胡金艮医生的科普号

上肢周围神经综合征概述Author:Seward B Rutkove, MDSection Editor:Jeremy M Shefner, MD, PhDDeputy Editor:April F Eichler, MD, MPH译审:蒋超, 副主任医师Contributor Disclosures我们的所有专题都会依据新发表的证据和同行评议过程而更新。文献评审有效期至：2020-08.|专题最后更新日期：2019-12-18.There is a newer version of this topic available in English.该主题有一个新的英文版本。引言—上肢周围神经损伤的原因和程度差异很大。患者出现肩、臂或手疼痛、感觉缺失或无力时，需考虑到多种疾病：从轻度腕管综合征(carpal tunnel syndrome, CTS)到重度臂丛神经病。下肢周围神经综合征详见其他专题。(参见“下肢周围神经综合征概述”)解剖学—从脊髓C2及以下水平发出的神经根从各自的椎间孔穿出。C2-C4神经根在脊柱附近合并聚集，称为颈丛。颈丛发出的神经包括膈神经和耳大神经。虽然神经系统疾病一般不累及此区域，但是偶有病变会累及此区域，导致头部伸肌无力或膈肌麻痹。C5-T1神经根也从脊柱发出，并在近端发出小分支，参与形成支配前锯肌的胸长神经。然后这些神经根合并成复杂的结构，称为臂丛。解剖学家已界定了臂丛内的数个区域，包括干、股、束、支和近端神经，但是实际上了解各干、束和神经就足以对影响此区域的问题进行正确分类(图 1)：●C5和C6神经根合成臂丛上干；C7神经根独自形成中干；C8和T1神经根合成下干。●上干的部分分支参与形成后束，剩余分支则形成外侧束；下干的部分分支也参与形成后束，剩余分支则形成内侧束；中干的部分分支参与形成外侧束，剩余部分参与形成后束。●臂丛外侧区会发出一些神经，从近端到远端包括肩胛背神经、肩胛上神经、肌皮神经以及(部分参与形成)正中神经。尺神经是臂丛内侧区的主要神经，而后束发出多条重要神经，包括腋神经、肩胛下神经、胸背神经以及最重要的桡神经。●在主要神经沿手臂下行的过程中，桡神经和正中神经又发出2条重要分支，分别为骨间后神经和骨间前神经。所有神经均向更远端发出多条分支，除了非常特殊的情况外，这些分支大多不具有临床意义。这些小分支将在临床独特综合征中讨论。发病机制—多种不同病程可能会局部影响正常神经功能，而多发性神经病等疾病会出现更广泛的神经元功能障碍。(参见“多发性神经病概述”)压迫—神经节段受压(包括神经失用和轴突中断)是最常影响上肢神经元结构的问题。神经受压可影响远端神经节段(如CTS中)，但也可见于神经根水平极近端区域(例如，颈椎间盘突出压迫脊神经根)。任何卡压部位的病理过程都基本类似。一定程度的神经直接压迫及相关神经缺血在其中起到作用。●最轻微的表现可能是特定体位引发的间歇性症状，一种常见情况是CTS患者腕部弯曲时手部出现感觉异常，这最可能继发于暂时性神经缺血。●随着神经受到更一致、长期的压迫，可出现脱髓鞘。此时症状通常会持续存在，但常因某些运动或体位而恶化。疼痛和无力在早期一般极不明显，但此时越来越突出。●随着神经受压进展，出现Wallerian变性，远端神经节段将丧失功能。重度病例整个远端神经节段都会变性，类似于神经横断(参见下文‘横断’)。从生理学角度看，只要所有神经冲动能通过受压区进行传递，患者就会保持无症状。随着缺血或脱髓鞘的出现，神经传导首先会变慢并最终完全阻滞。神经传导变慢对生理学产生的影响极小；只有在神经元冲动传导完全阻滞时，才会出现功能性感觉缺失或肌无力。随着神经受压加重，越来越多的神经纤维传导会被阻滞。最终，几乎没有神经冲动能通过受压区，同时也开始发生远端神经元变性。横断—急性神经横断(神经断裂)比慢性神经受压要少见得多，可发生于手臂严重创伤时(例如刀伤)，此时远端神经与近端神经完全分离。与重度神经受压不同的是，神经横断后每个神经细胞的基底膜不再保持完好，若不进行干预(即，再接手术)，神经不可能再生。感觉和运动反应会完全丧失。神经缺血/梗死—神经梗死通常仅发生于血管炎和动脉粥样硬化性疾病。血管炎患者的神经梗死会导致轴突损伤，通常于特定区域发生。上肢某些神经往往最易受累：上臂正中神经和肘段近端的尺神经。(参见“血管炎性神经病的临床表现和诊断”)与压迫性神经病不同的是，神经传导速度并不会减慢。在出现局部神经梗死的数日内，整个远端神经节段都发生变性。但是由于基底膜保持完好，在控制基础疾病后神经可能再生。严重动脉粥样硬化性疾病偶尔也会产生类似表现。放射诱发性损伤—治疗区域包括臂丛的放疗可导致一过性、急性、自限性臂丛神经病。症状包括患侧拇指和食指麻木，以及肩部和肱二头肌无力。臂丛放疗也可引起更严重的迟发性臂丛神经病，表现为感觉异常、感觉减退、无力和反射受损，并可进展为慢性疼痛和进行性手臂瘫痪。该病发生之前的潜伏期不定，潜伏期可持续多年，且病变通常不可逆。主要的诊断困难在于区分放射诱发的迟发性臂丛神经病与肿瘤复发。(参见“臂丛神经综合征”，关于‘肿瘤性和放射诱发性臂丛神经病’一节)炎症—神经或神经根炎性过程也可导致显著的手臂问题。感染性疾病，如单纯疱疹病毒、EB病毒和最常见的带状疱疹病毒感染，均可引发感觉缺失和运动功能障碍综合征。特发性炎性反应也会造成臂丛神经炎综合征(神经痛性肌萎缩)。变性—某些疾病中可能发生神经元局灶变性。最引人关注的平山病(Hirayama disease)是一种局灶性运动神经元丢失，表现为数月期间单侧或双侧上肢进行性无力。这也可能是肌萎缩侧索硬化症的早期表现。(参见“肌萎缩侧索硬化症和其他类型运动神经元病的诊断”，关于‘单肢肌萎缩’一节)代谢性疾病—除了糖尿病或甲状腺功能减退间接性导致局灶神经病变外，代谢疾病通常不会造成局灶性神经病变。压迫性神经病(如CTS)在这类疾病中常见得多，其原因不明。糖尿病偶尔也会表现出血管炎样临床特征(糖尿病多数性单神经病)。(参见“糖尿病性神经病的流行病学和分类”)流行病学—CTS是最常见的单神经病，但不同研究人群的患病率有差异。一项荷兰的人群研究显示，临床CTS患者约占总人数的3.4%，而另外有5.8%的人虽未诊断但很可能存在该病[1]。该病更常见于女性，男性的总患病率仅为0.6%。另一项来自美国Mayo诊所的研究显示，该病的年发病率仅为99/100,000(0.1%)，而男女患者比例为1:3[2]。颈神经根病也很常见。Mayo诊所的研究显示，1976-1990年间颈神经根病的平均发病率为83/100,000，男性发病率高于女性[3]。50-54岁人群的发病率最高，C6和C7神经根病变占病例总数的64%。根据Mayo诊所的病历记录，研究者也调查了臂丛神经炎的发病率。该病在12年间的年发病率仅为1.6/100,000[4]。以上数据可能低估了实际发病率，因为轻微的神经根病或臂丛神经炎患者可能从未就医或被误诊为肌肉骨骼损伤。临床表现—提示周围神经疾病的体征和症状详见其他专题。(参见“周围神经和肌肉疾病的鉴别诊断”)极轻度的上肢神经局灶异常可能在因其他原因(例如，检查是否有多发性神经病)进行电生理检查时发现。例如，尺神经跨肘部节段运动传导速度减慢可能符合极轻度的尺神经病。同样，年龄较大的无症状者可在电生理检查或MRI检查时发现颈神经根病或多发性神经根病的证据。然而，仅凭电生理检查和影像学检查结果通常不足以诊断特定的综合征。因此，若检测出正中神经跨腕段传导速度轻度减慢且无相关症状，可做出腕部轻度正中神经病的诊断，而非CTS的临床诊断。诊断性检查电生理检查—肌电图检查(electromyography, EMG)和神经传导检查(nerve conduction studies, NCS)仍是识别上肢神经疾病并对其进行分类的最有效方法。(参见“肌电图概述”和“神经传导检查概述”)EMG/NCS通常易发现正中神经、桡神经或尺神经的局部卡压。肌电图检查者对可能受累的神经节段进行检测(例如CTS患者腕部正中神经)，以寻找脱髓鞘的证据(神经传导速度减慢和传导阻滞)。在尺神经病患者的肘段以及桡神经病患者的桡神经沟可能发现类似结果。EMG多为确诊性检查，能提示病变严重程度。对于神经丛病患者，通常在神经丛某一区域(例如上干)发出的数条神经中发现异常。出于技术原因，一般不对神经丛进行传导检查，因此无法寻找脱髓鞘的常见表现。相反，检查仅限于远端神经节段，并寻找有无轴突缺失。例如，在上干病变患者中，正中神经、桡神经和肌皮神经感觉反应波幅通常会降低。由于正中神经和尺神经标准运动检查均局限于下干支配的肌肉，所以检查结果往往是正常的。然而，针极EMG可以检测上干神经纤维支配的肌肉，检查可发现纤颤电位、正尖波以及慢性神经再支配。若下干出现问题，尺神经和前臂内侧皮神经的感觉反应会减弱，并且尺神经和正中神经运动检查会表现出异常。在C8-T1支配的肌肉中，EMG可发现去神经支配和慢性神经再支配的证据。在神经根病中，由于病灶位于后根神经节的近端，所以感觉反应不受影响。除非累及C8-T1神经根，否则运动检查往往也正常。通常只有针极EMG才能发现异常，受累神经根支配的肌肉存在异常。影像学检查—影像学检查是某些患者的首选初始检查。比如，有放射性颈部疼痛、第2-4指感觉缺失以及C7支配肌肉肌无力的患者可能最好先接受颈椎MRI检查。不过，在某些情况下，患者的主诉难以归类。疼痛可能是非局灶性的，肌无力极轻微，并且未发现固定的感觉缺失。在这种情况下，可能首先进行EMG，然后根据其结果，必要时对恰当区域进行影像学检查。一项研究发现，60%的病例中MRI与EMG结果保持一致，但是有40%的患者这两种检查结果不一致，表明这两种检查常可提供互补性信息[5]。X线平片检查效用一般有限，但有少数例外情况。●颈椎屈伸位X线平片有助于发现颈椎不稳，并且能推测退行性变的程度。某平面的椎间盘间隙消失可能提示椎间盘髓核突出。正常颈椎前凸变直可能提示椎旁肌痉挛。还可发现溶骨性病变。●当肺尖病变引发下干神经丛病时，胸部X线检查可能有助于确定病因。胸部X线片还可确定是否存在颈肋。(参见“臂丛神经综合征”)●很少需要行手臂远端平片检查，除非发生创伤或发现可触及的肿块病变。MRI已成为大多数神经系统成像的主要方法。对于颈椎疾病，MRI能确定椎间盘突出、退行性变以及某一神经根受压程度，因此该检查非常重要，尤其是考虑手术选择时。对于特发性神经丛病患者，可能有必要进行一次影像学检查，以排除该区域肿块病变的可能，尤其是对于症状恶化或具有肿瘤病史的患者。当EMG/NCS提示病灶具体定位后，偶尔也进行神经MRI检查。例如，某些急性发作的CTS患者通过腕部MRI发现肿瘤。超声已逐渐成为许多上肢神经系统疾病评估时的重要辅助工具。高分辨率超声尤其能提供神经压迫综合征(如CTS)方面的信息，局部神经增大似乎强烈提示局部病变。超声可能对炎症性和创伤性神经病检查有帮助，并且也可识别出神经的肿瘤性改变。(参见“神经肌肉病的超声诊断”，关于‘神经性病变的超声检查’一节)对于有起搏器或其他植入装置而不能接受MRI检查的患者，CT(尤其是联合脊髓造影)会有帮助。CT也可提供骨结构方面的有用信息。血清学检查—对于出现手臂局部症状的患者，血清学检查往往价值有限，不过，某些检查也值得考虑：●检查CTS患者的甲状腺功能●检查CTS患者的空腹血糖，尤其是可能伴有轻度多发性神经病的患者●对多发性神经根病患者进行莱姆抗体滴度试验，尤其是流行地区的患者●对多发单神经病(至少累及2个肢体)患者进行遗传性压迫易感性神经病基因检测对于多数性单神经病患者，还需进行多种其他实验室检查，以识别潜在疾病。(参见“非系统性血管炎性神经病的治疗和预后”)腰椎穿刺—有不寻常临床表现的神经根病患者需接受腰椎穿刺。应检查脑脊液(cerebrospinal fluid, CSF)是否有炎症证据(包括脑脊液蛋白水平和单个核细胞水平上升)，还需进行针对莱姆病和梅毒的血清学检查。正中神经综合征腕管综合征—腕管是由上方的腕横韧带(屈肌支持带)和下方的腕骨构成(图 2)。正中神经及9根前臂屈肌腱一定会穿过该解剖管道(图 3)。CTS具有多种病理生理学因素，认为腕管内压力升高在CTS临床发病中起重要作用。(参见“腕管综合征的病因和流行病学”)CTS是最常见的上肢单神经病。症状通常包括正中神经支配区的疼痛性感觉异常，累及第1-3指以及第4指桡侧半(图 4)。这些症状通常会在夜间加剧，常使患者从睡眠中醒来。然而，该病具有广泛变异性。疼痛和感觉异常可能局限于腕部或累及整个手部。感觉症状常向近端放射至前臂，少数情况下放射至肘部以上至肩部。随着正中神经卡压加剧，患者可出现固定的感觉缺失和无力。(参见“腕管综合征的临床表现和诊断”)CTS的治疗包括采用腕部夹板固定的保守治疗，尤其是在夜间或进行可加剧症状的活动时。当保守治疗无效时，向腕部注射类固醇往往有助于缓解症状(大多数病例至少可获得暂时缓解)。手术松解屈肌支持带适用于保守治疗无效且持续存在症状的患者，手术效果通常极佳。(参见“腕管综合征的治疗和预后”)旋前圆肌综合征—正中神经卡压偶尔发生于前臂近端神经穿过旋前圆肌的部位。此综合征罕见，一般见于体能活跃者，如专业自行车骑手。患者可能出现前臂疼痛和整个外侧手掌感觉缺失。鱼际感觉缺失也很典型，据此可与CTS相区分，CTS中鱼际区域感觉正常。电生理检查能够发现前臂传导速度减慢，病情严重者可出现传导阻滞。针极检查可发现正中神经支配的前臂肌肉(包括桡侧腕屈肌)存在异常。旋前圆肌综合征的治疗通常需要减少促发症状的活动。非甾体类抗炎药可一定程度缓解疼痛；若疼痛持续，向旋前圆肌压痛部位注射皮质类固醇和局部麻醉剂(10-20mg醋酸甲泼尼龙加1mL的1%盐酸利多卡因，采用23G或25G针头)有所帮助。若采取以上治疗措施后仍持续存在失能数月，可考虑旋前圆肌内神经减压术。骨间前神经病变—正中神经在肘部发出分支形成骨间前神经。骨间前神经然后沿前臂前部下行，负责支配以下肌肉：拇长屈肌、第2和第3指深屈肌以及旋前方肌。骨间前神经并不参与皮肤感觉，因此该神经功能障碍仅以这组肌肉无力为特征。体格检查时，患者无法用拇指和食指做出标准的“O”形(“okay”手势)。单纯骨间前神经损伤非常罕见，但可见于严重的前臂创伤。骨间前神经病更常见于神经痛性肌萎缩(臂丛神经炎)患者。(参见下文‘臂丛神经病’)其他疾病—一些成人的肱骨远端附着有一条小韧带(Struthers韧带)，罕见情况下，更近端的正中神经受压可发生在这些人的肘部稍上方区域。血管炎性病变患者在类似的肘部近端区域最易出现正中神经梗死。临床检查若发现正中神经和骨间前神经支配的多个肌肉出现肌无力，则有助于这两种疾病的诊断。电生理检查也会发现这些肌肉存在纤颤电位和正波。感觉缺失仍局限于手外侧面。尺神经综合征肘部和腕部尺神经病—肘部和腕部尺神经病将简要总结在此，详细内容见其他专题。(参见“肘部与腕部尺神经病变”)肘部尺神经病(图 5)是影响上肢的第二常见压迫性神经病。轻度病例的症状包括第4指和第5指感觉缺失和感觉异常(图 6)。更严重的患者会出现明显的手部骨间肌无力，患者或许会诉握力减弱和动作笨拙。肘部疼痛也较常见，不过并非普遍现象。尺神经支配的前臂肌肉受累会导致手指和腕屈曲无力。(参见“肘部与腕部尺神经病变”，关于‘临床特征’一节和“肘部与腕部尺神经病变”，关于‘肘部尺神经病变’一节)腕部偶尔会出现尺神经受压(图 7)。与正中神经一样，尺神经也穿过腕部，其穿行管道称为腕尺管(Guyon's canal)。神经受压可发生于腕尺管内或其远端(手的近端区域)。腕部尺神经受压的临床表现可能与肘部受压类似：骨间肌无力以及第4指和第5指感觉缺失和感觉异常。不过，该综合征患者受尺神经支配的手指屈肌不受影响，某些患者小鱼际肌的受累程度要轻于其他手部肌肉，如第一骨间背侧肌。(参见“肘部与腕部尺神经病变”，关于‘腕部尺神经病变’一节)多数情况下，若根据临床症状或体征怀疑有尺神经病变，可通过电生理检查或影像学检查确诊。有一些激发手法可用于检测尺神经病，但是这些手法的敏感性和特异性似乎欠佳。(参见“肘部与腕部尺神经病变”，关于‘诊断’一节)对于通常表现为间歇性感觉症状并且电生理检查发现跨肘传导速度减慢的轻度尺神经病患者，保守治疗常能改善病情，或者病情可维持稳定数年。有持续性感觉缺失和肌无力但无萎缩的患者通常发病较急(有时具有较轻微的间歇性症状既往史)，而且电生理检查常会发现兼有传导阻滞和传导速度减慢。这类患者通常在3-6个月内出现临床及电生理指标改善。肌无力和麻木症状持续超过6个月的患者应考虑手术干预。(参见“肘部与腕部尺神经病变”，关于‘治疗’一节和“肘部与腕部尺神经病变”，关于‘保守治疗’一节)应根据临床情况和影像学检查结果来治疗腕部尺神经病。对于有创伤性病因或外在/内在神经受压证据的患者，应考虑手术治疗。肘部或腕部尺神经病引起重度肌无力、萎缩和持续性感觉缺失的患者，其电生理检查会发现轴突损伤的证据。对于较年轻患者或急性发病(<6个月)患者，应考虑转至外科。然而，对于年龄较大或医学状况欠佳的患者以及慢性(2年或以上)重度受累的患者，手术干预的益处不太确定。(参见“肘部与腕部尺神经病变”，关于‘手术治疗’一节)其他综合征—尺神经穿出肘管的位置偶尔会发生尺神经病。糖尿病患者中，尺神经病可发生于前臂。在血管炎性病变中，尺神经梗死通常发生于肘部近端。桡神经综合征桡神经沟的桡神经病变—桡神经沿上臂内侧下行，之后绕过肱骨中段，靠后方走行。桡神经靠近肱骨走行的区域称为桡神经沟，桡神经极易在此处受压。长时间施压常会使该区域的神经受压。“周末晚麻痹(Saturday night palsy)”指的就是这种疾病，因为醉酒的人常出现此问题。体格检查时可见肱三头肌肌力正常，但腕伸肌无力(即“腕下垂”)、手指伸肌无力且肱桡肌无力。患者还可能出现手背感觉缺失，并可能向上延伸至前臂后侧。确定细微肱桡肌无力的最佳方法是让患者前臂保持在介于旋前与旋后中间的姿势(“锤桌”姿势)，接着要求患者对抗阻力屈曲前臂，然后通过触诊来评估患侧肌肉体积，并与健侧相对比。患者也常伴有尺神经支配的手部肌肉无力和拇指外展无力，前者很可能与手指伸肌维稳作用缺失情况下动作执行困难相关。因为拇长展肌属于桡神经支配的肌肉，所以拇指外展受累。有时难以区分桡神经沟急性桡神经病与导致手臂无力的中枢神经系统病变。大多数导致手臂无力的中枢神经系统疾病对伸肌的影响往往大于对屈肌的影响。因此，腕部伸展无力(即腕下垂)和手指伸展无力的病因不太明确，可能是急性桡神经病，也可能是中枢神经系统病变。肱三头肌肌力相对保留以及局限于手背的感觉缺失是有助于提示桡神经沟桡神经病的表现。最重要的是，桡神经病也会导致肱桡肌无力，而中枢神经系统疾病对肱桡肌的影响往往较小。骨间后神经病变—桡神经在肘部近端发出分支形成骨间后神经，支配前臂伸肌。桡神经沿前臂下行形成不含运动成分的桡神经浅支，为手背提供皮肤感觉。大多数情况下，骨间后神经病仅表现为明显疼痛。伸展中指诱发疼痛，通过神经阻滞能缓解疼痛，这两点有助于识别轻微病变[6]。重度外上髁炎(网球肘)患者的持续性疼痛是由于该区域神经受压。(参见“肱骨上髁炎(网球肘和高尔夫球肘)”)与骨间前神经病变类似，骨间后神经病变也可以是臂丛神经炎的一部分。(参见下文‘臂丛神经病’)若手指伸肌无力患者的更近端肌肉(包括肱桡肌和桡侧腕伸肌)肌力保留，也应考虑骨间后神经病变。对于严重病例，详细检查可能发现患者腕伸展时腕部向桡侧偏斜，其原因是尺侧腕伸肌受累而桡侧腕伸肌肌力得以保留。前臂旋后也无力。治疗—对于单次压迫性桡神经损伤(例如，桡神经周末晚麻痹)患者，通常采用保守治疗。物理治疗、腕部夹板固定(以保持腕部功能)以及疼痛管理最为重要。预后通常较好，可完全康复。一项纳入51例压迫性桡神经病变患者的回顾性研究中，23例可获得随访数据，在平均3.4个月期间(范围0.5-6个月)，这23例患者均达到完全临床恢复[7]。创伤所致严重神经损伤的患者可能需后续检查和EMG。重度进行性神经受压或神经横断可能难以与受创时神经损伤的单次发作相区分。若临床上或电生理学均未见任何改善，则需要进一步影像学检查或手术探查。对于确诊的前臂骨间后神经病变患者，神经减压术外科干预有所帮助[6]。不过，也应考虑神经痛性肌萎缩的可能。(参见“臂丛神经综合征”，关于‘神经痛性肌萎缩’一节)近端神经病变—其他多种单纯性局部神经病变可能影响上肢，包括肩胛上神经病变、胸长神经病变以及腋神经病变，这些疾病少见。肩胛上神经病变和腋神经病变可能表现为手臂外展和外旋无力；胸长神经病变通常会导致翼状肩胛(图片 1)。感觉缺失和感觉异常仅见于腋神经病变。这些疾病通常都会出现疼痛。EMG和NCS会发现异常局限于受累神经支配的肌肉。肩胛上神经病变—肩胛上神经起自臂丛上干(图 1)，发出感觉支到盂肱关节和肩锁关节，并发出运动支支配冈上肌和冈下肌。肩胛上神经损伤最常见的病因是肩胛上切迹处神经卡压，其次是冈盂切迹处神经卡压[8]。大多数肩胛上切迹神经卡压患者都会出现明显的肩部疼痛，并伴有冈上肌(肩外展)无力和冈下肌(肩外旋)无力。肌萎缩也可能较明显。相比之下，冈盂切迹水平发生的肩胛上神经损伤会导致无痛性肩外旋无力以及冈下肌萎缩。直接创伤是肩胛上神经病变的常见病因，例如橄榄球比赛中擒抱并摔倒(对方抱球球员)、跌倒或肩袖撕裂引起的[8,9]。拉伸、牵引或重复动作的活动也可损伤神经，正如报道显示，举重、排球、棒球和体操运动员发生过肩胛上神经损伤[10-12]。少数情况下，肩胛上神经可因肿块(如腱鞘囊肿或肿瘤)压迫而损伤。一项研究纳入了27例MRI显示有神经周肿块的肩胛上神经卡压患者，其中腱鞘囊肿21例，恶性肿瘤5例[13]。根据疼痛、肌无力、肌萎缩以及肩胛胸运动受限等临床表现可怀疑为肩胛上神经卡压。虽然电生理检查和影像学检查可能有助于确诊临床疾病，但是许多疑似肩胛上神经卡压病例的检查结果均呈阴性。因此，有必要继续进行临床观察。治疗和预后因神经损伤类型不同而异[8]。对于重复创伤患者，避免诱发性运动常常足以使患者恢复，配合物理治疗和锻炼维持关节活动度并强化肩部和肩袖肌力。对于保守治疗无法缓解病情的患者，可考虑肩胛横韧带松解手术和关节镜肩胛上神经减压术[14-16]。