基础研究和临床治疗提供参考。     

Sclerostin单克隆抗体治疗骨质疏松的研究进展

硬骨素(Sclerostin)是由硬化性骨病(sclerosteosis,SOST)基因编码的蛋白质,可以通过与低密度脂蛋白受体相关蛋白5/6(low density lipoprotein receptor-related protein,LRP5/6)结合达到拮抗Wnt蛋白并抑制成骨的作用,已经作为新的药物靶点用于抗骨质疏松药物研发。目前,围绕Sclerostin单克隆抗体已经进行了许多基础研究和临床研究,结果提示该类药物可以提高骨量、促进骨形成、抑制骨吸收,对于骨质疏松有一定治疗效果。但该类药物应用后的副反应,对骨折的影响等方面的研究数据尚不足,有待完善进一步研究。     

儿童骨质疏松的诊疗进展

骨质疏松症属代谢性骨病范畴,常见于老年人,儿童骨质疏松相对少见但更值得关注。在病因学上同样分为原发性和继发性,原发性主要见于潜在遗传性疾病的儿童,而继发性主要起因于慢性病及其相关治疗。既往骨折史以及后背痛常提示骨质疏松的存在,而在影像学上骨皮质变薄或低骨密度同样预示着骨折的风险。儿童骨质疏松的诊断工具优选双能X线骨密度仪,对于那些处于继发性骨质疏松风险的儿童,要保持高度警惕,而对于那些已经罹患骨质疏松的儿童,应尽量避免或减少可能进一步损伤骨骼的因素,以及尽早给予充足的钙及维生素D。治疗重点应侧重于改善功能结局,同时也应认识到生长发育期本身椎体重塑或症状自发缓解的可能性,因此应尽量避免不必要的治疗。双膦酸盐目前为治疗首选,但在儿童骨质疏松中证据有限,长期应用的时间及剂量仍有争议。尽管目前抗骨吸收的药物有很多种,但仍缺乏促进骨形成药物的研究,希望未来有更多适合儿童骨质疏松治疗的证据来填补这个空缺。     

胰岛素样生长因子结合球蛋白(IGFBP)与骨质疏松症相互关系的探究

骨质疏松症的高发病率及其继发的脆性骨折给老年骨质疏松患者健康造成了巨大威胁,近年来,得益于骨质疏松的生理病理学机制探究,临床上涌现出多种的治疗方案,并取得了一定的治疗效果,然而,当前治疗骨质疏松的药物主要以两种途径,一是抑制破骨细胞的骨吸收,可以达到短期内防止骨量快速丢失,缺点是长期应用会使骨折老化,陈旧,脆性增加,增大了脆性骨折的发生率;另一类是以促进骨形成为主,如PTH片段,但是长期应用副作用大,甚至会诱发肿瘤。因而寻找新的骨质疏松药物靶点,设计新的药物,成为迫切需要解决的问题。随着蛋白质组学技术的发展,越来越多的骨质疏松作用相关蛋白被发现,为新药的研制提供了新的契机,而胰岛素样生长因子结合球蛋白(IGFBP)是目前被认为与骨质疏松症高度相关的一个靶蛋白,但机制及当前情况却鲜被提及,本文就胰岛素样生长因子结合球蛋白(IGFBP)与骨质疏松的相关研究进展进行综述。     