手术切除适用于有囊肿或肿瘤的患者。胸长神经病变—胸长神经是一条单纯运动神经，起自第5、第6和第7颈神经根(图 1)。胸长神经功能障碍会导致前锯肌麻痹，从而形成翼状肩胛。检查翼状肩胛时，患者伸展双臂并按压墙面，从后方看，受累的肩胛骨会从胸部突出(图片 1)。胸长神经损伤的主要原因如下[8,17]：●神经痛性肌萎缩●创伤或受压●重复性运动拉伸或牵引神经典型神经痛性肌萎缩的特征为：臂丛干、束或多条神经支配区剧烈疼痛发作，然后出现斑片状无力，通常伴有翼状肩胛。某些神经痛性肌萎缩病例是单纯的胸长神经病变。(参见“臂丛神经综合征”，关于‘神经痛性肌萎缩’一节)肩部或侧胸壁遭受直接打击(例如，橄榄球运动)或侵入性操作(例如，第1肋骨切除术、乳房切除联合腋窝淋巴结清扫术、斜角肌切除术、放置胸管、锁骨下神经丛麻醉以及心胸外科手术)可导致胸长神经创伤[8,18,19]。某些术后发病的病例可能因麻醉中固定上臂位置导致神经血管受压或牵引所致。据推测，神经受压是搬运重物(例如，用肩背背包)引发神经损伤的机制。体育运动或体力劳动相关的重复性动作可能导致神经拉伸或牵引，尤其是手臂处于高于头、伸展的姿势，而整脊手法偶尔也会导致神经拉伸或牵引[20]。治疗和预后随神经损伤机制不同而有差异[8]。神经痛性肌萎缩恢复缓慢，需要1-3年时间(参见“臂丛神经综合征”，关于‘神经痛性肌萎缩’一节)。搬运或重复性活动引起的胸长神经损伤大多为不完全损伤，可在6-24个月内自行消退。患者应避免诱发性运动以及避免用肩搬运重物[8]。物理治疗和锻炼对保持关节活动度以及强化斜方肌和菱形肌而言很重要。创伤引起的胸长神经损伤通常较严重，且恢复程度有限或根本不会恢复。对于功能无法恢复的患者，可以选择手术治疗[8,21,22]。这些手术包括肌肉转移和筋膜移植的各种联合术(例如，胸大肌胸骨头转移)。也有一些病例报告称，使用胸背神经或胸内侧神经进行神经移位获得了成功[23,24]。然而，单纯前锯肌无力引发的功能受限大多相对轻微，无需手术干预。腋神经病变—腋神经源自臂丛后束(图 1)，发出皮肤感觉纤维至肩外侧的椭圆区域，并支配三角肌(肩外展)和小圆肌(肩外旋)。腋神经病变最常见的病因是创伤，通常由肩关节脱位或肱骨骨折引起[8]。全身麻醉或手臂高于头部的俯卧睡姿也可引发腋神经病变。此外，四边孔内偶尔会发生神经卡压，四边孔的上界为小圆肌，外侧界为肱骨，内侧界为肱三头肌长头，下界为大圆肌[25,26]。腋神经受累也可以是神经痛性肌萎缩综合征的一部分，但很少单独发病。腋神经病变的临床特征包括肩外侧出现边界清楚的感觉缺失区域[8]。由于其他肌肉可协助肩外展和外旋，所以肌无力的程度各异，但重度肌无力较少见。保守治疗包括旨在保持关节活动度的物理治疗和锻炼。不完全神经损伤患者通常需要3-4个月恢复。重度病变患者、保守治疗的最初数月未见缓解的患者[27,28]以及复发性肩关节脱位的患者，可选择包括神经移植术在内的手术干预。脊髓副神经病变—脊髓副神经是从上颈神经根发出的颅神经，负责支配胸锁乳突肌和斜方肌，斜方肌的主要功能在于维持肩关节稳定。单纯性脊髓副神经病变最常见的原因包括颈后三角颈淋巴结活检以及颈全清扫术等局部手术[29]。钝性神经损伤也很常见(例如由体育运动或搏斗所致)。一份报告显示，大力按摩引起过脊髓副神经病变[30]。副神经病变的临床表现包括患侧肩部下垂或肩胛带压低以及外展无力[29,31]。更近端的脊髓副神经病变会出现胸锁乳突肌萎缩和无力，而更远端的病变会导致斜方肌萎缩和无力。临床特征不包括感觉缺失，这是因为脊髓副神经是单纯运动神经。然而，患者常会出现疼痛，这可能是臂丛受牵引造成的[29]。通常会观察到明显的翼状肩胛[17]。检查肩部无力最简单的方法是让患者手臂外展至180°，副神经病变患者无法完成后90°的手臂外展动作。重要的是，由于肩部不稳定，所以无法准确评估三角肌、菱形肌和前锯肌等其他肩部肌肉的肌力。预后随病因不同而异。对于较严重的病变，肌肉转移有助于稳定肩胛骨和改善功能。肌皮神经病变—肌皮神经起自臂丛外侧束，包含C5、C6和C7神经根发出的神经纤维。肌皮神经穿过喙肱肌后，沿手臂前侧在肱二头肌与肱肌之间下行，继续前行进入前臂成为前臂外侧皮神经。肌皮神经支配喙肱肌、肱二头肌和肱肌，并为前臂外侧提供皮肤感觉。因此，肌皮神经病变的临床特征包括屈肘无力，并伴前臂外侧感觉缺失。单纯性肌皮神经病变较罕见，但直接创伤、肩关节脱位、剧烈运动或麻醉过程中手臂位置不正均可损伤此神经[32-35]。该病通常适合保守治疗[35]。若保守治疗无效，外科减压术可能有帮助[35,36]。臂丛神经病—臂丛(图 1)是周围神经系统中最复杂的结构[37]，易受创伤，或可能因相邻结构病变而继发受损。大多数臂丛疾病呈区域性受累，而非整个臂丛受累。(参见“臂丛神经综合征”)将疾病定位于臂丛的具体区域通常是诊治臂丛神经病患者最重要的第一步。一旦成功定位，确定具体病因往往变得相对简单。一些简单的规律能有助于准确定位臂丛病灶。●肌无力一般呈“肌节”模式分布：C8-T1肌肉无力表明臂丛下干/内侧束可能出现问题；C5和C6肌肉无力可能是臂丛上干/外侧束出现问题；局限于单一神经的肌无力不太可能由臂丛神经病变引起，但臂丛神经炎除外。●桡神经或腋神经支配的肌肉(例如三角肌、肱三头肌、肱桡肌、腕伸肌及腕屈肌)受累与臂丛后束受累相符。●几乎没有单纯的臂丛中干病变，通常会同时出现臂丛下干或上干一定程度受累。C7神经根病的可能性明显更高。●延伸至前臂内侧的固定感觉缺失符合臂丛下干/内侧束病变；延伸至前臂外侧的感觉缺失符合臂丛上干/外侧束病变。这些区域的皮肤受臂丛直接发出的神经分支支配。●前锯肌无力(导致翼状肩胛)、棘肌无力(导致手臂外旋无力和手臂外展初始无力)或菱形肌无力(肩胛回缩和上抬)更有可能是神经根病或是神经根病的一部分，因为这些肌肉均受臂丛极近端分支或脊神经本身的分支所支配。一个重要例外是臂丛神经炎，因为前锯肌往往会受累。臂丛的具体疾病详见其他专题。(参见“臂丛神经综合征”)颈神经根病—神经根病是一种累及神经根的病理过程。颈神经根病是急性和慢性颈痛的常见原因。该病将简要总结在此，详细内容参见其他专题。(参见“颈神经根病的临床特点和诊断”)大多数神经根病由神经根受压引起。压迫性颈神经根病的发病机制主要有两种，分别是颈椎病和颈椎间盘突出症。低位颈神经根(尤其是C7神经根)比高位颈神经根更常受压。非压迫性神经根病的一些病因包括感染(尤其是带状疱疹和莱姆病)、神经根梗死、肿瘤浸润、肉芽肿组织浸润、根性撕脱伤和脱髓鞘。几乎所有颈神经根病患者都会出现颈部、肩部或手臂疼痛，但疼痛通常不能协助准确定位病变神经根水平。疼痛可能是非典型的，可表现为胸痛(假心绞痛)、乳房疼痛或面部疼痛。头部转动、咳嗽或打喷嚏可能会加重症状。对于疑似颈神经根病患者，神经系统评估的主要目的在于发现肌节和皮区分布模式的肌无力和感觉障碍。单纯性神经根病变的典型临床表现总结在表中(表 1)。若出现提示神经根损伤的局部体征和症状，或出现保守治疗无法缓解的持续性症状，则需进行神经影像学检查和电生理检查。治疗—颈神经根病患者的治疗详见其他专题。(参见“颈神经根病的治疗和预后”)其他局灶性肌萎缩—局灶性或单肢肌萎缩(包括平山病)是一种以单个肢体单纯运动无力为特征的罕见疾病(一些平山病病例出现双侧肢体症状)，是一种局限性运动神经元病。(参见“肌萎缩侧索硬化症和其他类型运动神经元病的诊断”，关于‘单肢肌萎缩’一节)多数性单神经病—累及多条神经的缺血性病变可能会引起令人混淆的临床表现。尽管如此，大多数患者存在分布更广(包括双腿)的神经受累。治疗基础疾病仍是多数性单神经病的治疗原则。尽管最初的神经损伤很严重，但只要患者的疾病类型对免疫抑制疗法有反应，那么患者的恢复情况会很好。不同病因(包括Churg-Strauss病、类风湿关节炎、Wegener肉芽肿病等)的血管炎患者均可通过免疫抑制治疗显著改善神经系统失能。血管炎(系统性受累或仅限于神经受累)引起的多数性单神经病详见其他专题。(参见“血管炎性神经病的临床表现和诊断”)多灶性运动神经病—多灶性运动神经病(multifocal motor neuropath, MMN)也称多灶性运动神经病伴传导阻滞，是一种罕见的免疫介导性脱髓鞘神经病变，其特征为进行性不对称性肌无力和肌萎缩但不伴感觉异常，该表现与运动神经元病表现相似。(参见“多灶性运动神经病”)MMN最常为亚急性发病，症状为非对称性肌无力，同时出现手臂和手部肌无力的下运动神经元体征，但不伴感觉缺失。MMN中的神经元受累通常为斑片状，一些神经不受累而另一些神经严重受累。运动神经传导检查通常会发现传导阻滞的证据。同一神经节段的感觉神经传导正常。30%-80%的患者会出现抗GM1抗体滴度升高。(参见“多灶性运动神经病”，关于‘临床特征’一节)静脉用免疫球蛋白和其他形式的免疫抑制疗法可治疗MMN。(参见“多灶性运动神经病”，关于‘治疗’一节)带状疱疹性神经根神经节炎—除疼痛性皮疹外，带状疱疹患者还可能出现与皮疹分布接近的神经分布区的肌无力和感觉缺失。炎症可累及神经根和后根神经节，可能导致明显的神经源性损伤。偶尔还会出现相关的脊髓病。总结●上肢周围神经损伤的主要机制是压迫、横断、缺血、炎症、神经元变性以及辐射暴露。(参见上文‘发病机制’)●腕管综合征(CTS)是最常见的影响上肢的单神经病，其次是肘部尺神经病。颈神经根病也很常见。(参见上文‘流行病学’)●肌电图(EMG)和神经传导检查(NCS)有助于识别上肢周围神经疾病并对其进行分类。(参见上文‘诊断性检查’)●典型CTS的特点是正中神经支配区域疼痛或感觉异常，并累及手部外侧(图 4)。这些症状通常会在夜间加剧，常会使患者从睡眠中醒来。保守治疗包括腕部夹板固定，而保守治疗无效的中至重度CTS患者可选择接受糖皮质激素注射和手术松解。(参见上文‘腕管综合征’)●罕见的正中神经综合征包括正中神经穿过旋前圆肌处被卡压，以及正中神经在肘部发出的骨间前神经的单纯性损伤。(参见上文‘旋前圆肌综合征’和‘骨间前神经病变’)●肘部尺神经病(图 5)是影响上肢的第二常见压迫性神经病。轻度病例的症状包括第4指和第5指感觉缺失和感觉异常(图 6)。较严重的病例会出现手部骨间肌无力。偶见腕部尺神经受压(图 7)，其临床表现类似于肘部尺神经受压。然而，该综合征患者尺神经支配的手指屈肌不受累。通常，轻度肘部尺神经病经保守治疗可获得改善，或保持稳定。肌无力和麻木症状持续超过6个月的患者应考虑手术干预。(参见上文‘尺神经综合征’)●桡神经容易在其靠近肱骨走行的区域(即桡神经沟)受压。肱三头肌肌力正常，但是会出现腕伸肌无力(即腕下垂)、指伸肌无力和肱桡肌无力。患者也可出现手背感觉缺失，并可能向上延伸至前臂后侧。骨间后神经病患者通常会出现前臂疼痛和手指背屈无力。对于桡神经单次压迫性损伤患者，一般采用保守治疗。对于确诊的前臂骨间后神经病患者，在排除神经痛性肌萎缩后，行神经减压术外科干预有所帮助。(参见上文‘桡神经综合征’)●上肢近端局灶性神经病变包括肩胛上神经病变、胸长神经病变和腋神经病变。(参见上文‘近端神经病变’)●臂丛(图 1)易受创伤，并可能因邻近结构病变而继发性受损。大多数臂丛神经病呈区域性受累，而非整个臂丛受累。(参见上文‘臂丛神经病’)●颈神经根病是急性和慢性颈部疼痛的常见病因。大多数神经根病的病因是颈椎病和/或颈椎间盘突出症导致的神经根受压。低位颈神经根(尤其是C7神经根)更常受压。非压迫性神经根病的一些病因包括感染(尤其是带状疱疹和莱姆病)、神经根梗死、肿瘤浸润、肉芽肿组织浸润、根性撕脱伤和脱髓鞘。单纯性神经根病变的典型临床表现总结在表中(表 1)。(参见上文‘颈神经根病’)●其他影响上肢的少见周围神经综合征包括局灶性肌萎缩、多数性单神经病、多灶性运动神经病(MMN)以及带状疱疹性神经根神经节炎。(参见上文‘其他’)使用UpToDate临床顾问须遵循用户协议.参考文献de Krom MC, Knipschild PG, Kester AD, et al. 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引言—脊髓损伤(spinal cord injury, SCI)是常见事件；在美国，创伤性脊髓损伤的发病率约为每年54例/100万人，2017年，创伤性脊髓损伤的幸存者约有280,000例[1]。尚不清楚非创伤性脊髓损伤的患病率，但估计是创伤性脊髓损伤的3-4倍[2]。脊髓损伤会对全身性生理带来多种变化，可引起许多并发症，其对功能和生活质量的影响堪比神经功能障碍。脊髓损伤后的医学并发症常见且严重。在脊髓损伤模型系统数据库(Model Spinal Cord Injury Systems Database)中，脊髓损伤后第1年的再住院率为55%，在接下来20年的再住院率维持在每年约37%[3]。泌尿生殖系统和呼吸系统并发症及压疮是最常见的住院原因。患者年龄增长和脊髓病变严重程度也会影响发生并发症需要住院的风险。本文将总结创伤或其他原因所致慢性脊髓损伤的常见并发症的治疗。脊髓损伤的急性表现和并发症详见其他专题。(参见“急性创伤性脊髓损伤”和“影响脊髓的疾病”)期望寿命—脊髓损伤幸存者的期望寿命缩短，第1年内的死亡率最高。创伤性脊髓损伤后存活至少1年的患者，其期望寿命约为正常寿命的90%[4-6]。脊髓损伤时神经损伤水平较高、损伤较严重，以及年龄较大都会对存活造成负面影响。创伤性脊髓损伤后死亡的最常见原因是呼吸系统疾病，其次为心血管事件[4,5]。在早些年间(1972年之前)，泌尿系统并发症是死亡的主要原因。脊髓损伤患者的自杀风险也增加[6]。(参见下文‘精神并发症’)心血管并发症自主神经反射异常—T6以上的脊髓损伤可能并发自主神经反射异常现象，表现为对心率和血管张力需求的协调性自主反应丧失[7,8]。对损伤水平以下伤害性刺激的不受抑制的或过度的交感神经反应会导致弥漫性血管收缩和高血压。代偿性副交感神经反应会引起心动过缓和病变水平以上的血管舒张，但这并不足以降低升高的血压。而低于T6的脊髓损伤病变不会引起这种并发症，因为完好的内脏神经支配能实现内脏血管床的代偿性扩张。估计这种并发症的发生频率变化较大，其在T6以上脊髓损伤患者的发生率范围是20%-70%[7,8]。自主神经反射异常极少发生在脊髓损伤的第1个月内，但其通常在第1年内出现[9,10]。典型的刺激因素包括膀胱膨胀、肠嵌塞、压疮、骨折或隐匿性内脏功能障碍[7,8]。性行为可以是触发因素。医疗操作、临产和分娩也可并发自主神经反射异常。(参见“妊娠合并神经系统疾病”，关于‘脊髓损伤’一节)常见的临床表现有头痛、出汗和血压升高[9]。也可能出现潮红、竖毛、视物模糊、鼻塞、焦虑和恶心。常见心动过缓；但也有部分患者反而出现心动过速。发作的严重程度从无症状性高血压至高血压危象并发严重心动过缓和心搏骤停或颅内出血和癫痫发作。脊髓损伤的严重程度会影响发作的频率和严重程度。急性发作的处理包括[7,9]：●测量和监测血压。●立即使患者坐直以便直立性降低血压。●脱去紧身衣物。●寻找并纠正伤害性刺激。膀胱膨胀和粪便嵌塞是最常见的诱发因素。应进行导尿并评估有无泌尿道感染(urinary tract infection, UTI)；应检查留置导尿管是否阻塞，并行直肠检查。●根据发作的严重程度和对上述措施的反应，采用起效迅速/作用时间短的药物迅速降低血压。此时常用的药物包括硝酸酯类[1英寸的2%硝酸甘油软膏(nitropaste)]、硝苯地平(10mg口服或舌下给药)、静脉用肼屈嗪(10mg)和静脉用拉贝洛尔(10mg)。若患者可能因勃起功能障碍而在使用西地那非，则应避免使用硝酸酯类。识别和避免刺激因素对预防发作很重要。有报道称，预防性给予硝苯地平、哌唑嗪和特拉唑嗪能预防发作，治疗脊髓损伤患者膀胱功能障碍的肉毒毒素也能有效减少发作[7,8,11-13]。冠状动脉疾病—随着患者长期存活的改善，冠状动脉疾病(coronary artery disease, CAD)已经成为脊髓损伤越来越重要的并发症[5]。与体格健全的人群相比，CAD危险因素在慢性脊髓损伤患者中更为常见，如不利的血脂谱(高密度脂蛋白水平低、低密度脂蛋白胆固醇升高)和葡萄糖代谢异常(糖耐量受损、胰岛素抵抗和糖尿病)[14]。促成这些异常发生的因素包括肌肉量降低、脂肪增加和不活动[15]。研究提示，脊髓损伤患者的CAD患病率为一般人群的3-10倍[14]。此外，中国台湾开展的一项队列研究发现，脊髓损伤与脑卒中风险增加相关(HR 2.9)[16]。脊髓损伤患者的CAD死亡率似乎也更高[5]。一个促成因素可能是T5以上的脊髓损伤病变可能导致心肌缺血的非典型表现；表现可能包括自主神经反射异常或痉挛状态改变，而非典型的胸痛。脊髓损伤患者CAD危险因素管理和治疗类似于身体健全的人。(参见“确定的心血管疾病危险因素概述”)脊髓损伤患者的运动选择包括手摇曲柄肌力测试、手驱自行车、游泳及肌肉的功能性电刺激[17]。有报道指出，减重平板训练(body weight-supported treadmill training)能改善不完全脊髓损伤患者的葡萄糖调节[18]。然而，交感神经反应减少、心排血量降低、通气受损和肌肉量降低会导致慢性脊髓损伤患者的运动能力降低[14]。在更高水平的脊髓损伤时，对运动的生理反应(包括心率增加、心肌收缩力增加和血管调节)也会受损。其他—脊髓损伤导致的自主神经系统功能障碍会扰乱正常的心血管系统稳态。T6水平以上脊髓损伤时，基线血压通常会降低，基线心率可能低至每分钟50-60次[14,19]。这通常不是临床问题，但可能导致血流动力学不稳和运动不耐受。外周血管舒张所致直立性低血压更常见于脊髓损伤的最初数月，并趋向于随着下肢肌张力的恢复而消退[9]。但特别是在过度卧床休息和液体摄入减少时，慢性脊髓损伤也可能出现直立性低血压。逐渐变换体位、医用压力袜以及腹带能减少静脉血液淤积并可能改善站立位的耐受性。偶尔可能需要增加盐摄入、α肾上腺素能受体激动剂(米多君)或盐皮质激素药物(氟氢可的松)。(参见“直立和餐后低血压的治疗”)急性颈部脊髓损伤会因迷走神经紧张过度而带来心律失常风险，并且还有缺氧、低血压以及液体和电解质紊乱的风险。而慢性脊髓损伤中心律失常少见得多。但是，完全性颈髓损伤患者似乎存在持续的心肺骤停风险[20,21]。肺部并发症—颈部和高位胸部脊髓损伤会影响呼吸肌。通气衰竭的严重程度和辅助通气需求均取决于脊髓损伤的水平和严重程度。较轻程度的通气衰竭可能引起呼吸困难和运动不耐受。颈部脊髓损伤患者接受呼吸肌训练能有效改善呼吸肌的力量和功能[22]。(参见“脊髓损伤后的呼吸系统生理改变”和“慢性脊髓损伤的呼吸系统并发症”，关于‘呼吸功能不全’一节)由于咳嗽功能受损和难以排出肺部分泌物，脊髓损伤后的患者发生肺炎的风险也增加。虽然脊髓损伤后肺炎的发生率在第1年最高，但这些患者在其一生中发生肺炎的风险仍是增加的[23]。年龄较大患者的风险高于较年轻患者。预防肺炎的措施包括胸部理疗和接种疫苗。(参见“慢性脊髓损伤的呼吸系统并发症”，关于‘肺部感染’一节)尽管认识和治疗有进步，但深静脉血栓形成和肺栓塞仍是脊髓损伤的常见早期并发症。大多数脊髓损伤患者首选预防性使用低分子量肝素。虽然尚无良好的临床试验数据指导治疗的持续时间，但我们建议对瘫痪患者的治疗应在脊髓损伤后持续至少3个月，此后的风险似乎才接近一般人群的风险[24]。具体方案详见其他专题。(参见“成人非骨科手术患者中静脉血栓栓塞症的预防”)泌尿系统并发症—脊髓损伤会引起膀胱功能障碍，这常称为神经源性膀胱，还可导致其他并发症，包括感染、膀胱输尿管反流、肾衰竭和肾结石。推荐对所有脊髓损伤患者进行泌尿系统评估并定期随访；即使是可走动的脊髓损伤患者也可能有会导致并发症的膀胱功能障碍[25]。膀胱输尿管反流、肾衰竭和肾结石等并发症可能没有症状，但若不治疗，会产生严重后果。检查频率和具体检查(血清肌酐、膀胱镜检查、尿动力学检查、肾脏超声检查)尚未明确界定，但这部分取决于患者泌尿系统问题的性质和其他危险因素[26,27]。膀胱功能障碍—脊髓损伤会干扰膀胱的两大主要功能：尿液储存和排空。膀胱控制是一项复杂的活动，需要大脑皮层、脑桥和骶髓排尿中枢与周围神经系统协调发挥功能[28](参见“脊髓病变的解剖学和定位”，关于‘自主神经纤维’一节)。脊髓损伤时，膀胱充盈感以及膀胱和括约肌功能的运动控制受损。根据脊髓损伤的急性程度、水平以及完全性，可引起许多问题：●膀胱或逼尿肌过度活跃会引起反射性膀胱排空。患者可能会受到膀胱痉挛、尿频和尿急的困扰，并常伴有尿失禁。随着时间的推移，这可导致膀胱容量降低。●括约肌过度活跃会损害膀胱的完全排空。●逼尿肌括约肌协同失调是逼尿肌和括约肌过度活跃一同出现，这可导致膀胱收缩对抗闭合的括约肌，从而引起膀胱压力升高和膀胱输尿管反流。●影响马尾或脊髓圆锥的下运动神经元损伤，以及急性上运动神经元损伤(脊髓休克)时会出现膀胱弛缓。这会导致慢性尿潴留伴充盈性尿失禁和不完全排空。不管损害的水平如何，大多数不完全脊髓损伤患者和所有完全性脊髓损伤患者都需要膀胱功能方面的辅助治疗[23]。虽然尚无临床试验对脊髓损伤中膀胱功能障碍的长期治疗给予指导，但积累的临床经验已经得出了一些治疗策略[29,30]。这些方法的疗效可能通过降低脊髓损伤患者的泌尿道相关并发症的发病率和死亡率而表现出来[5,23]。脊髓损伤相关膀胱并发症的治疗目标是保留肾功能，让患者能在规律且社交允许的时间排尿，避免高膀胱压力、尿潴留、尿失禁和感染。应在脊髓损伤后尽早开始此项治疗，同时移除留置的导尿管。与留置导尿管相比，清洁间歇性导尿术(clean technique intermittent catheterization, CIC)的感染率更低[23]；现有数据还不足以推荐某种导尿管类型，也无法推荐采用清洁技术还是无菌技术[31]。定期进行CIC，通常每4小时1次。目标是使膀胱容量小于500cm3尿液，以避免膀胱膨胀、膀胱内压过高和反流，并降低感染发生率。调整CIC的时间和液体摄入量以达到此目标。通常将脊髓损伤患者的液体摄入量限制为每日2L。如果有充盈感，则鼓励在进行CIC之前尝试自主排尿，因为一些不完全损伤的患者将会恢复正常的排尿功能。预计会出现间歇性尿失禁。阴茎套导尿管(用于男性)和成人纸尿布是重要的短期措施。在排除感染并调节CIC频率和液体摄入量后，应考虑药物治疗。应考虑进行尿流动力学检查以评估生理机能并指导药物干预[26]：●抗胆碱能药(例如，奥昔布宁和托特罗定)能降低膀胱张力和抑制膀胱收缩，因而可能减少尿频和尿失禁。三环类抗抑郁药(如丙米嗪)具有增加尿道阻力的额外副作用。●α-肾上腺素能药物(麻黄碱和苯丙醇胺)可以增加括约肌病理性松弛患者的膀胱存储能力。●胆碱能药物(乌拉胆碱)可能有助于低张性膀胱患者完全排空膀胱。●α-受体阻滞剂(例如，哌唑嗪和特拉唑嗪)有助于松弛括约肌，从而降低收缩时的膀胱压力。可以使用这些药物治疗逼尿肌括约肌协同失调，但可能会加重低血压。大多数患者联合CIC和口服抗胆碱能药物进行治疗[32]。对于无法进行CIC和无照料者的患者，长期留置导尿管可能是必要的。与CIC相比，这会导致UTI的风险增加[33]。通过每月更换留置导尿管以尽量减少感染。氯奥昔布宁(一次5mg，一日2次)可以减轻导尿管引起的膀胱痉挛。使用留置导尿管，前列腺炎、附睾炎和尿道狭窄的风险增加。耻骨上置管可有助于将感染和尿道狭窄的风险降至最低。因为膀胱癌和结石的发病率增加，推荐每2年进行膀胱镜检查监测[26]。对逼尿肌过度活跃患者的逼尿肌注射A型肉毒毒素的研究表明，该治疗能安全有效地控制症状和改善生活质量[32,34-37]。但尚未确定最佳剂量，也不清楚远期疗效[38]。尚无将其与抗胆碱能药物的比较研究[39]。使用肉毒毒素治疗非神经源性下泌尿道功能障碍的内容详见其他专题。(参见“肉毒毒素治疗非神经源性下尿路疾病”)植入骶神经调节器的研究表明其有望作为脊髓损伤后尿失禁的治疗[40,41]。若患者对药物和导尿管治疗的效果不满意，可对特定病例考虑其他疗法，例如膀胱扩大术、尿流改道术、括约肌切开术、尿道支架术和电子植入装置[2,26,38]。泌尿道感染—脊髓损伤患者常见UTI，发病率为每年每例患者发作2.5次[42]。在脊髓损伤患者中，尿路是败血症的最常见病源，并且有较高的死亡率(15%)[42,43]。与男性相比，UTI更常见于女性。低频和高容量导尿会增加UTI的风险，留置导尿管和辅助(与自主相反)间歇性导尿也一样会增加UTI的风险[33,44,45]。有症状的UTI表现为发热、自主神经反射异常、痉挛状态增加、尿液恶臭、尿失禁、尿频或排尿困难，需要立即使用抗生素治疗以避免败血症和其他并发症。(参见“女性急性单纯性膀胱炎”和“男性急性单纯性膀胱炎”和“成人急性复杂性泌尿道感染(包括肾盂肾炎)”)对于无症状的UTI一般不做治疗；并且虽然事实上脊髓损伤后常见无症状性菌尿且出现有症状UTI的风险较高，但对脊髓损伤患者常规应用预防性抗生素预防UTI并无作用[44]。一项对已发表文献的meta分析发现，对脊髓损伤患者预防性应用抗生素能减少无症状性菌尿，但不能减少有症状的感染，并且出现耐药细菌的风险增加至2倍[46]。然而，一些复发性UTI患者可能会受益于预防性抗生素治疗，这取决于感染的频率和临床严重程度。特别是联合出现频繁UTI和膀胱输尿管反流时，出现肾衰竭的风险较高。(参见“女性复发性单纯性膀胱炎”)其他降低UTI发病率的方法正在研究中，包括泌尿道惰性菌株的定植[47]。认为蔓越莓汁能够减少细菌黏附于尿路上皮，从而预防UTI[48]。但其疗效未经证实，并且脊髓损伤患者的相关液体摄取和热量摄取可能存在问题。在两项小型临床试验中，结果发现蔓越莓补充剂不能有效地减少脊髓损伤患者的菌尿、脓尿或UTI[49,50]。尿路结石—脊髓损伤后，肾、输尿管或膀胱的结石会增加，尤其是存在反复UTI、留置导尿管和制动性高钙尿症的患者[23](参见下文‘骨代谢’)。由于膀胱感觉改变，患者可能不会有疼痛感来提醒医生其存在输尿管梗阻。其他临床症状，例如肢体痉挛状态增加和自主神经反射异常发作，应提示可能有尿路结石(参见上文‘自主神经反射异常’)。尿路结石的诊断和治疗详见其他专题。(参见“成人疑似肾结石的诊断与紧急处理”和“成人肾和输尿管结石的治疗选择”)膀胱输尿管反流—膀胱输尿管连接部的功能受损可能源于膀胱高压力和复发性UTI。估计该并发症在脊髓损伤患者中的发病率高达25%[51,52]。由于持续反流与肾盂肾炎和肾功能不全的风险升高相关，所以必须对其进行治疗。尽管使用抗胆碱能药物和增加导尿频率但仍然存在持续反流，则可能需要放置留置导尿管或进行外科手术。留置导尿管会引起膀胱痉挛，而使用奥昔布宁可能减少膀胱痉挛导致的膀胱压力阶段性升高[53]。肾功能不全—肾功能不全的累积发病率随着脊髓损伤后时间的推移而升高，在20年时高达25%[23,54,55]。肾衰竭与留置导尿管、膀胱输尿管反流和高龄相关。性功能障碍—脊髓损伤对性功能的影响包括性欲减退、阳痿和不育[56]。●有脊髓损伤的男性患者中，阳痿发病率为75%[26]。与不完全性损伤患者相比，该并发症在完全性损伤患者中的发病率最高，病情最为严重。目前有多种治疗勃起功能障碍的方案，包括药物治疗、辅助装置和手术植入假体。已证实西地那非、伐地那非和他达拉非对脊髓损伤患者有效，但合并CAD时禁用这些药物及其他磷酸二酯酶-5抑制剂[57-62]。(参见“男性性功能障碍的治疗”)●在脊髓损伤患者中，由于勃起功能障碍、射精功能障碍和/或精子质量差，所以男性不育症的患病率较高[27,56]。一般而言，脊髓损伤后男性生殖需要人工授精。(参见“男性不育的诊断评估”和“男性不育的治疗”)●脊髓损伤后女性的性反应也可能受损，但排卵和生育能力一般不受影响[26,56]。与一般人群相比，脊髓损伤女性的妊娠率较低反映了个人的选择问题。脊髓损伤女性的妊娠一般归类为高风险，这是因为并发症的发生率较高，包括感染和自主神经反射异常。相关内容详见其他专题。(参见“妊娠合并神经系统疾病”，关于‘脊髓损伤’一节)胃肠道并发症—脊髓损伤后，排便障碍常见、导致失能，会显著影响功能结局和生活质量结局[63-65]。为获得最佳结果，常需要开展多维度的项目[66]。可能出现两种排便障碍[67]。损伤位于脊髓圆锥以上时，脊髓和肠之间的神经连接仍得以维持，从而导致反射亢进的骨盆肌肉收缩，并无法自主地松弛肛门外括约肌，这会导致便秘和粪便潴留。损伤位于脊髓圆锥以下时，会出现反射消失性肠道(即下运动神经元性肠道)，从而导致运输变慢、括约肌张力降低和便秘伴频繁失禁。由于几乎没有研究对这一问题的治疗进行评估，所以相关推荐基于临床经验和专家意见[67,68]。将患者受伤前的排便模式作为指导，在脊髓损伤后尽早将一致的、有组织的方案整合到患者的生活方式中，以实现可预测的及时排便从而避免大便失禁和嵌塞[9,56]。典型的日常治疗可在每日固定时间点开始(例如，餐后30分钟)，置入化学刺激性直肠栓剂。几分钟后，缓慢轻柔地转动手指进行刺激，持续15-60秒，每5-10分钟重复1次，直至完成排便。腹部按摩、深呼吸、Valsalva动作和前倾姿势都可能有助于排便[66]。在建立规律排便模式的初始阶段经常使用口服肠道药物(大便软化剂-多库酯钠；肠道刺激剂-番泻叶和比沙可啶；容积性制剂-洋车前草)，然后缓慢停用[67]。长期使用刺激性轻泻药会出现许多副作用。(参见“成人慢性便秘的治疗”，关于‘其他轻泻药’一节)规律饮食是肠道方案的一个重要特征，并且应包括充足的纤维摄入(30g)，乳制品和脂肪含量的总量相对较低[9,67]。液体摄入量目标通常由患者的膀胱状态决定，但是如果可能，液体摄入量应高到足以产生每日2-3L的尿量。尽管采取上述措施，某些患者仍会出现排便障碍的并发症：●如果发生便秘或嵌塞，可考虑试用灌肠剂、轻泻药或容积性药物[67]。应考虑行腹部X线检查以筛查有无梗阻证据。应排除与脊髓损伤不相关的疾病，特别是结直肠癌。促动力药(例如，西沙必利和甲氧氯普胺)只用于对肠道方案调整无效的持续性严重便秘[66]。一些严重排便障碍的患者需要进行结肠造口术。非对照观察性研究提示，对于一些脊髓损伤后的慢性排便障碍患者，定期经肛门灌洗可以减少便秘和大便失禁，并提高生活质量[69-71]。骶神经或其他电刺激技术可能对某些患者有效[72]。便秘和大便失禁的治疗详见其他专题。(参见“成人慢性便秘的治疗”和“Fecal incontinence in adults: Management”)●脊髓损伤的肠道方案中常用的干预措施(栓剂、灌肠剂和手指刺激)可增加痔疮。治疗包括应用将创伤最小化的粪便软化剂、局部抗炎乳膏和栓剂。引起持续性出血、疼痛或自主神经反射异常的痔疮需请外科会诊。(参见“症状性痔的家庭和门诊治疗”)●严重的腹部并发症包括胆囊炎、上消化道出血、胰腺炎或阑尾炎，占脊髓损伤后死亡的10%，并在损伤后最初数月内风险最大[19,73]。慢性脊髓损伤患者的胆结石患病率增加，可能与去神经支配相关[74]。脊髓损伤引起的感觉障碍会导致诊断延误，并导致与这些并发症相关的死亡率增加。模糊或非特异性症状(如恶心、厌食或自主神经反射异常)应考虑有无隐匿性腹部疾病的可能[19]。●肠系膜上动脉综合征是脊髓损伤的少见并发症，通常见于颈髓损伤患者[75,76]。体重减轻会导致肠系膜脂肪垫丢失和肠系膜上动脉压迫十二指肠，从而引起小肠梗阻症状。(参见“肠系膜上动脉综合征”)骨代谢骨质疏松—脊髓损伤后，骨质疏松会累及损伤水平以下的骨骼并增加下肢骨折的风险。一项纳入41例男性的病例系列研究中，脊髓损伤后中位时间15年后，61%有骨质疏松，34%有过骨折[77]。尚不清楚骨质疏松的发病机制；一般认为神经因素和废用退化具有一定作用[78]。骨吸收的生物标志物增加，可早在损伤后第1周开始，而骨形成的标志物是正常的或仅有轻微升高[78,79]。一些研究表明，大约在脊髓损伤后2年，骨吸收与骨形成之间会重新建立新的稳态水平[78]。年龄较大、脊髓损伤水平较高、痉挛状态程度较低和损伤时间较长与所见骨丢失程度较高并不始终相关[23,78-82]。在脊髓损伤患者中，男性和绝经前女性的骨质疏松发生率相近；研究纳入的脊髓损伤绝经后女性极少，所以目前尚不知该人群是否存在额外风险[27]。有时，有症状的高钙血症和高钙尿症会在脊髓损伤的最初数月内并发于骨质的早期吸收[9]。表现可包括恶心、呕吐、厌食、嗜睡和多尿。肾结石的风险增加[79]。根据症状的严重程度对治疗进行分级。静脉帕米膦酸二钠已用于治疗脊髓损伤后的急性制动性高钙血症[83,84]。(参见“高钙血症的临床表现”和“高钙血症的治疗”)随着时间的推移，脊髓损伤患者会发生特异性模式的骨异常，伴近端胫骨和股骨骨密度明显降低，脊柱骨质丢失相对较少[80,85]。坐着和使用轮椅时，承重对脊柱的影响可能造成了这种差异[79]。四肢轻瘫患者也可能出现前臂远端骨质丢失[82]。小型观察性研究和开放性随机研究表明，使用双膦酸盐类(如替鲁膦酸钠、依替膦酸盐、帕米膦酸二钠和阿仑膦酸钠)治疗能减轻脊髓损伤患者的骨质丢失[86-89]。一项纳入31例患者的小型双盲随机试验也表明，在急性脊髓损伤后10日内给予阿仑膦酸钠(一次70mg，一周1次)显示能预防髋部骨质丢失[90]。功能性电刺激对于改善骨密度作用极小，并且很大程度上为非持续性获益[79,91-93]。异位骨化—异位骨化是指在外周关节周围的软组织内出现骨沉积。异位骨化发生于多达一半的脊髓损伤患者中，并在损伤后平均12周开始[94]。虽然脊髓损伤后异位骨化较为常见，但仅有10%-20%的患者有临床症状，即受累关节活动度减小和炎性症状。损伤水平以下的大关节通常受累，最常为髋关节。尚未完全清楚这种现象的发病机制，但认为其源于受累软组织内处于休眠状态的骨祖干细胞。有适当刺激时，如髋部手术、脊髓损伤和脑卒中，这些干细胞可分化为成骨细胞，形成类骨质并最终形成骨。全髋关节成形术的异位骨化将单独讨论。一项关于脊髓损伤患者的病例对照研究显示，完全性脊髓损伤、脊髓损伤平面较高以及伴有胸部创伤的患者中，异位骨化更常见[95]。(参见“全髋关节成形术的并发症”，关于‘异位骨化’一节)对于脊髓损伤患者的局限性疼痛，应将深静脉血栓形成、蜂窝织炎、感染、血肿和肿瘤考虑为备选诊断。由于出现临床表现后的数周可能不会出现钙化，所以X线平片对早期诊断的作用有限。血清碱性磷酸酶水平升高可以有助于鉴别早期异位骨化与其他疾病，但该发现不具特异性[96]。三相骨骼扫描是异位骨化诊断的最可靠检查。根据2010年一篇纳入2项随机试验的系统评价，脊髓损伤后早期给予非甾体类抗炎药(nonsteroidal anti-inflammatory drugs, NSAIDs)似乎能降低异位钙化的发生率，所用药物为吲哚美辛75mg/d、持续3周，或者罗非昔布25mg/d、持续4周[97-99]。但需要进一步研究确定哪些患者将会受益于这种干预。华法林和低强度脉冲电磁场疗法也可能有助于预防异位骨化，但尚未确定这些方法对该适应证的临床作用。异位骨化的初始治疗是使用NSAIDs和被动关节活动度训练，后者目标为保持关节活动性。双膦酸盐类也可能有用[97]。根据非对照病例系列研究，依替膦酸盐(静脉给药3日，然后口服6个月)减少肿胀并减慢或停止了异位骨化的进展，特别是在早期给予时(此时骨骼扫描呈阳性，但X线片仍正常)效果会更好[97,100-102]。一项纳入52例脊髓损伤后发生异位骨化患者的病例系列研究中，放射疗法也似乎限制异位骨化的进展[97,103]。对于难治性病例，外科手术是一种治疗选择，以恢复功能性活动范围；但手术后大多数患者会复发[104]。一项小型回顾性研究发现，静脉给予帕米膦酸二钠(一种双膦酸盐)预防了接受切除手术患者的异位骨化的复发[94]。报告显示，联合早期切除术与药物和放射治疗似乎也具有前景[105,106]。肌肉骨骼并发症—脊髓损伤后，若肌肉处于缩短状态维持较长时间，会出现胶原组织基质的重组，从而导致肌肉挛缩。制动和痉挛状态均能促进这种情况的发生[107]。预防性治疗极其重要，应在脊髓损伤后立即开始并持续长期治疗：●体位摆放。当卧床时，应对患者进行体位摆放，即利用枕头将髋部和膝部的屈曲及肩部的内收和内旋最小化。轮椅上的体位应保持正常的腰椎前凸。频繁变换体位能预防皮肤破坏及挛缩；这些并发症常常共存[107]。●活动度训练。应使麻痹的肢体关节每日运动5-20分钟。预防畸形所需的运动强度因人而异，但目标是维持全范围活动。出现任何运动受限都需要调查是否有异位骨化、骨折、血肿、感染或血栓形成。●夹板疗法。夜间休息夹板固定或可拆卸双壳铸模(bivalve casting)能够预防上肢屈曲挛缩和踝关节跖屈挛缩。必须根据皮肤和疼痛耐受度调整夹板的合适度和使用时间。这些干预措施的目的是诱导易损肌肉长时间的肌肉伸展；但尚未证实其预防挛缩的疗效[108]。确定的挛缩可能需要手术治疗。某些挛缩可以促进功能。C6水平的脊髓损伤患者可能会通过手指屈曲挛缩增强腕关节伸展的抓握能力，而获得改善的功能性手肌腱固定。轻微的肘屈曲挛缩可以改善已经变弱的二头肌的力学优势。脊髓损伤患者上肢常出现反复性过度使用性损伤，这与患者移动和使用轮椅相关。肩袖及其他肌腱损伤、腕管综合征、滑囊炎和骨关节炎是常见后遗症[109-111]。肩部最常受累(75%)，其次是腕、手和肘(分别为53%、43%和35%)。尽量减轻损伤和保护关节功能的特定运动方案会有帮助，使用电动轮椅和人体工程学评估也有帮助[112]。(参见“关节保护的概述”)压疮—骨突处通常会出现未予缓解的压力，引起组织损伤，导致压疮。剪切力、摩擦、营养不良和病变水平以下的皮肤生理学改变也能促进压疮的发生[23]。难以获得慢性脊髓损伤患者的压疮患病率，但据估计，脊髓损伤后20年的患病率约为30%[23,113]。脊髓损伤的水平和严重程度对压疮的发生风险均有显著影响。超过1/3的患者有多发压疮[21]。脊髓损伤患者中压疮的最常见部位有[23]：●坐骨–31%●转子–26%●骶骨–18%●足跟–5%●踝–4%●足–2%预防策略包括：●每日检查最易形成压疮部位的皮肤●在易感部位每日涂抹润肤剂来减轻摩擦●教上半身有力量的患者整天“缓解受压部位的压力”●避免易感部位不活动及过度潮湿●使用能减轻压力的轮椅、靠垫及其他设备●维持充足的营养摄入和体重综合治疗包括健康状况和溃疡状态的评估。溃疡治疗计划包括清洁、清创、营养支持和处理组织负荷。压疮的预防和治疗详见其他专题。(参见“压力性皮肤及软组织损伤的预防”和“Clinical staging and management of pressure-induced skin and soft tissue injury”)痉挛状态—痉挛状态是指速度依赖性的肌张力增加。体格检查时，快速被动活动肢体可引出该表现[114]。痉挛状态是由于α运动神经元的下行抑制性调节破坏，从而产生过度兴奋，表现为肌张力增加和痉挛[115,116]。痉挛状态的负面影响包括疼痛、活动性下降、挛缩和肌肉痉挛，这些均能干扰睡眠和日常生活活动[117]。同时，痉挛状态也有一些正面影响：肌张力增加可促进某些功能活动，包括站立和转移。肌张力增加还可能促进静脉回流，从而尽量减少深静脉血栓形成和直立性低血压。难以消除痉挛状态，并且消除痉挛状态并不一定是令人如意的[116]。当痉挛状态与功能障碍有关时，治疗应以尽量减少痉挛状态为目标，并且应遵循分级方法，以侵入性最小的方法开始治疗。非药物治疗包括物理疗法。定期伸展和使用支具均有助于维持活动度并预防挛缩，但研究并未明确显示这对重要临床结局有益[116,117]。(参见上文‘肌肉骨骼并发症’)若痉挛状态加重，应尽量查明原因并予以治疗。这类患者痉挛状态加重的原因包括感染、疼痛和神经系统病变(如脊髓空洞症)。(参见下文‘神经功能恶化’)口服药物—虽然经常针对痉挛状态开具口服药物，但并无关于常用口服药物疗效的实质证据；副作用通常为剂量限制性，且尚未确定这些治疗的相对益处[117,118]。所有药物均可缓慢逐渐增加剂量来减轻不良反应，包括镇静、口干、头晕和无力。这些药物的给药指南和不良反应总结于表中(表 1)。●巴氯芬是一种γ-氨基丁酸(γ-aminobutyric acid, GABA)-B受体激动剂，是最常用于治疗痉挛状态的口服药物，不过疗效缺乏循证支持[118-120]。虽然镇静和无力可为剂量限制性不良反应，但长期使用巴氯芬安全，且没有证据显示其产生耐受性[116]。巴氯芬不能突然停药，否则可能引起戒断症状。(参见“神经阻滞剂恶性综合征”，关于‘其他药物相关综合征’一节)●替扎尼定是一种作用于中枢的α-2肾上腺素能受体激动剂，一项治疗脊髓损伤患者痉挛状态的大型研究对比了该药与安慰剂[121]。在78例(来自124例随机患者)完成了此项研究的患者中，结果发现使用替扎尼定显著减少了痉挛状态，但对日常生活活动及其他功能评价无影响。镇静是最常见的限制性副作用[122]。●地西泮是一种GABA-A受体激动剂，它是治疗痉挛状态最常用的苯二氮卓类药物，常与巴氯芬或替扎尼定联用[115,123]。镇静、意识模糊、低血压和胃肠道症状均可为剂量限制性。地西泮或氯硝西泮可能对控制夜间痉挛特别有用。苯二氮卓类不能与阿片类合用，否则会增加阿片类药物过量的风险[124]。●丹曲林钠不同于其他讨论的药物，因为其在外周起效，抑制肌肉的肌质网释放钙[116]。相比使用的其他药物，丹曲林钠更容易使受累和未受累肌肉均出现无力[120]。由于丹曲林钠可能存在肝脏毒性，需要每3-6个月监测1次肝功能[115]。●较少用于治疗痉挛状态的药物包括可乐定、加巴喷丁、大麻类物质和赛庚啶，这些药物的益处还不太确定(表 1)[115-117,125-128]。鞘内给予巴氯芬—巴氯芬具有中枢作用，但不能有效穿过血脑屏障，从而限制了其口服生物利用度。鞘内给予口服剂量1%的巴氯芬就能使输送至脊髓的巴氯芬量达到口服的4倍[19,116]。通过外科手术植入计算机程序化控制的输注泵给药，该泵有导管伸入鞘内间隙。患者在植入输注泵之前一般会接受鞘内巴氯芬输注试验。虽然鞘内给予巴氯芬通常能避免全身性副作用，但并发症可能包括脑脊液漏、出血、感染、导管移位和泵故障；不过，大多数患者一般能良好耐受输注泵，尤其是患者和/或其照料者保持警惕时。两项双盲交叉研究比较了脊髓损伤后患者进行鞘内巴氯芬输注与盐水安慰剂输注[129,130]。结果显示接受鞘内巴氯芬治疗的患者痉挛状态减少和失能改善。这种方法也可能减轻痉挛状态相关的疼痛[131]。注射技术—化学去神经法能局部治疗肌肉或肌肉群内的痉挛状态。虽然避免了药物治疗相关的全身性副作用，但脊髓损伤中大量肌肉受累限制了该方法应用于这类患者。但在一些患者中，定向缓解某些肌群的痉挛状态可以改善走动能力及其他特异性功能。注射药物包括肉毒毒素、苯酚和乙醇。肉毒毒素作用于神经肌肉接头，防止了乙酰胆碱的释放。治疗在数日内起效，4-6周达到最佳效果，并持续数月；患者需要重复注射以维持疗效[117]。副作用包括肌无力和注射部位反应，但总的来说这种治疗安全且有效[132]。一项随机研究比较了肉毒毒素注射与替扎尼定治疗脑卒中或创伤性脑损伤后上肢痉挛状态的情况[122]。相比于替扎尼定，肉毒毒素治疗能更有效地降低张力，并且不良反应更少。美国FDA现已批准使用肉毒毒素治疗上肢和下肢痉挛状态。苯酚和乙醇神经阻滞的本质是在上运动神经元缺陷上叠加一种下运动神经元病变[115,116]。该操作可成问题的并发症可包括无力、注射部位疼痛、静脉炎、永久性神经损害和感觉倒错。手术—手术破坏性操作只应用于难治性病例，操作如脊神经根切断术、脊髓切开术、脊髓索切断术和脊髓切除术[19]。肌肉或肌腱松解手术可用于治疗确定的挛缩。疼痛综合征—很多患者会在脊髓损伤后数月至数年出现慢性疼痛综合征。报道的患病率差异很大。平均而言，2/3的患者有慢性疼痛，1/4-1/3的患者有明显影响生活质量的重度疼痛[120,133]。脊髓损伤后的神经源性疼痛可为自发性和刺激诱发性，定位往往不准，患者常述为烧灼痛、刺痛或电击痛。感觉过敏较常见。这些特点有助于区分神经源性疼痛与肌肉骨骼疼痛，后者常为钝痛且定位准确，可由脊髓损伤患者共有的许多并发症所致。