双膦酸盐在骨科相关疾病治疗中的地位及再认识

 双膦酸盐是目前临床上治疗骨质疏松症的首选药物, 它能够靶向性地沉积在骨骼中,紧密吸附在骨的羟基磷灰石表面,与之结合并选择性聚积在破骨细胞周围;同时能够有效抑制破骨细胞活性及对骨质的吸收,通过预防骨丢失、提高骨质量以降低骨折风险。迄今为止,双膦酸盐类药物已经研究发展到第三代。第一代双膦酸盐为不含氮的双膦酸盐, 代表药物为羟乙膦酸钠,其分子结构中侧链是直链烃,药物活性和结合力相对较弱,有抑制骨钙化,干扰骨形成,导致骨 软化或诱发骨折的可能,且胃肠道不良反应大。第二代双膦 酸盐药物结构中的侧链引入了氨基称为氨基双膦酸盐,代表药物为帕米膦酸钠和阿仑膦酸钠,其药物活性和结合力比羟乙膦酸钠增加10～100倍,对骨的钙化作用干扰小,选择性强。而第三代双膦酸盐为具有杂环结构的含氮双膦酸盐,如利塞膦酸钠、唑来膦酸等,鉴于其强效、低剂量、使用方便等特点,被认为是具有更强的临床疗效且适应证更加广泛的抗骨吸收药物。目前,双膦酸盐已经广泛用于原发性骨质疏松症、继发性骨质疏松症(如糖皮质激素引起的骨质疏松)以及骨质疏松性骨折的预防及治疗。随着临床应用的深入推广, 越来越多的临床医生和研究人员发现,双膦酸盐除适用于上述疾病外,在关节置换术、脊柱融合术、骨坏死、骨关节炎、软骨损伤的治疗,以及乳腺癌、食管癌、结肠及直肠癌等重大疾病的预防中,扮演着十分重要的角色。为此,本文就双膦酸 盐在骨科相关疾病治疗中的重要作用及新进展做一阐述。     

2014年骨质疏松领域进展回顾 ——美国骨矿盐研究学会(ASBMR)年会精粹(2014.休斯顿）

随着全球研究者和临床医师对骨质疏松症及骨代谢过程的认知逐步提高,骨质疏松领域的研究热点逐渐增多且研究方向逐渐清晰。首先,由于原发性骨质疏松症主要是一类老年性疾病,因此骨质疏松与其他年龄相关的慢性病有密切联系,在抗衰老机制的研究中,可以包含骨质疏松病因与治疗机制的研究;其次,随着现代成像技术的研发、微创器械的开发和其他诊断技术的突破,骨质疏松诊断和骨质量评估从过去单一的平面影像学测量矿物质含量,逐渐过渡到对骨强度、骨微结构、骨材料特性等多维度鉴定,使研究者能更准确地评估骨组织损害程度和药物作用;最后,抗骨质疏松药物治疗日趋靶向化,新药研发从细胞活性水平深入至信号传导通路水平,以提高药物效能,而临床上从单一用药推进至序贯和联合用药,或两者组合的给药策略,以便患者获得最长的骨保护期,并减少长期使用单一药物的严重不良事件。本文笔者回顾了2014年骨质疏松领域的重大研究结果,重点关注以下3方面：（1)骨质疏松与其他慢性病之间的联系;（2)骨质疏松诊断和骨折风险评估;(3)新药研发和临床治疗策略的研究。     

锝[~(99)Tc]亚甲基二膦酸盐治疗骨质疏松症的研究进展

骨质疏松症是一种全身性代谢性骨骼疾病,临床主要表现为骨骼疼痛、骨密度降低和骨折危险性增加,严重影响患者的生活质量。现阶段我国老年人中骨质疏松患病比例超过50%以上,其中骨折发生率接近1/3。双膦酸盐是目前治疗骨质疏松的主要药物之一,因其具有强有力的破骨细胞抑制作用,临床应用广泛,而锝[~(99)Tc]亚甲基二膦酸盐(technetium methylenediphosphonate,~(99)Tc-MDP)注射液,商品名云克,是我国自主研制成功的新药,其主要成分是锝经氯化亚锡还原后与亚甲基双膦酸盐形成的螯合物,具有清除人体自由基、保护超氧化物歧化酶活力、抑制病理复化物的产生、抑制白细胞游走、降低胶原酶对软骨组织的破坏并修复破骨作用。可抑制骨吸收、改善骨质量、提高各个部位的骨密度、减低骨折风险,促进成骨,缓解骨痛。近年来已广泛应用于骨质疏松症的治疗,并已取得了较好的效果,且使用安全,无明显的副作用。本文对近年来云克应用于骨质疏松症的动物实验、临床疗效及安全性研究进行综述。     

FLS – Drei Buchstaben verändern die sekundäre Frakturprävention

The increasing importance of preventive measures in the field of orthopedics and trauma surgery becomes apparent because of the demographic changes and the high risk for secondary fractures following osteoporotic fractures. Within the fracture treatment chain, orthopedics and trauma surgery are in the “pole position” to initiate these measures in geriatric patients. In the past orthopedists and trauma surgeons have constantly accused of neglecting secondary fracture prevention in fragility fracture patients. There are several reasons that speak in favor of us undertaking a role in secondary fracture prevention: osteoporosis medication is highly effective in fracture prevention when correctly indicated, the positive effects of osteoporosis therapy on fracture healing and legal issues. Arguments that have been used to justify neglect of secondary fracture prevention are undesired side effects related to osteoporosis medications, such as atypical femoral fractures and osteonecrosis of the jaws, interference of some specific drugs with fracture healing and the working conditions in emergency departments. These run contrary to the consideration of chronic diseases such as osteoporosis, secondary osteoporosis and the underlying disease could be overlooked and the increasing complexity of medicinal osteoporosis therapy.     