(参见上文‘肌肉骨骼并发症’)虽然神经源性疼痛似乎与神经元过度兴奋相关，但对其机制知之甚少。神经源性疼痛综合征有两种类型：损伤水平疼痛(即，脊髓损伤水平节段的疼痛)和损伤水平下疼痛。认为两类疼痛的神经解剖学和病理生理学基础不同，神经根和背侧灰质损害导致损伤水平疼痛，而脊髓丘脑束损害和/或丘脑传入神经阻滞导致损伤水平下疼痛[134]。出现损伤水平疼痛时，应评估有无创伤后脊髓空洞症，其与损伤水平疼痛相关。(参见下文‘脊髓空洞症’)药物治疗效果通常不满意；可尝试使用抗抑郁药、抗癫痫药和标准镇痛药，且常常联用：●抗癫痫药能抑制异常的神经元过度兴奋，从而改善神经病理性疼痛。两项对脊髓损伤后疼痛患者进行的关于普瑞巴林(150-600mg/d)的随机研究发现，盲法评估的疼痛评分、睡眠障碍、焦虑和抑郁均有所改善[135,136]。其他随机试验研究了脊髓损伤患者使用拉莫三嗪、加巴喷丁和丙戊酸盐的作用，但疗效证据不一致[137-140]。●抗抑郁药也用于多种中枢和外周神经病理性疼痛综合征。关于曲唑酮和阿米替林治疗脊髓损伤的随机试验未证实其疗效[140-142]。●医用大麻对神经病理性疼痛有一定效果[143]。●一项小型随机研究纳入40例脊髓损伤后出现神经病理性疼痛的患者，发现向疼痛区域注射A型肉毒毒素有效[144]。●在个案报道中，阿片类可缓解病情，但应重点考虑到副作用、耐受性、依赖性和过量问题[145]。不应长期使用阿片类药物，除非已用尽其他所有方法，包括药物、手法、手术和介入治疗。未经治疗的睡眠呼吸暂停、精神疾病和多种物质滥用患者尤其不应使用阿片类，正在使用苯二氮卓类的患者因有过量风险也不应使用阿片类[146]。舒缓医疗有助于监测使用阿片类药物的患者。我们有理由认为非口服给药途径的疗效更好且副作用更少；但对于脊髓损伤，这些疗法的支持证据稍有限。治疗包括鞘内给予吗啡、可乐定和巴氯芬[147,148]。目前已有侵入性治疗方法的尝试，包括深部脑刺激、运动皮质刺激、脊髓切断术和脊髓背根入髓区损毁术，但同样无成功的实质性证据[120,149,150]。没有较好治疗的情况下也可以考虑非传统疗法，例如针刺治疗、生物反馈和认知行为治疗，不过尚无疗效证据[19,150]。慢性疼痛管理的给药方案、副作用和其他方面内容详见其他专题。神经功能恶化脊髓空洞症—迟发的进展性髓内囊性变性并发于3%-4%的创伤性脊髓损伤及其他急性脊髓病。从脊髓损伤至发病的间隔时间差异很大，可从数月至多年[151]。假设的机制包括瘢痕形成伴脑脊液流动受阻和组织顺应性改变，从而导致中央管扩张及周围脊髓组织受压[152]。症状与进展性脊髓病一致，包括逐渐恶化的运动、感觉、肠道及膀胱功能障碍和疼痛[151]。蛛网膜炎、脊髓压迫和/或椎管狭窄，以及骨畸形(尤其是脊柱后凸)似乎是囊肿进展性扩大和神经功能恶化的危险因素[153-156]。无症状的空洞是脊髓损伤患者神经影像学的常见偶然发现。该病通常预后良好，很可能代表局灶性脊髓组织液化性坏死区域。治疗旨在降低扩张性囊内压和改善脑脊液流动[151]。手术方法包括植入分流器、蛛网膜下粘连松解术、囊肿开窗术和硬膜增补术。个案报道中，当有显著骨畸形和椎管受压并伴有脑脊液循环受限时，硬膜外减压有一定作用[157,158]。不幸的是，有长期治疗获益的患者不到一半，并且常见分流失败[158,159]。与运动症状相比，疼痛对干预措施可能更有治疗反应[160,161]。创伤后进展性脊髓软化脊髓病—创伤后进展性脊髓软化脊髓病是一种不太常见的脊髓损伤并发症，其病理特征为微囊、反应性神经胶质增生和脊膜增厚。粘连和脊髓栓系似乎与之有因果关系；手术解除栓系和扩大蛛网膜下腔的硬膜成形术可以改善临床表现[151,162]。精神并发症—与脊髓损伤相关的心理社会并发症包括抑郁、自杀、药物成瘾及离婚[6,9]。创伤性脊髓损伤后20%-45%的患者发生抑郁[9,163]。这种症状通常出现于早期(脊髓损伤后的第1个月内)，并且与损伤的严重程度并无紧密联系。脊髓损伤患者的自杀率为年龄匹配人群样本的4-5倍[6,164]。对于年龄小于55岁的创伤性脊髓损伤患者，自杀是死亡的主要原因；75%的自杀发生于损伤后的最初5年内[9]。据观察，在创伤性脊髓损伤后与横贯性脊髓炎后的抑郁和自杀发生率相近[165]。由于抑郁患病率高且后果严重，所以应定期筛查脊髓损伤患者有无抑郁症状。高程度的疼痛和缺乏社会支持与患者具有抑郁和自杀高风险相符[163]。抑郁的筛查工具详见其他专题。(参见“成人抑郁筛查”，关于‘筛查工具’一节)应当对脊髓损伤后的抑郁和焦虑予以治疗；不应假定这些症状是对该情况的“正常”反应且不需要治疗[9]。推荐的干预措施包括心理咨询、药物干预和同伴支持团队。盐酸文拉法辛是一种5-羟色胺-去甲肾上腺素再摄取抑制剂，一项关于脊髓损伤患者的研究显示，其缓释剂能有效治疗重性抑郁且耐受性良好[166]。抑郁的诊断和治疗详见其他专题。(参见“成人单相抑郁的评估和诊断”和“成人单相重性抑郁：初始治疗的选择”)体温调节功能障碍—脊髓损伤后自主神经通路的破坏可导致无感觉皮肤区域的血管舒缩反应和促汗反应受损，对特定核心温度的体温调节效应器应答降低，以及瘫痪肢体骨骼肌肉泵活动丧失[167]。其后果包括运动或高温环境时体温过高，以及低温环境时体温过低。感染时可出现发热反应减弱或低温反应。其他人还注意到在无感染或无环境温度变化时，脊髓损伤患者出现体温过高或体温过低发作。功能缺陷—脊髓损伤的水平及完全性是功能能力需求、目标和预期的主要决定因素。年龄、一般健康状况、体型、并发损伤、脊柱固定装置、智力和积极性也会影响恢复[168]。在急症医疗环境下，只要脊髓损伤患者的医学情况稳定，就应开始通过活动度训练和抗阻运动、直立/直坐体位及转移性运动进行功能恢复。在住院康复环境下，具有脊髓损伤康复方面经验的理疗师和作业治疗师会制定个体化方案，这种方案强调强化、关节保护和补偿策略，并联合创造性地使用辅助装置和设备以最大限度地恢复功能。尚无研究提示哪种治疗方法更有效，尽管技术在不断发展进步，但最简单的传统方法往往效果最好[169,170]。基于运动水平的功能恢复一般预期见表(表 2)[171]。这些是假定对无并发症的完全性脊髓损伤后健康且积极的个体进行的适当康复干预的情况。预立医疗自主计划—脊髓损伤后，患者期望寿命缩短。因此，推荐患者的初级保健医护人员探讨治疗目标、优选的代理决策者以及心肺复苏(cardiopulmonary resuscitation, CPR)和维持生命治疗的偏好。这些内容应定期重新讨论，尤其是在急性疾病发作和/或患者住院后。病历中应详细记录患者的选择，应让相关医护人员知晓，并视作指令。应尽量鼓励患者制定预立医疗指示和维持生命治疗医嘱(provider orders for life-sustaining treatment, POLSTs)。(参见“Advance care planning and advance directives”)舒缓医疗—由于脊髓损伤患者及其家属有较高的情绪、躯体和社会负担，如果患者有躯体症状、情绪痛苦或社交需求且通过现有医疗资源无法处理，医护人员最好提供舒缓医疗咨询服务。脊髓损伤患者可通过舒缓医疗获得更多支持，服务人员包括擅长处理症状和痛苦的临床医生，以及可帮助患者和照料者安排家庭服务和指导财务问题的社会工作者。舒缓医疗一般通过咨询服务在医院或在家实施，大型卫生系统常可在门诊给予舒缓医疗。(参见“舒缓治疗亚专科的获益、服务与模式”)临终关怀—对于不愿因脊髓损伤终末期并发症返回医院的患者，临终关怀能提供额外支持。临终关怀包含多学科团队，可以前往患者家中或长期护理机构评估和处理躯体/情绪症状，辅助制定预立医疗自主计划，帮助照料者。他们也为患者和照料者提供全天候电话支持，提供医疗用品(如氧气、病床)，还能送药上门。出现下列情况的脊髓损伤患者适合接受临终关怀[172]：●脊髓损伤并发症相关的急诊科就诊、住院或门诊增多。●治疗不再有效的脊髓损伤并发症，如反复严重感染或3-4期褥疮。●危及生命的脊髓损伤并发症，并且患者表明不接受现有治疗选择，例如发生终末期肾病(end-stage renal disease, ESRD)但拒绝透析时，或者发生通气不足但拒绝通气支持时。●进行性营养不足，例如尽管予以管饲但最近6个月体重减轻>10%、白蛋白<2.5g/dL。如果不确定患者是否适合临终关怀，可以通过所选临终关怀机构安排上门信息访问。在“临终关怀预选评估(Hospice Pre-Election Evaluation)”中，临终关怀代表将审查患者及照料者可选的服务，并确认患者的临终关怀资格。患者教育—UpToDate提供两种类型的患者教育资料：“基础篇”和“高级篇”。基础篇通俗易懂，相当于5-6年级阅读水平(美国)，可以解答关于某种疾病患者可能想了解的4-5个关键问题；基础篇更适合想了解疾病概况且喜欢阅读简短易读资料的患者。高级篇篇幅较长，内容更深入详尽；相当于10-12年级阅读水平(美国)，适合想深入了解并且能接受一些医学术语的患者。以下是与此专题相关的患者教育资料。我们建议您以打印或电子邮件的方式给予患者。(您也可以通过检索“患者教育”和关键词找到更多相关专题内容。)●基础篇(参见“患者教育：成人神经源性膀胱(基础篇)”和“患者教育：截瘫和四肢瘫(基础篇)”)总结与推荐—脊髓损伤(SCI)后的医疗并发症常见且严重，导致再住院率较高和期望寿命缩短。(参见上文‘期望寿命’)●T6以上的脊髓损伤可并发自主神经反射异常。这是一种过度交感神经反应，特征为头痛、出汗和血压升高，发生于伤害性刺激时，例如膀胱膨胀所致疼痛、便秘或压疮。(参见上文‘自主神经反射异常’)●脊髓损伤患者的冠状动脉疾病(CAD)发病率也会增加。血流动力学不稳定和心律失常是急性和亚急性脊髓损伤中的问题，但在慢性脊髓损伤中较少见。(参见上文‘心血管并发症’)●通气衰竭的严重程度和是否需要辅助通气取决于脊髓损伤的水平和严重程度。较轻程度的通气衰竭可能引起呼吸困难和运动不耐受。(参见“脊髓损伤后的呼吸系统生理改变”和“慢性脊髓损伤的呼吸系统并发症”，关于‘呼吸功能不全’一节)●肺炎风险增加在脊髓损伤后第1年最明显，但患者一生中的肺炎风险均会增加。(参见“慢性脊髓损伤的呼吸系统并发症”，关于‘肺部感染’一节)●在脊髓损伤后，应持续预防性使用低分子量肝素至少3个月来预防深静脉血栓形成和肺栓塞，之后的风险似乎接近于一般人群。(参见“成人非骨科手术患者中静脉血栓栓塞症的预防”)●脊髓损伤会引起膀胱功能障碍，通常称为神经源性膀胱，还可导致其他并发症，包括感染、膀胱输尿管反流、肾衰竭和肾结石。初始治疗常用清洁间歇性导尿术(CIC)，并根据需要辅以药物治疗。有些患者需要长期留置导尿管。肉毒毒素和骶神经调节器可用于替代传统的药物治疗。(参见上文‘泌尿系统并发症’)●脊髓损伤后的性功能障碍可包括性欲减退、阳痿和不育。磷酸二酯酶-5抑制剂可有效治疗勃起功能障碍。(参见上文‘性功能障碍’)●脊髓损伤后的排便障碍通常需要采用排便方案和多维度方法。含有足够纤维的规律饮食是治疗的重要内容。(参见上文‘胃肠道并发症’)●骨质疏松会累及脊髓损伤水平以下的骨骼并增加骨折风险。目前正在研究双膦酸盐治疗该病的作用。(参见上文‘骨代谢’)●体位摆放和活动有助于改善脊髓损伤后的挛缩和压疮。(参见上文‘肌肉骨骼并发症’和‘压疮’)●脊髓损伤后常见痉挛状态，而痉挛状态具有正面和负面影响。治疗为经验性治疗，旨在最大限度地减少疼痛，同时使功能最大化。治疗选择包括口服药物、鞘内给予巴氯芬、肉毒毒素和神经阻滞。难治性痉挛状态可能需要外科手术。(参见上文‘痉挛状态’)●脊髓损伤后的神经源性疼痛通常很难治疗，但标准镇痛治疗、抗癫痫药治疗和/或抗抑郁治疗可能有效。不应长期使用阿片类药物。(参见上文‘疼痛综合征’)●脊髓损伤常并发抑郁；患者自杀风险很高，应接受监测。(参见上文‘精神并发症’)●神经功能障碍取决于脊髓损伤的水平和完全性，通过适当的康复干预措施能得以改善。如果患者出现神经功能减退，则需行神经影像学检查以排除脊髓空洞症、创伤后脊髓软化性脊髓病或其他神经病变。(参见上文‘功能缺陷’和‘神经功能恶化’)参考文献National 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Fibrodysplasia ossificans progressiva进行性骨化性纤维发育不良 （Fibrodysplasia ossificans progressiva）Author:John E Tis, MDSection Editor:William A Phillips, MDDeputy Editor:Mary M Torchia, MDContributor DisclosuresLiterature review current through:Jul 2020.|This topic last updated:Aug 14, 2019.Topic Outline·SUMMARY AND RECOMMENDATIONS·INTRODUCTION·EPIDEMIOLOGY·PATHOGENESIS·CLINICAL FEATURES·LABORATORY FEATURES·RADIOGRAPHIC FINDINGS·DIAGNOSIS·DIFFERENTIAL DIAGNOSIS·MANAGEMENT·Prevention of flare-ups·Avoid biopsies, surgery, and trauma·Prevention of falls·Prevention of viral illnesses·Immunizations·Glucocorticoid prophylaxis·Symptomatic management of early lesions·Preventive dental care·Hearing evaluation·Respiratory health·PROGNOSIS·SUMMARY AND RECOMMENDATIONS·REFERENCEINTRODUCTION—Fibrodysplasia ossificans progressiva (FOP; MIM #135100; also called myositis ossificans progressiva or "stone man disease") is a rare connective tissue disorder characterized by severe, progressive heterotopic ossification of soft tissues that spans joints and results in an ectopic skeleton [1]. It severely decreases mobility and causes significant disability with no effective treatment.The clinical features and treatment of FOP will be reviewed here. Heterotopic ossification as a complication of surgery or trauma is discussed separately. (See "Complications of total hip arthroplasty", section on 'Heterotopic ossification'and "Surgical management of severe lower extremity injury", section on 'Heterotopic ossification'and "Surgical management of severe lower extremity injury".)EPIDEMIOLOGY—The prevalence is approximately 1 in 2 million with no sex, racial, ethnic, or geographic predisposition [1]. There are no known risk factors.PATHOGENESIS—FOP is caused by mutations in the ACVR1/ALK2gene on chromosome 2q24, which encodes activin A receptor type I/activin-like kinase 2, a bone morphogenetic protein type I receptor [2]. Most cases are sporadic, but autosomal dominant germline transmission has been reported in a small number of cases.CLINICAL FEATURES—Patients with FOP generally appear normal at birth except for bilateral malformation of the great toes, which are characteristically short and laterally deviated (hallux valgus); the first metatarsals are malformed and the first toes have an absent or fused interphalangeal joint [1] (picture 1).Variable clinical features of FOP include short, malformed thumbs (in approximately 50 percent), clinodactyly, neck stiffness, and hearing loss (in approximately 50 percent) [3,4].Sporadic, painful episodes of rapidly progressive soft tissue swelling ("flare-ups") typically begin during the first decade of life [4-7]. These usually present as nodules on the head or back and occur at a median age of 1.5 years, although 10 percent of patients present with nodules in the neonatal period [8]. The soft tissue swellings may resolve but more often transform skeletal muscles, tendons, ligaments, fascia, and aponeuroses into ribbons, sheets, or plates of heterotopic bone [9]. Flare-ups may be precipitated by soft tissue injury, intramuscular injection, surgical incisions, falls, muscular stretching, or viral illness [10]. They typically begin in the head, neck, and shoulders and progress from cranial to caudal, dorsal to ventral, axial to appendicular, and proximal to distal [4]. The diaphragm, tongue, extraocular muscles, cardiac muscles, and smooth muscles are spared.FOP lesions go through predictable stages. Pain, erythema, tenderness, swelling, and warmth are present in the first few weeks. During the intermediate stage, induration increases but pain and erythema improve. During the late stage (after 12 weeks), the nodule hardens with radiographic ossification, but the swelling resolves [11]. In a survey of 44 patients with FOP, the average age of onset of heterotopic ossification was 5 years, restrictive ossification was present in 80 percent of patients by age 7, and 95 percent of patients had severely restricted motion in the upper extremity by age 15 [12].The heterotopic bone eventually extends across joints, resulting in progressive and