The effects of medications on bone

Medications taken for the treatment of arthritis and psychotropic and epileptic disorders, as well as anticoagulants, antacids, bisphosphonates, corticosteroids, and antineoplastic drugs, can profoundly affect bone metabolism. In some scenarios (eg, osteoporosis), these effects are intended; in others (eg, rickets, osteomalacia secondary to antiepileptic drugs), potentially adverse side effects of medications on bone may occur. Nonsteroidal anti-inflammatory drugs appear to delay fracture healing and bone ingrowth, although these effects are reversible. Disease-modifying antirheumatic drugs do not appear to affect bone metabolism adversely when taken in the low dosages currently prescribed. Bisphosphonates are useful in restoring bone mass in cases of postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, and neoplastic conditions with bone loss and hypercalcemia. Corticosteroids and cancer chemotherapeutic agents generally affect bone adversely and increase fracture risk.     

Effect of osteoporosis medications on fracture healing

Antiosteoporotic medications are often used to concurrently treat a patient’s fragility fractures and underlying osteoporosis. This review evaluates the existing literature from animal and clinical models to determine these drugs’ effects on fracture healing. The data suggest that these medications may enhance bone healing, yet more thorough prospective studies are warranted. Pharmacologic agents that influence bone remodeling are an essential component of osteoporosis management. Because many patients are first diagnosed with osteoporosis when presenting with a fragility fracture, it is critical to understand how osteoporotic medications influence fracture healing. Vitamin D and its analogs are essential for the mineralization of the callus and may also play a role in callus formation and remodeling that enhances biomechanical strength. In animal models, antiresorptive medications, including bisphosphonates, denosumab, calcitonin, estrogen, and raloxifene, do not impede endochondral fracture healing but may delay repair due to impaired remodeling. Although bisphosphonates and denosumab delay callus remodeling, they increase callus volume and result in unaltered biomechanical properties. Calcitonin increases cartilage formation and callus maturation, resulting in improved biomechanical properties. Parathyroid hormone, an anabolic agent, has demonstrated promise in animal models, resulting in accelerated healing with increased callus volume and density, more rapid remodeling to mature bone, and improved biomechanical properties. Clinical data with parathyroid hormone have demonstrated enhanced healing in distal radius and pelvic fractures as well as postoperatively following spine surgery. Strontium ranelate, which may have both antiresorptive and anabolic properties, affects fracture healing differently in normal and osteoporotic bone. While there is no effect in normal bone, in osteoporotic bone, strontium ranelate increases callus bone formation, maturity, and mineralization; forms greater and denser trabeculae; and improves biomechanical properties. Further clinical studies with these medications are needed to fully understand their effects on fracture healing in order to simultaneously treat fragility fractures and underlying osteoporosis.     

Fracture healing in osteoporotic fractures: is it really different? A basic science perspective

Osteoporosis is a major health problem characterized by compromised bone strength that predisposes patients to an increased risk of fracture. Osteoporotic patients differ from normal subjects in bone mineral composition, bone mineral content, and crystallinity. Poor bone quality in patients with osteoporosis presents the surgeon with difficult treatment decisions. Much effort has been expended on improving therapies that are expected to preserve bone mass and thus decrease fracture risk. Manipulation of both the local fracture environment in terms of application of growth factors, scaffolds and mesenchymal cells, and systemic administration of agents promoting bone formation and bone strength has been considered as a treatment option from which promising results have recently been reported. Surprisingly, less importance has been given to investigating fracture healing in osteoporosis. Fracture healing is a complex process of bone regeneration, involving a well-orchestrated series of biological events that follow a definable temporal and spatial sequence that may be affected by both biological factors, such as age and osteoporosis, and mechanical factors such as stability of the osteosynthesis. Current studies mainly focus on preventing osteoporotic fractures. In recent years, the literature has provided evidence of altered fracture healing in osteoporotic bone, which may have important implications in evaluating the effects of new osteoporosis treatments on fracture healing. However, the mechanics of this influence of osteoporosis on fracture healing have not yet been clarified and clinical evidence is still lacking.     