irreversible immobility, weight loss (secondary to ankylosis of the jaw), and thoracic insufficiency syndrome (image 1). Patients are dependent upon diaphragmatic breathing because the diaphragm is spared. Most patients die of respiratory depression or pneumonia. Starvation (related to ankylosis of the jaw) used to be a common cause of death, but modern feeding tubes have made starvation a less common cause of death. (See 'Prognosis'below.)LABORATORY FEATURES—Biochemical studies (eg, serum alkaline phosphatase, parathyroid hormone level, renal function, urinary calcium, and phosphate) are usually normal [13]. Alkaline phosphatase is elevated in some patients during new episodes of heterotopic ossification formation [14].RADIOGRAPHIC FINDINGS—Characteristic radiographic features of FOP include joint malformations, particularly of the great toe (eg, bilateral hallux valgus deformity, malformed first metatarsal, absent or fused interphalangeal joint), and soft tissue ossification [3]. Preosseous lesions and early heterotopic ossification are visible on bone scan, computed tomography, or magnetic resonance imaging before radiographs [13,15].Variable radiographic features of FOP include proximal medial tibial osteochondromas (approximately 90 percent); orthotopic fusions of the posterior elements of the cervical spine (approximately 80 percent); broad, short femoral necks (approximately 50 percent); and malformations of the thumbs (approximately 50 percent) [1,3].DIAGNOSIS—FOP is a clinical diagnosis that is confirmed with molecular genetics. FOP should be suspected in children with hallux valgus, progressive soft tissue swelling, and nodules on the head or back. Biopsy of the soft tissue lesions may precipitate a flare-up and should be avoided [10,16].Definitive diagnosis requires genetic confirmation with specific molecular genetic studies that detect missense mutations or "in frame" deletions in the protein-encoding region of the ACVR1gene [3,8,17]. Consultation with a clinical geneticist is recommended before genetic testing [16].DIFFERENTIAL DIAGNOSIS—The differential diagnosis of FOP includes other conditions associated with malformed great toes, soft tissue swelling, or heterotopic ossification. The combination of these three findings generally distinguishes FOP from these conditions.●Other conditions with malformed great toes– Other conditions associated with malformed great toes include isolated congenital malformations, brachydactyly, synostosis and symphalangism syndromes (ie, fusion of bones and joints of the fingers or toes), and juvenile bunions [3,18]. In contrast to these conditions, children with FOP often have other skeletal malformations (eg, malformations of the thumb, cervical spine abnormalities, osteochondromas of the proximal medial tibia), rapidly progressive soft tissue swelling, and heterotopic ossification [3]. Juvenile bunions are not present in the neonatal period, whereas the hallux valgus deformity in FOP is present at birth.●Other conditions with femoral or tibial osteochondromas– Distal femoral and proximal tibial osteochondromas also may occur in patients with hereditary multiple osteochondromas [19]. However, patients with hereditary multiple osteochondromas do not typically have malformed great toes or episodic flare-ups. (See "Nonmalignant bone lesions in children and adolescents", section on 'Osteochondroma and hereditary multiple osteochondromas'.)●Other conditions with heterotopic ossification– Heterotopic ossification also may occur in children with progressive osseous heteroplasia (POH; MIM #166350), a rare genetic condition characterized by cutaneous ossification that progresses to involve subcutaneous and deep connective tissues [1]. POH is distinguished from FOP by the sites of ossification and lack of great toe malformation and "flare-ups." Although acquired heterotopic ossification also occurs at sites of trauma, it is rare in young children and not usually associated with great toe malformation or flare-ups.●Other conditions with rapidly progressive soft tissue lesions– Rapidly progressive soft tissue lesions may raise concern for neoplasms and other tumors (eg, soft tissue sarcoma, osteosarcoma, aggressive juvenile fibromatosis [extra-abdominal desmoid tumors]) or lymphedema [3,19]. However, the sudden onset and rapid change in size and shape (often within hours) of soft tissue lesions associated with FOP is not characteristic of these conditions. Evaluation of the great toes and consideration of FOP should be considered before biopsy is performed. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Clinical presentation'and "Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and histology", section on 'Clinical presentation'and "Desmoid tumors: Epidemiology, risk factors, molecular pathogenesis, clinical presentation, diagnosis, and local therapy", section on 'Clinical presentation and diagnosis'.)MANAGEMENT—There is no medical or surgical treatment to prevent or reverse the ossification associated with FOP. Instead, management of FOP is supportive and focuses on prevention of flare-ups, patient and family education and counseling, and improved quality of life.Children with FOP should be managed in consultation with an expert in FOP. Consensus guidelines from the International Clinical Council on FOP (ICC) and consultants for the medical management of FOP are available on the International Fibrodysplasia Ossificans Progressiva Association website[16].Prevention of flare-upsAvoid biopsies, surgery, and trauma—Biopsies and removal of lesions are contraindicated because they precipitate aggressive ossific reaction in the soft tissues. Similarly, correction of fixed deformities often leads to further ossification and loss of motion [4].Attempts at resecting the ankylosis across the jaw have been unsuccessful and are not recommended [20,21]. Scoliosis is usually not addressed surgically because spinal fusion, especially posterior fusion, in younger patients generally results in worsening of the curve [22]. However, rapidly progressive lumbar curves in children younger than five years of age may warrant anterior, with or without posterior, surgical treatment to prevent progression [23].FOP patients have increased anesthetic risks due to restrictive lung disease, fused cervical vertebrae, restricted oral access, and abnormal cardiac conduction. Considerations for general anesthesia in patients with FOP are provided in the ICC guidelines[16].Prevention of falls—Falls may lead to injury and painful flare-ups. In a survey of 135 patients with FOP, 81 percent reported an injury related to a fall; two-thirds of falls led to painful flare-ups and one-half of falls led to permanent disability [24]. Strategies to prevent falls include limiting high-risk activities, installing handholds and other safety measures in living spaces, and the use of headgear [16].Prevention of viral illnesses—Viral illnesses can cause flare-ups of FOP [25]. Strategies to prevent viral illness include frequent washing of the hands with soap and water or an alcohol-based hand sanitizer; not touching the eyes, nose, or mouth with hands unless the hands are washed; and limiting contact with people who are sick [16,26]. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Hand hygiene'.)Immunizations●Influenza vaccine– Influenza infections may trigger flare-ups of FOP [25]. The ICC suggests annual influenza vaccination for patients with FOP, with specific caveats [16]:The live attenuated influenza vaccine(LAIV) is not recommended because it may precipitate a flare-up.The inactivated influenza vaccine(IIV) should be administered according to a modified protocol in which it is administered subcutaneously rather than intramuscularly.Influenza vaccine should notbe administered during a flare-up or within six to eight weeks of a flare-up.Influenza vaccine should notbe administered near a joint or muscle group that has been affected by FOP.Close contacts of patients with FOP also should receive annual influenza immunization. The ICC recommends that close contacts of patients with FOP receive IIV rather than LAIV [16].●Other vaccines– Recommendations for other vaccines are individualized according to the potential benefits and harms for the particular vaccine in a particular patient. Factors to be considered include the risk of precipitating a flare-up, the risk of exposure to a vaccine-preventable disease, and the number of doses of vaccines received before the child was diagnosed with FOP. Detailed recommendations are provided in the ICC guidelines[16]. In general:Vaccines should notbe administered during a flare-up or within six to eight weeks of a flare-up.Vaccines should notbe administered near a joint or muscle group that has been affected by FOP.Diphtheria- or tetanus-toxoid containing vaccines (eg, the combination diphtheria, tetanus, and acellular pertussis vaccine) may cause flare-ups, heterotopic ossification, and permanent loss of joint motion [16,27]. They should be avoided in children with FOP unless indicated to prevent life-threatening illness [16].Flare-ups also may be caused by vaccines that contain components of diphtheria and tetanus as protein conjugates (eg, Haemophilus influenzaetype b [Hib] vaccine; meningococcal serogroups A, C, W, and Y vaccine; pneumococcal conjugate vaccine; combination Hib and meningococcal serogroup C vaccine). The safety of these vaccines for patients with FOP is uncertain.Intramuscular (IM) injections are contraindicatedbecause they precipitate flare-ups.Whether vaccines that are typically administered IM are effective when administered subcutaneously is uncertain. There is some evidence to effectiveness for hepatitis A and B vaccines when administered subcutaneously [28,29], but evidence for other vaccines that are typically administered IM (eg, human papillomavirus vaccine, meningococcal serogroup B vaccine) is lacking.Subcutaneous administration is routinely recommended for the following vaccines, which are generally considered safe for patients with FOP: measles, mumps, and rubella (MMR) vaccine; the varicella vaccine; the combination MMR and varicella vaccine; and inactivated poliovirus vaccine[16,30].Glucocorticoid prophylaxis—A short course of glucocorticoids may be warranted to prevent flare-ups within 24 hours of severe soft tissue trauma or emergency, elective, major, or minor surgery (eg, appendectomy, dental surgery) [16]. The ICC suggests prednisone1 to 2 mg/kg orally once or twice per day (maximum daily dose 100 mg) for three to four days [16]. Equivalent doses of other oral glucocorticoids may be administered. Although glucocorticoid prophylaxis has not been studied systematically in patients with FOP, inflammation plays in important role in the development of FOP flare-ups [31,32].Symptomatic management of early lesions—A short course of glucocorticoids may be warranted for the early symptomatic management of flare-ups affecting the jaw, submandibular area, or major joints (eg, hip); consultation with an expert in FOP is recommended for patients with submandibular flare-ups. The ICC suggests prednisone1 to 2 mg/kg orally once or twice per day (maximum daily dose 100 mg) for three to four days [16]. Equivalent doses of other oral glucocorticoids may be administered.When administered within the first 24 hours of a flare-up, a short course of glucocorticoids may reduce inflammation and tissue edema and prevent flare-ups. Glucocorticoids usually are not used in the symptomatic management of the neck or trunk because these flare-ups are typically prolonged and recurrent.After discontinuation of the glucocorticoid, or if glucocorticoids are not used, topical or systemic nonsteroidal anti-inflammatory medication (eg, ibuprofen) may be used for symptomatic management during the remainder of the flare-up. Local application of cool packs also may be helpful.The use of glucocorticoids in the symptomatic management of FOP flare-ups is based upon the importance of inflammation in FOP flare-ups [31,32]. In a survey, 75 percent of 500 patients used short-term glucocorticoids for flare-ups of the limbs; among these, 31 percent reported that glucocorticoids always improved symptoms, and 55 percent reported that they occasionally did; 12 percent reported that they had complete resolution of a flare-up with glucocorticoids [9].Use of ibuprofen(or other prostaglandin inhibitors) may prevent heterotopic ossification because inflammatory prostaglandins are thought to stimulate induction of heterotopic bone [33-35].Preventive dental care—Preventive dental care is a crucial component of the management of FOP and should begin as soon as possible. Preventive dental care is discussed separately. (See "Preventive dental care and counseling for infants and young children".)Consultation with a dental professional with expertise in FOP is recommended before any dental procedure [16]. Injections of local anesthetic for dental procedures should be avoided [36].Hearing evaluation—Children with FOP are at increased risk for conductive hearing loss. They should undergo evaluation for hearing impairment with audiometry at least every other year [16]. (See "Hearing loss in children: Screening and evaluation", section on 'Formal audiology'.)Respiratory health—Chest deformity and scoliosis in patients with FOP may decrease respiratory capacity. Respiratory health can be maintained in patients with FOP through active respiratory activity (eg, singing, incentive spirometry, peak flow whistles) [16].PROGNOSIS—Most patients require a wheelchair by age 20 years [1]. Alternative feeding methods (eg, feeding tubes, gastrostomy tubes) have prolonged the life span of patients with ankylosis of the jaw. In a review of information from two large registries, the median lifespan was approximately 40 years; the most common causes of death were thoracic insufficiency (54 percent) and pneumonia (15 percent) [37].SUMMARY AND RECOMMENDATIONS●Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a rare connective tissue disorder caused by mutations in the ACVR1/ALK2gene, which encodes a bone morphogenetic protein receptor. Most cases are sporadic. (See 'Epidemiology'above and 'Pathogenesis'above.)●Characteristic clinical features include bilateral malformation of the great toes at birth (they are short and laterally deviated [ie, hallux valgus]) (picture 1);sporadic, painful episodes of rapidly progressive soft-tissue swelling ("flare-ups"); and heterotopic ossification that eventually spans joints, resulting in progressive and irreversible immobility, weight loss, and thoracic insufficiency syndrome. (See 'Clinical features'above.)●Flare-ups usually begin in the first decade of life, presenting as nodules on the head or back. They can be precipitated by soft tissue injury, intramuscular (IM) injection, surgical incision, falls, muscular stretching, or viral illness. (See 'Clinical features'above.)●FOP should be suspected in children with hallux valgus, progressive soft tissue swelling, and nodules on the head or back. Definitive diagnosis requires molecular genetic studies that detect missense mutations or "in frame" deletions in the protein-encoding region of the ACVR1gene. Biopsy of soft tissue lesions may precipitate a flare-up and should be avoided. (See 'Diagnosis'above.)●The differential diagnosis of FOP includes other conditions associated with malformed great toes, soft tissue swelling, or heterotopic ossification. The combination of these three findings generally distinguishes FOP from these conditions. (See 'Differential diagnosis'above.)●There is no medical or surgical treatment to prevent or reverse the ossification associated with FOP. Management is supportive and focuses on prevention of flare-ups, patient and family education and counseling, and improved quality of life (see 'Management'above):Biopsies, surgery, and trauma should be avoided if possible. (See 'Avoid biopsies, surgery, and trauma'above.)Limiting activities with a high-risk of falls, installing handholds and other safety measures, and use of headgear may prevent falls or severe trauma from falls. (See 'Prevention of falls'above.) IM injection of vaccines is contraindicated. Additional immunization precautions are discussed above. (See 'Immunizations'above.) Preventive dental care is discussed separately. (See "Preventive dental care and counseling for infants and young children".)Children with FOP should undergo evaluation for hearing impairment with audiometry at least every other year. (See 'Hearing evaluation'above.)Respiratory health can be maintained through active respiratory activity (eg, singing, incentive spirometry, peak flow whistles). (See 'Respiratory health'above.)REFERENCES1.Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis 2011; 6:80.2.Kaplan FS, Xu M, Seemann P, et al. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat 2009; 30:379.3.Kaplan FS, Xu M, Glaser DL, et al. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics 2008; 121:e1295.4.Rogers JG, Geho WB. Fibrodysplasia ossificans progressiva. A survey of forty-two cases. J Bone Joint Surg Am 1979; 61:909.5.Kartal-Kaess M, Shore EM, Xu M, et al. Fibrodysplasia ossificans progressiva (FOP): watch the great toes! Eur J Pediatr 2010; 169:1417.6.Mantick N, Bachman E, Baujat G, et al. The FOP Connection Registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva. Bone 2018; 109:285.7.Baujat G, Choquet R, Bouée S, et al. Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. Orphanet J Rare Dis 2017; 12:123.8.Piram M, Le Merrer M, Bughin V, et al. Scalp nodules as a presenting sign of fibrodysplasia ossificans progressiva: a register-based study. J Am Acad Dermatol 2011; 64:97.9.Pignolo RJ, Bedford-Gay C, Liljesthrm M, et al. The Natural History of Flare-Ups in Fibrodysplasia Ossificans Progressiva (FOP): A Comprehensive Global Assessment. J Bone Miner Res 2016; 31:650.10.Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 2005; 116:e654.11.Orthopaedic-related syndromes. In: Tachdjian's Procedures in Pediatric Orthopaedics: From the Texas Scottish Rite Hospital for Children, Herring JA (Ed), WB Saunders Company, Philadelphia, PA 2002. Vol 3rd, p.1632.12.Cohen RB, Hahn GV, Tabas JA, et al. The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients. J Bone Joint Surg Am 1993; 75:215.13.Verma AK, Aga P, Singh SK, Singh R. The stone man disease: fibrodysplasia ossificans progressiva: imaging revisited. BMJ Case Rep 2012; 2012.14.Al Kaissi A, Kenis V, Ben Ghachem M, et al. The Diversity of the Clinical Phenotypes in Patients With Fibrodysplasia Ossificans Progressiva. J Clin Med Res 2016; 8:246.15.Trikha V, Kumar R, Khan SA, Rastogi S. Characteristic appearance on bone scintigraphy of a 'stone man'. Clin Nucl Med 2005; 30:517.16.The International Clinical Council on FOP (ICC) and Consultants. The medical management of fibrodysplasia ossificans progressiva: Current treatment considerations. March 2019. Available at: https://www.ifopa.org/for_medical_professionals (Accessed on May 27, 2019).17.Di Rocco M, Baujat G, Bertamino M, et al. International physician survey on management of FOP: a modified Delphi study. Orphanet J Rare Dis 2017; 12:110.18.Towler OW, Shore EM, Xu M, et al. The congenital great toe malformation of fibrodysplasia ossificans progressiva? - A close call. Eur J Med Genet 2017; 60:399.19.Kaplan FS, Le Merrer M, Glaser DL, et al. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 2008; 22:191.20.Kaplan FS, Glaser DL, Shore EM, et al. The phenotype of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 2005; 3:183.21.Eekhoff EMW, Netelenbos JC, de Graaf P, et al. Flare-Up After Maxillofacial Surgery in a Patient With Fibrodysplasia Ossificans Progressiva: An [18F]-NaF PET/CT Study and a Systematic Review. JBMR Plus 2018; 2:55.22.Shah PB, Zasloff MA, Drummond D, Kaplan FS. Spinal deformity in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 1994; 76:1442.23.Moore RE, Dormans JP, Drummond DS, et al. Chin-on-chest deformity in patients with fibrodysplasia ossificans progressiva. A case series. J Bone Joint Surg Am 2009; 91:1497.24.Glaser DL, Rocke DM, Kaplan FS. Catastrophic falls in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Relat Res 1998; :110.25.Scarlett RF, Rocke DM, Kantanie S, et al. Influenza-like viral illnesses and flare-ups of fibrodysplasia ossificans progressiva. Clin Orthop Relat Res 2004; :275.26.Centers for Disease Control and Prevention. Influenza. Preventive steps. Available at: https://www.cdc.gov/flu/prevent/prevention.htm (Accessed on May 28, 2019).27.Lanchoney TF, Cohen RB, Rocke DM, et al. Permanent heterotopic ossification at the injection site after diphtheria-tetanus-pertussis immunizations in children who have fibrodysplasia ossificans progressiva. J Pediatr 1995; 126:762.28.Carpenter SL, Soucie JM, Presley RJ, et al. Hepatitis B vaccination is effective by subcutaneous route in children with bleeding disorders: a universal data collection database analysis. Haemophilia 2015; 21:e39.29.Ragni MV, Lusher JM, Koerper MA, et al. Safety and immunogenicity of subcutaneous hepatitis A vaccine in children with haemophilia. Haemophilia 2000; 6:98.30.Kroger AT, Duchin J, Vázquez M. General best practice guidelines for immunization. Best practices guidance of the Advisory Committee on Immunization Practices (ACIP). Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html (Accessed on May 16, 2019).31.Kaplan FS, Pignolo RJ, Shore EM. Granting immunity to FOP and catching heterotopic ossification in the Act. Semin Cell Dev Biol 2016; 49:30.32.Convente MR, Chakkalakal SA, Yang E, et al. Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an Acvr1R206H Mouse Model of Fibrodysplasia Ossificans Progressiva. J Bone Miner Res 2018; 33:269.33.Convente MR, Wang H, Pignolo RJ, et al. The immunological contribution to heterotopic ossification disorders. Curr Osteoporos Rep 2015; 13:116.34.Jones MK, Wang H, Peskar BM, et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 1999; 5:1418.35.Weinreb M, Suponitzky I, Keila S. Systemic administration of an anabolic dose of PGE2 in young rats increases the osteogenic capacity of bone marrow. Bone 1997; 20:521.36.Luchetti W, Cohen RB, Hahn GV, et al. Severe restriction in jaw movement after routine injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996; 81:21.37.Kaplan FS, Zasloff MA, Kitterman JA, et al. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 2010; 92:686.

腕骨骨折概述Author:Kevin deWeber, MD, FAAFP, FACSMSection Editors:Patrice Eiff, MDChad A Asplund, MD, MPH, FAMSSMDeputy Editor:Jonathan Grayzel, MD, FAAEM翻译:刘浩, 主任医师，教授Contributor Disclosures我们的所有专题都会依据新发表的证据和同行评议过程而更新。文献评审有效期至：2020-06.|专题最后更新日期：2019-02-08.There is a newer version of this topic available inEnglish.该主题有一个新的英文版本。引言腕骨为手腕部的一组骨，其近端与桡骨和尺骨相接，远端与掌骨相接。该组骨一共有8块，合称为腕骨，通常分为近侧列(手舟骨、月骨、三角骨和豌豆骨)和远侧列(大多角骨、小多角骨、头状骨和钩骨)。一般情况下，腕骨骨折由直接或间接创伤引起。本专题将概述基本的腕骨解剖、损伤机制、体格检查和影像学检查的一般原则，以及成人腕骨骨折的初始诊疗。常见且重要腕部损伤详见其他专题。(参见“成人亚急性或慢性腕部疼痛的评估”和“成人急性腕部疼痛的评估”和“成人桡骨远端骨折”和“手舟骨骨折”和“三角骨骨折”和“月骨骨折及月骨周围损伤”和“头状骨骨折”和“钩骨骨折”)流行病学—手部骨折是最常见的肢体损伤，约占所有骨折的18%。腕骨骨折则占手部骨折的8%以上[1-3]。手舟骨骨折是目前最常见的腕骨骨折，占所有手部骨折的10%，并占所有腕骨骨折的60%-70%[4,5]。其次为三角骨骨折，占腕骨骨折的13%-28%。随后是大多角骨、钩骨、头状骨和小多角骨骨折，占腕骨骨折的2%-4%。豌豆骨骨折最罕见，占0.5%-1%[1,6-8]。分类和临床表现腕骨骨折分类的主要依据是骨折所在的解剖位置(参见下文‘临床解剖学’)，其次是损伤的特点，包括伴随的移位、脱位，以及骨折(粉碎性骨折与非粉碎性骨折)产生的骨碎块的数目。需要注意的是，很大一部分腕骨骨折涉及多块腕骨，因此若有一块腕骨发生骨折，临床医生应当寻找有无其他腕骨损伤。累及桡骨或尺骨远端的孤立性骨折虽然被归为“腕部骨折”，但并不累及腕骨。(参见“骨折处理的一般原则：骨折愈合和骨折描述”)骨折的简要介绍—与8块腕骨(影像 1)骨折相关的问题将在相应的专题单独讨论，列举如下：●手舟骨骨折(影像 2)手舟骨骨折是最常见的腕骨骨折，约占所有腕骨骨折的2/3。最常见的发生机制为跌倒时用手掌撑地，且手腕呈伸展、桡侧偏移的姿势。患者通常表现为手腕桡侧疼痛、肿胀、腕部活动受限、鼻烟窝压痛(图 1)，以及受到沿拇指的轴向载荷时出现疼痛。手舟骨骨折的诊断和处理详见其他专题。(参见“手舟骨骨折”)●月骨骨折(影像 3)急性月骨骨折最常见于跌倒时以手掌撑地且手腕呈伸展姿势，或见于其他一些腕部过度背伸性损伤。患者通常表现为腕部疼痛，活动腕关节或抓握动作可加重疼痛。由于月骨位于关节囊内，肿胀可能并不明显。若就诊较晚，则患者可能仅主诉腕关节僵硬或活动度降低。月骨骨折的诊断和处理详见其他专题。(参见“月骨骨折及月骨周围损伤”)●三角骨骨折(影像 4)三角骨骨折是第二常见的腕骨骨折，多为韧带撕脱性骨折。患者通常有创伤史以及腕部尺侧疼痛。体格检查一般能发现腕部背侧(图片 1)或沿尺骨远端边缘的压痛点。三角骨骨折的诊断和处理详见其他专题。(参见“三角骨骨折”)●豌豆骨骨折(影像 5)豌豆骨骨折最常见的发生机制是跌倒时以手掌撑地且腕部呈伸展姿势，或者是用掌根敲击硬物。患者通常表现为腕部掌面尺侧的疼痛和肿胀。豌豆骨处(图片 2)及小鱼际区域有压痛。豌豆骨骨折的诊断和处理详见其他专题。(参见“豌豆骨骨折”)●大多角骨骨折(影像 6)大多角骨骨折通常发生在跌倒时以手掌撑地时。患者通常没有明显肿胀，但有显著不适，比其他腕骨骨折更严重。捏拢指尖时有疼痛和无力表现，如比“OK”手势，或用拇指去接触小指指尖。大多角骨骨折的诊断和处理详见其他专题。(参见“Trapezium fractures”)●小多角骨骨折(影像 7)小多角骨骨折一般发生在第二(食指)掌骨受到轴向载荷时，罕见情况下也可见于腕部背侧的直接创伤。患者通常表现为手背肿胀，手背侧紧邻第二掌骨底近端处有压痛点(图片 3)。小多角骨骨折的诊断和处理详见其他专题。(参见“小多角骨骨折”)●头状骨骨折(影像 8)头状骨是最大的腕骨。单纯头状骨骨折通常是由跌倒时手握拳撑地导致。患者表现为手背侧疼痛和肿胀。背侧面头状骨区域(紧邻第三掌骨近端)通常有压痛。头状骨骨折的诊断和处理详见其他专题。(参见“头状骨骨折”)●钩骨骨折(影像 9)钩骨骨折可涉及钩骨钩或钩骨体。钩骨钩骨折更常见，发生于跌倒时以手掌撑地，或是做挥鞭动作时(如网球、高尔夫或棒球)，该过程中球拍或球棒握持部分的底端可造成骨损伤。患者表现为掌侧面钩骨钩处有深部压痛(图片 4)。钩骨骨折的诊断和处理详见其他专题。(参见“钩骨骨折”)临床解剖学腕部解剖结构详见其他专题。(参见“腕关节的解剖学和基础生物力学”)手部近端约3cm由8块腕骨构成(影像 1)。腕骨细分为近侧列和远侧列。腕骨近侧列包括(从桡侧向尺侧)：●手舟骨●月骨●三角骨(背侧)●豌豆骨(掌侧)腕骨远侧列包括(从桡侧到尺侧)：●大多角骨●小多角骨●头状骨●钩骨损伤机制如果患者能够描述腕部受伤时的情况，这一信息可能提示哪个或哪些腕骨发生了损伤，并可影响初始影像学检查[2,3,9]。需注意的是，下面的描述仅涉及腕骨骨折，而这些机制可能导致其他损伤(如，跌倒时腕伸展着地造成的桡骨远端骨折)。轴向载荷—腕部的轴向载荷可能造成手舟骨骨折，还可能引起舟月韧带断裂，导致舟月骨分离(影像 10)。第一掌骨(拇指)的轴向载荷可导致大多角骨发生垂直于大多角骨-第一掌骨关节面的关节内骨折；而食指掌骨的轴向载荷可能导致与之相关节的小多角骨骨折。(参见“成人急性腕部疼痛的评估”，关于‘舟月不稳定’一节和“Trapezium fractures”和“小多角骨骨折”)腕部过度背伸—涉及腕部过度背伸的损伤，如跌倒时手部伸展着地，可迫使舟骨向桡骨背侧移位而造成骨折(影像 2)。伸展过度性损伤也可造成月骨和三角骨骨折。(参见“手舟骨骨折”和“月骨骨折及月骨周围损伤”和“三角骨骨折”)跌倒时手掌着地可能导致豌豆骨的线性骨折，但此类骨折更可能是由对豌豆骨本身的直接冲击造成，而非由腕部过度伸展造成。偶尔，腕部过度背伸可能导致豌豆骨的撕脱性骨折，这通常发生在尺侧腕屈肌肌腱的远端附着点。(参见“豌豆骨骨折”)腕部过度屈曲—腕部过度屈曲可能导致累及三角骨韧带附着处的撕脱性骨折。(参见“三角骨骨折”)偏移、牵拉或旋转—由腕部(或第一掌骨)强力偏移、牵拉或旋转导致的损伤，可能引起韧带或关节囊应力，进而引起任何一个腕骨的撕脱性骨折。对掌面的直接冲击—由直接冲击导致的豌豆骨与三角骨挤压(如，用掌根敲击硬物)可能导致豌豆骨骨折，或造成豌豆骨背侧关节面的软骨损伤。(参见“豌豆骨骨折”)钩骨钩也容易因作用于腕横韧带的直接压力而受到损伤，导致钩骨钩从钩骨体撕脱。跌倒时以手掌撑地或经作用在钩骨钩部的棍棒、球拍或球棒末端传递的力，也可导致钩骨骨折。(参见“钩骨骨折”)多种力的组合—轴向载荷和过度屈曲或过度背伸联合作用时，比如跌倒时手握拳撑地，可能导致头状骨骨折，常伴有相关的脱位。(参见“头状骨骨折”)症状和检查发现评估急性腕痛患者时需了解的重要问题包括疼痛部位、患者的优势手、从事的职业或运动以及什么活动会加重疼痛。腕痛患者的表现及病史采集详见其他专题。(参见“成人急性腕部疼痛的评估”和“成人亚急性或慢性腕部疼痛的评估”)疼痛和压痛的位置有助于确定损伤最可能发生于哪块骨或哪些骨，还能指导影像学检查的需求(影像 1和图 2和图 3)。鼻烟窝压痛(图片 5和图 1)提示手舟骨损伤，但也可能是大多角骨损伤。触诊手背桡侧的Lister结节(图 2和图片 6)有助于明确舟月关节的位置，该关节紧邻Lister结节远端。疼痛主要在掌面时损伤较可能发生在豌豆骨(位于小鱼际近端根部(图片 2))或钩骨钩(位于小鱼际区域内(图片 4))，或者是鱼际近端根部的舟骨掌侧(远端)(图片 7)。腕骨骨折后出现的疼痛通常造成腕部活动减少以及腕部屈伸和手部抓握的肌力减弱。应评估患者的神经血管功能，因为骨折和脱位可损伤邻近神经或血管。任何可能伴有神经血管损伤的骨折都需要紧急治疗并请手外科会诊。其他特异性检查将在具体骨折的相关专题中详细讨论。影像学检查怀疑为腕骨骨折时，要获取的标准X线平片包括后前位片(posteroanterior, PA)、斜位片和正侧位片。其他位X线平片的选择取决于骨折的可疑部位；这些额外摄片将在针对特定损伤的专题中进行更详细的讨论。特定情况下，某些视图的X线平片可能提供有用信息，简要总结如下：●手舟骨位片(最大尺侧移时腕部的后前位片)有助于发现可疑的手舟骨骨折(影像 11)。(参见“手舟骨骨折”)●腕管位片有助于发现钩骨钩骨折(影像 9)。(参见“钩骨骨折”)●握拳姿势下的后前位片有助于显示舟月韧带断裂造成的舟月关节不稳。腕骨间的间距一般为2-3mm，超过3mm时提示韧带断裂(影像 12)[10]。(参见“成人急性腕部疼痛的评估”，关于‘舟月不稳定’一节)●Bett位片(手腕旋前约20°时的前后位)有助于识别临床怀疑的大多角骨骨折。临床医生应谨记，常规X线平片对识别腕骨骨折的敏感性较低[6,7]。因此，如果X线检查未发现明显异常，但临床上仍怀疑有骨折(如，有骨性压痛以及损伤机制符合条件)，应进行CT或MRI检查。CT能非常准确地识别腕骨骨折或脱位，也可在怀疑关节内移位时评估关节面[11]。而MRI在此基础上还能发现急性和慢性骨/软组织损伤[12]。如果怀疑有严重软组织损伤(如韧带断裂或脱位)，则应进行MRI检查。如果超声技能娴熟，也是诊断包括腕骨骨折在内的多种腕部损伤的有效辅助手段。实施腕部超声检查详见其他专题。(参见“Musculoskeletal ultrasound of the wrist”)鉴别诊断除了骨折，腕部可发生其他的创伤性损伤，包括：●腕部关节囊的扭伤●多个腕骨间韧带中任何韧带扭伤，这可能导致腕骨的半脱位或脱位●多条横跨腕部的肌腱的任何肌腱损伤●浅表软组织挫伤●不伴骨折的骨挫伤●神经损伤(桡神经，尺神经，正中神经)●三角纤维软骨复合体(triangular fibro-cartilage complex, TFCC)的挫伤和撕裂●既存腱鞘囊肿的破裂●既存炎性关节病(如，类风湿性关节炎)的加重如何评估腕部疼痛患者的更全面讨论参见其他专题(参见“成人急性腕部疼痛的评估”和“成人亚急性或慢性腕部疼痛的评估”)。手术转诊的指征手术转诊的指征因受累骨及损伤机制而不同。这些内容将在针对特定腕骨损伤的各个专题进行讨论。立即转诊的基本指征相同，包括：任何持续的血管损伤或神经功能障碍、开放性骨折、移位性骨折、伴有脱位或骨性不稳定的骨折，以及发生任何严重并发症。(参见“骨折治疗的一般原则：早期和晚期并发症”)处理骨折处理的一般原则适用于腕骨骨折。以下是推荐的处理措施：●固定骨折，最小化进一步的组织损伤，尤其是神经和血管结构的损伤。由于骨折可能导致软组织严重肿胀，初始固定通常采用可拆卸石膏或玻璃纤维夹板或热塑形夹板。随后可拆除夹板，以便进行骨折复位、固定和石膏塑形。(参见“肌肉骨骼损伤的夹板固定基本技术”)●冰敷受伤部位，尽可能减轻肿胀(参见“急性骨折的一般处理原则”)●通过骨折固定、冰敷和服用非处方镇痛药(如对乙酰氨基酚)，可充分缓解大多数患者的疼痛。在最初3-5日，有时需要阿片类镇痛药来控制疼痛。若之后患者还要求使用阿片类药物，则应重新评估是否存在夹板或石膏固定不佳、漏诊损伤或出现骨折并发症而引起的疼痛不适。(参见“急性骨折的一般处理原则”，关于‘疼痛管理’一节和“骨折治疗的一般原则：早期和晚期并发症”)非甾体类抗炎药对骨折愈合是否有效还有争议，但如果有明确的或者可疑的急性骨折，最好避免使用此类药物，以降低骨折不愈合的风险。相关问题详见其他专题。(参见“非选择性非甾体类抗炎药的不良反应概述”，关于‘肌肉骨骼损伤的愈合’一节)腕骨骨折固定以后，腕部的康复非常重要。如果没有高质量的康复，腕部功能完全恢复可能很慢，甚至可能恢复不完全，从而导致慢性残疾。只要有可能，我们推荐将患者转诊至有处理腕部损伤经验的职业治疗师或物理治疗师。腕骨骨折的治疗和康复一般由以下几个阶段构成：●炎症和修复阶段–发生在骨折固定期间，如上文所述。●过渡至成熟阶段–固定后，腕部出现僵硬和疼痛。在进行轻柔、被动的关节活动度锻炼之前，热疗(在热水或固体石蜡中浸泡数分钟)等治疗可能有帮助。