抗骨质疏松症药物序贯治疗研究现状

骨质疏松症是一种常见的全身性骨骼疾病，其造成的骨折等一系列临床终末事件正严重影响着我国国民健康水平。目前抗骨质疏松药物长程用药的风险、疗效尚不明确，骨质疏松症的慢病管理面临挑战。近年来许多临床研究表明不同类型药物的序贯治疗可以有效改善患者的骨密度、降低骨折风险，序贯治疗已经成为治疗骨质疏松症的重要手段，但是具体的序贯方案还有待进一步研究、探讨。笔者旨在对近年来抗骨质疏松药物序贯治疗的重要研究成果进行归纳总结，为临床工作提供参考和借鉴。     

Therapeutic potential of parathyroid hormone

Teriparatide, recombinant human parathyroid hormone (1-34) (rhPTH [1-34]), is approved for the treatment of osteoporosis in men and postmenopausal women at high risk for fracture. The best candidates are those who have already had vertebral compression fractures (symptomatic or asymptomatic) or other osteoporosis-related fractures, or those who have very low bone mineral density, in the T score range of -3.5 or below. Teriparatide is the first anabolic drug approved by the US Food and Drug Administration for osteoporosis. It not only dramatically improves bone mass, but also restores bone microarchitecture and increases bone diameter. All of these mechanisms contribute to increasing bone strength and reducing the risk for osteoporosis-related fractures. Although PTH has been used in combination with other agents such as estrogens, calcitonin, and bisphosphonates, the relative benefit of the combined approach versus teriparatide alone for fracture risk reduction has not been shown. In fact, some data suggest that initiating PTH and alendronate together in previously untreated patients or pretreating patients for a short time with alendronate before initiating PTH may somewhat reduce the anabolic response to PTH. There are many unanswered questions regarding PTH, such as the optimal duration of treatment, the optimal sequence of medications for severe osteoporosis, the mechanism of resistance to effect after 18 to 24 months, the effect of subsequent rechallenge with PTH and, most importantly, surrogates to measure PTH effect.     

Can bone loss in rheumatoid arthritis be prevented?

Rheumatoid arthritis (RA) is a systemic inflammatory disease that can lead to local joint deformations (bone erosions and joint space narrowing) and to extra-articular phenomena, including generalized osteoporosis. In addition, in patients with RA, the risk of vertebral and nonvertebral fractures is doubled. High disease activity (inflammation), immobility, and glucocorticoid use are common factors that substantially increase fracture risk in these patients, on top of the background fracture risk based on classical risk factors such as high age, low body mass, and female gender. New insights on the links between the immune system and the bone system, the field of osteoimmunology, have shown that local and generalized bone loss share common pathways. The receptor activator of nuclear factor κB ligand/osteoprotegerin pathway (RANKl/OPG) is one of the most important pathways, as it is (strongly) upregulated by inflammation. In modern treatment of RA with biologics, for example, TNFα-blocking agents and combination therapy of conventional disease-modifying antirheumatic drugs (DMARDs), clinical remission is a realistic treatment goal. As a consequence, in recent studies, it has been documented that both local and generalized bone loss is absent or minimal in those patients who are in clinical remission.     

Stabilized severe osteoporosis: should the treatment be stopped?

Several medications have been proven to decrease the risk of postmenopausal osteoporotic fractures of the spine, hip, or peripheral skeleton. However, the optimal duration of treatment with these medications has not been determined. The efficacy data come chiefly from controlled trials conducted over 3 to 5 years in elderly women at high risk for fractures. Some of these trials were followed by open-label extension phases that showed sustained bone mineral density gains over 7 to 10 years. The data pointing to a sustained decrease in the fracture rate beyond 4-5 years of treatment vary across studies and drugs but are generally scant and open to criticism. The published evidence does not suggest a need for stopping osteoporosis medications after the first 4-5 years out of concern about bisphosphonate-induced osteonecrosis of the jaw or alendronate-induced atypical fractures. Given that pharmacotherapy targets patients with severe osteoporosis, continued treatment beyond the first 5 years is probably warranted in most cases.