关节活动度锻炼可在腕部活动的三个平面进行：屈-伸、尺-桡侧偏和旋前-旋后。如果需要的话，应注意恢复手指活动度。完全恢复腕部活动度可能需要数周时间，但在1-2周后通常可获得显著改善。●成熟阶段–一旦骨折愈合且腕部活动能力恢复，患者需2-8周恢复腕部和手部肌肉的力量。这些肌肉包括：腕屈肌和腕伸肌、尺侧倾肌群和桡侧倾肌群、旋前肌和旋后肌，以及指屈肌和指伸肌。相关训练可通过使用弹性阻力带(由健侧手提供手动阻力)或专门设计的器械(见于物理治疗诊所)完成。治疗师也可使患者逐渐过渡到特殊训练，这些训练是对需要重新掌握的职业相关或体育相关任务进行重复。额外信息资源腕骨骨折的额外信息可从其他文献获得，这些文献分别从骨科手术的角度[9,13]、初始处理的角度[14]及运动医学的角度[3,10,15]对腕骨骨折进行讨论。患者教育UpToDate提供两种类型的患者教育资料：“基础篇”和“高级篇”。基础篇通俗易懂，相当于5-6年级阅读水平(美国)，可以解答关于某种疾病患者可能想了解的4-5个关键问题；基础篇更适合想了解疾病概况且喜欢阅读简短易读资料的患者。高级篇篇幅较长，内容更深入详尽；相当于10-12年级阅读水平(美国)，适合想深入了解并且能接受一些医学术语的患者。以下是与此专题相关的患者教育资料。我们建议您以打印或电子邮件的方式给予患者。(您也可以通过检索“患者教育”和关键词找到更多相关专题内容。)●基础篇(参见“患者教育：石膏和夹板护理(基础篇)”和“患者教育：骨折(基础篇)”和“患者教育：常见腕部损伤(基础篇)”)●高级篇(参见“Patient education: Cast and splint care (Beyond the Basics)”)总结●腕骨骨折分类的主要依据是骨折所在的解剖位置和骨折特征。八块腕骨可被细分为近侧列和远侧列(影像 1)。具体每块腕骨骨折参见相应专题。(参见上文‘分类和临床表现’和‘临床解剖学’)●疼痛的位置和受伤机制为损伤的部位提供了线索。本文阐述了不同腕骨骨折的特定损伤机制和检查发现。(参见上文‘损伤机制’和‘症状和检查发现’)●怀疑腕骨骨折时，要获取的标准X线平片包括腕部的后前位(PA)片和标准侧位片。还可针对疑似骨折部位进行其他视图的X线检查，但X线平片的总体敏感性较低。如果初始X线检查无明显异常，但临床上仍怀疑骨折，可使用夹板固定腕部并在7-10日内再次进行X线检查，或者是进行高级影像学检查(如CT或MRI)。(参见上文‘影像学检查’)●腕骨骨折的初始处理包括固定、冰敷和镇痛。骨折愈合后，适当的物理治疗对恢复腕部的活动和肌力至关重要。(参见上文‘处理’)使用UpToDate临床顾问须遵循用户协议.参考文献van Onselen EB, Karim RB, Hage JJ, Ritt MJ. Prevalence and distribution of hand fractures. J Hand Surg Br 2003; 28:491.Suh N, Ek ET, Wolfe SW. Carpal fractures. J Hand Surg Am 2014; 39:785.Urch EY, Lee SK. Carpal fractures other than scaphoid. Clin Sports Med 2015; 34:51.Alshryda S, Shah A, Odak S, et al. Acute fractures of the scaphoid bone: Systematic review and meta-analysis. Surgeon 2012; 10:218.Duckworth AD, Jenkins PJ, Aitken SA, et al. Scaphoid fracture epidemiology. J Trauma Acute Care Surg 2012; 72:E41.Welling RD, Jacobson JA, Jamadar DA, et al. MDCT and radiography of wrist fractures: radiographic sensitivity and fracture patterns. AJR Am J Roentgenol 2008; 190:10.Balci A, Basara I, ekdemir EY, et al. Wrist fractures: sensitivity of radiography, prevalence, and patterns in MDCT. Emerg Radiol 2015; 22:251.Hey HW, Chong AK, Murphy D. Prevalence of carpal fracture in Singapore. J Hand Surg Am 2011; 36:278.Geissler WB, Slade JF. Fractures of the carpal bones. In: Green's Operative Hand Surgery, 6th ed, Wolfe SW, Hotchkiss RN, Pederson WC, Kozin SH (Eds), Churchill Livingstone, 2011.Ingari JV. Wrist and hand. In: DeLee and Drez's Orthopedic Sports Medicine Principles and Practice, 3rd ed, DeLee JC, Drez D, Miller MD (Eds), Saunders Elsevier, Philadelphia 2010.Kaewlai R, Avery LL, Asrani AV, et al. Multidetector CT of carpal injuries: anatomy, fractures, and fracture-dislocations. Radiographics 2008; 28:1771.Murthy NS, Ringler MD. MR Imaging of Carpal Fractures. Magn Reson Imaging Clin N Am 2015; 23:405.Gaebler C, McQueen MM. Carpus fractures and dislocations. In: Rockwood and Green's Fractures in Adults, 7th ed, Bucholz RW, Heckman JD, Court-Brown CM, Tornetta P (Eds), Lippincott, Williams, & Wilkins, Philadelphia 2010.Eiff MP, Petering RC. Carpal fractures. In: Fracture Management for Primary Care, 3rd ed, Eiff MP, Hatch RL (Eds), Saunders, Philadelphia 2013.Marchessault J, Conti M, Baratz ME. Carpal fractures in athletes excluding the scaphoid. Hand Clin 2009; 25:371.

引言—骨肉瘤是骨的原发恶性肿瘤，其特征是恶性肿瘤细胞产生类骨质或不成熟骨[1-3]。骨肉瘤比较少见。美国每年诊断的新发病例有750-900例，其中约400例发生于20岁以下的儿童和青少年[4,5]。骨肉瘤虽然少见，但却是儿童和青少年最常见的原发性恶性骨肿瘤(图 1)，在15-19岁青少年和年轻成人的最常见恶性肿瘤中居第5位[6,7]。通过有效的化疗，恶性骨组织肉瘤患者的生存情况已显著改善。在采用化疗前，80%-90%的骨肉瘤患者虽然局部肿瘤得到了控制，但仍发生了转移性疾病，并死于该病。据推测(后来得以证实)，大多数患者在诊断时已存在亚临床的转移性疾病，甚至在没有明显临床转移灶的情况下[8,9]。如果在疾病负担较低时开始化疗，则可成功根除这些沉积病灶。因此，除低级别骨旁骨肉瘤患者和某些骨膜骨肉瘤患者以外(化疗的价值存在疑问)，所有其他骨肉瘤患者均应行辅助化疗，且大多数在术前阶段进行。采取多学科治疗，则至少2/3的非转移性肢体骨肉瘤患者会长期存活，多达50%的局限性肺转移患者可治愈，约25%表现为更广泛转移性疾病的患者预计可获得长期无复发生存。本专题将概述骨肉瘤患者的流行病学、临床表现、诊断、分期和组织病理学。原发性骨肿瘤的诊断性评估和活检技术，治疗和结局概述，骨组织肉瘤的外科手术治疗指导原则，以及骨肉瘤治疗中的化疗将会单独详细讨论。 (参见“骨肿瘤的诊断与活检技术”和“骨源性肉瘤的术前评估、组织学分型和外科治疗原则”和“骨肉瘤治疗中的化疗和放疗”)流行病学—如上文所述，骨肉瘤是一种少见的肿瘤；仅占美国每年所有癌症诊断的1%。与尤文肉瘤不同(在年龄较大的成人中极为罕见)，骨肉瘤的发病年龄呈双峰分布，分别出现于青春期早期和65岁以上(图 2)[10]。肿瘤部位和患者生存情况视就诊时的年龄而异。儿童—骨组织肉瘤约占儿童期所有癌症的6%，而骨肉瘤约占儿童期所有癌症的3%[11]。然而，骨肉瘤是儿童和年轻成人最常见的原发性恶性骨肿瘤。在20岁以下的个体中，骨肉瘤占所有骨癌的56%，而尤文肉瘤占34%-36%，软骨肉瘤不到10%[10]。 (参见“尤文肉瘤家族肿瘤的流行病学、病理学和分子遗传学”)对于儿童，骨肉瘤的发病高峰是13-16岁(图 1)，与青少年生长突增期一致。骨肉瘤在男孩中更常见，黑人和其他人种多于白种人，但原因不明[4,10,12]。儿童骨肉瘤的最常见部位是长骨干骺端，尤其是股骨远端(在一项大型人群病例系列研究中占75%[10])、胫骨近端和肱骨近端[13,14]。成人—通常认为成人的骨肉瘤是由Paget骨病经肉瘤性转化而成的继发性肿瘤，或者是受照射骨、骨梗死或某些其他良性骨病变的继发性肉瘤[10]。 (参见“放疗相关肉瘤”)在美国，所有发生于60岁以上患者中的骨肉瘤，半数以上为继发性[15]。而在亚洲，Paget病相对少见，且40岁以上患者中的骨肉瘤大多为原发性[16,17]。Paget病情况下的骨肉瘤(Paget病性肉瘤)的预后总体较差。 (参见下文‘危险因素’)相比于诊断的儿童病例，成人骨肉瘤更常出现在中轴部位(虽然同儿童一样，但下肢骨是单一的最常见部位[10])，以及既往接受过放射或有基础骨异常的区域。诊断时年龄超过60岁的患者在就诊时发生转移性疾病的风险也更高[18]。对于年龄较大的成人骨肉瘤患者，与儿童一样，男性更多见[10]。但与儿童不同的是，白种人比黑人或其他人种更常见[10]。危险因素和发病机制—在儿童中，大多数骨肉瘤是散发性的，而少数病例具有遗传易感性。在年龄较大的成人中，约1/3的骨肉瘤病例出现于Paget骨病中，或者作为第二癌症或较迟发生的癌症出现[10]。危险因素—已经确定了几种易感因素[19]。先前放疗或化疗—儿童期实体肿瘤放疗后20年期间，骨肉瘤是最常见的第二原发性肿瘤。早期评价表明约3%的骨肉瘤可归因于先前的放疗。然而，可能会显示更高的发病率，因为更多患者在最初放疗后能活到发生这一并发症。放疗到出现继发性骨肉瘤的时间平均为12-16年；儿童期癌症存活者间隔时间更短。 (参见“放疗相关肉瘤”，关于‘流行病学与组织学分布’一节和“放疗相关肉瘤”，关于‘放疗剂量与暴露年龄’一节)对于儿童期癌症存活者，先前接受过化疗(尤其是烷化剂)也与继发性骨肉瘤相关，且可能会增强既往放疗的影响。 (参见“放疗相关肉瘤”，关于‘化疗药物’一节)Paget病和其他良性骨病变—40岁以上的骨肉瘤患者病例常与Paget病有关，Paget病是一种以骨转换加速为特征的局灶性骨骼病[20]。尽管Paget病患者的骨肿瘤发病率明显增加，但仅0.7%-1%[21]。肉瘤性转化最常见于长期Paget病中，但并不一定与骨受累程度有关。尽管这种情况在组织学上与其他骨肉瘤无法鉴别，但常见多处骨受累，且预后总体较差。 (参见“Paget骨病的临床表现与诊断”)Paget病的病因尚不明确，但现认为遗传因素起了致病作用。Paget病和Paget病性骨肉瘤均与18号染色体杂合性缺失有关，可能涉及了相同位点的某个假定抑癌基因[22-24]。在散发性Paget骨病和Paget病性骨肉瘤中，已发现染色体5q35上SQSTM1基因的体细胞突变[25]。除Paget病以外，其他良性骨病变据报道也会导致恶变为原发性骨肿瘤的风险增加。这些病变包括慢性骨髓炎、骨梗死灶，以及良性骨肿瘤(如骨纤维异常增殖症等)[26,27]。(参见“儿童及青少年良性骨肿瘤”，关于‘纤维异常增殖症’一节)也有报道称，骨肉瘤发生在金属植入物附近，但尚未确定具有明确的因果关系，可能仅仅是巧合。遗传性疾病—许多骨肉瘤患者存在遗传易感性，尤其是儿童。一项研究纳入了1120例癌症患儿，采用新一代测序技术来确定种系易感突变对骨肉瘤的促发作用，发现39例骨肉瘤患者中7例(18%)存在被认为致病或可能致病的突变[28]。大多数突变位于RB1基因(遗传性视网膜母细胞瘤相关基因)和TP53基因(Li-Fraumeni综合征相关基因)。●与遗传性视网膜母细胞瘤相关的基因异常(即视网膜母细胞瘤基因的种系突变)会导致发生第二原发性肿瘤的风险增加，其中60%的第二原发性肿瘤为软组织肉瘤和骨肉瘤[29-31]。较迟发生成骨性肉瘤的风险不仅存在于放疗照射野中，也存在于远离放疗照射野的长骨中。与遗传性视网膜母细胞瘤患者相比，散发型视网膜母细胞瘤患者中该风险低得多。例如，在一项纳入了1604例视网膜母细胞瘤患者的研究中，在诊断后第50年，遗传性病例的第二癌症累积发病率为51%，而对于非遗传性(散发性)病例仅为5%[29]。 (参见“视网膜母细胞瘤的临床表现、评估和诊断”，关于‘流行病学’一节和“放疗相关肉瘤”，关于‘遗传易感性’一节)●Li-Fraumeni综合征是一种家族性癌症综合征，受累的家族成员呈现出一系列肿瘤，包括乳房肿瘤、软组织肿瘤、肾上腺皮质肿瘤、脑肿瘤、白血病和骨肉瘤[32]。这些患者中很多都携带p53抑癌基因的生殖系失活突变，该抑癌基因参与了细胞周期调节和维持基因组完整性[33-35]。 (参见“Li-Fraumeni综合征”)尽管存在这种重要关联，但仅少数骨肉瘤归因于Li-Fraumeni综合征[36,37]。一项病例系列研究纳入了235例未经选择的骨肉瘤儿童，仅3%的儿童携带有p53组成性生殖系突变[36]。除了遗传性视网膜母细胞瘤和Li-Fraumeni综合征外，已知会使患者容易发生骨肉瘤的其他遗传性疾病包括：Rothmund-Thomson综合征(Rothmund-Thomson syndrome, RTS)，以及相关的Bloom综合征与Werner综合征。●RTS(也称为先天性皮肤异色症)是一种常染色体隐性遗传病，具有独特的皮肤表现(萎缩、毛细血管扩张、色素沉着)、毛发稀疏、白内障、身材矮小、骨骼异常，以及骨肉瘤风险显著增高[38,39]。一项队列研究纳入了41例RTS患者，其中有13例(32%)发生了骨肉瘤[38]。临床上，RTS患者发生这些肿瘤的年龄往往比一般人群小。●已发现约2/3的RTS患者存在RECQL4基因的一种特定功能缺失性突变，与骨肉瘤风险密切相关。一项病例系列研究纳入了33例RTS患者，结果表明在10例无该基因截短突变的患者中，无一例发生骨肉瘤，而23例有截短突变的患者在230人年的观察期内，骨肉瘤的发病率为每年5例[40]。Bloom综合征和Werner综合征存在RecQ基因家族的其他基因突变，且这两种疾病有重叠的临床特征，包括易发生骨肉瘤[40]。由于这些遗传性疾病与骨肉瘤有关，尤其是在有多处原发恶性肿瘤的情况下[41]，所以对于新诊断为骨肉瘤的患者，仔细详细询问家族史很重要。然而，上述新一代测序研究中，对于包括骨肉瘤患儿在内的大多数癌症患儿，无法根据其家族史预测是否有潜在的易感综合征[28]。分子发病机制—尽管骨肉瘤的病因学不明，但以下几点显示了骨肉瘤的发生与骨快速生长之间的关联：●骨肉瘤的发病高峰出现于青春期生长突增期●肿瘤似乎最常发生于骨长度和骨大小增长最多的部位(股骨远端、胫骨近端和肱骨近端的干骺区)(图 3)。●女孩发生骨肉瘤的年龄较小，这与其骨龄更大和青春期生长突增更早的情况相一致。人们据此推测，骨肿瘤的发生是因为在某一时间，即快速增殖细胞对致癌物、有丝分裂错误或其他导致肿瘤性转化的事件尤为易感时，正常的骨生长和重塑过程出现了异常[42]。然而，研究生长和发育相关因素与骨组织肉瘤风险间的关联性，未发现一致的关联模式[43,44]。这种异常或致肿瘤发生异常的具体特性仍不明，是要深入研究的主题[19,45,46]。与其他肉瘤不同，骨肉瘤不存在特征性的易位和其他分子遗传学异常。 (参见“软组织与骨肉瘤的致病因素”，关于‘遗传学和分子发病机制’一节)大多数骨肉瘤的核型复杂且不平衡。据报道，骨肉瘤中最常发生杂合性缺失(意味着某个推定的抑癌基因缺失)的是染色体3q、13q(视网膜母细胞瘤基因的位点)、17p(p53基因的位点)和18q(该染色体区域与Paget病中的骨肉瘤有关)(参见上文‘Paget病和其他良性骨病变’)[22,23,47-49]。骨肉瘤中常有视网膜母细胞瘤蛋白肿瘤抑制因子通路和p53肿瘤抑制因子通路的共同失活[19,50,51]。鉴于Li-Fraumeni综合征(一种p53突变性失活的遗传性疾病)家族中的骨肉瘤发病率增加，令人特别容易想到p53通路异常可能对肿瘤发生起到促进作用。 (参见上文‘遗传性疾病’)正常或“野生型”p53似乎对于骨的正常发育和生理功能起一定作用[52]，因为p53无效的小鼠在子宫内表现出颅骨不能生长和骨纵向生长延迟[53]。此外，p53无效小鼠的骨细胞裂解物也不能激活正常的细胞凋亡通路[50]。p53和其他分子通路(如，Wnt、Notch、IGF和mTOR信号通路)对骨肉瘤发病机制的促进作用不属于本专题的讨论范畴；参见其他优秀的综述[45,54]。正如下文要讨论的那样，推测大多数患者在就诊时有转移性疾病，且大多是亚临床的。基因表达谱分析(通过采用DNA微阵列分析)以及全基因组测序工作正开始揭示掌控转移可能性的分子学事件，这些发现可能为以后的分子靶向治疗创造了条件[45]。临床表现—大多数骨肉瘤患者表现为局限性疼痛，通常持续数月。疼痛通常开始于损伤之后，可能随时间时轻时重。通常没有诸如发热、体重减轻和不适等全身性症状。体格检查中最重要的发现是软组织肿块，通常较大且触诊有压痛。骨肉瘤好发于长骨干骺端区域(图 4)。最常受累部位的递减次序为：股骨远端、胫骨近端、肱骨近端、股骨中段和近端，以及其他骨[55]。除了碱性磷酸酶(约40%患者)[56]、乳酸脱氢酶(lactate dehydrogenase, LDH)(约30%患者)[57]和红细胞沉降率升高以外，实验室评估通常正常。实验室评估异常与疾病严重程度无关，但LDH水平极高患者的临床结局较差[58]。就诊时，10%-20%的患者有明确的大型转移性疾病，根据美国肌肉骨骼肿瘤协会(Musculoskeletal Tumor Society, MSTS)所用的分期系统，归为Ⅲ期(参见下文‘分期系统’)。远处转移瘤最常累及肺部，但也可累及骨[59]。据推测，隐匿性微转移瘤存在于大多数似乎有临床上局限性疾病的患者中，因为在辅助化疗时代之前，80%以上的骨肉瘤患者发生了转移性疾病，尽管其局部肿瘤得到了控制。据推测这些患者在诊断时已存在亚临床转移瘤[60]。常规使用全身性辅助化疗后，至少2/3的非转移性骨肉瘤儿童和青少年会长期存活，表明化疗可成功根除微转移瘤。骨肉瘤成人患者的预后较差，尤其是65岁以上的患者[61]。诊断与分期评估—首先引起医生怀疑是原发性骨肿瘤的诊断性检查通常是受累部位的普通X线摄影[62]。普通型骨肉瘤(占骨肉瘤病例的大多数，见下文)的特征包括：正常骨小梁受到破坏、肿瘤边界模糊，以及无骨内膜骨反应。受累骨的特征是射线不透区与射线可透区混合存在、皮质破坏和骨膜新生骨形成，伴有Codman三角形成(宿主骨膜骨不完全反应)(影像 1)。软组织肿块不同程度骨化，呈放射样或“日光四射”样。 (参见“骨肿瘤的诊断与活检技术”)鉴别诊断—在多达2/3具有特征性的放射影像学表现、临床特征和肿瘤部位的患者中，可预测骨肉瘤的正确组织学诊断[63]。然而，放射影像学表现不具有诊断意义，因此确诊需行活检。骨肉瘤的主要鉴别诊断包括：其他恶性骨肿瘤(即尤文肉瘤、淋巴瘤和转移瘤)，有时包括良性骨肿瘤(如软骨母细胞瘤、成骨细胞瘤(影像 2和影像 3))，以及非肿瘤性疾病(如骨髓炎、朗格汉斯细胞组织细胞增生症和动脉瘤样骨囊肿)。 (参见“儿童及青少年良性骨肿瘤”和“儿童及青少年骨朗格汉斯细胞组织细胞增生症(嗜酸性肉芽肿)”和“成人骨髓炎概述”和“疑似骨髓炎时的影像学检查方法总结”)偶尔，普通X线摄影上异常不明显。对于这类病例，如果临床上高度怀疑骨肿瘤(即长骨疼痛进行性加重或疼痛持续时间超过受伤后预计疼痛时间，如6周或以上)，则应行MRI检查。甚至对于普通X线摄影有特征性表现的患者，也需要行MRI来制定手术计划(参见下文‘分期系统’)。分期诊断性检查—相比于那些有局限性病变的患者，就诊时已有明显转移性疾病的患者，其结局显著更差。由于很大比例的转移瘤患者(包括多达半数的局限性肺累及患者)可治愈，所以有必要进行全面的分期诊断性检查帮助制定手术计划。影像学检查—骨肉瘤的分期诊断性检查应包含以下内容(表 1)[64]：●受累长骨全段需行MRI检查。一项多机构研究纳入了387例儿童和成人患者，其结论表明CT与MRI对于骨和软组织肿瘤局部分期的准确性相等[65]。然而，在大多数情况下优选MRI，因为其能更好地界定软组织受累范围(尤其是对于神经血管束、关节和骨髓受累)和是否存在跳跃性病灶(即，同一骨中的髓质病变，但未与原发灶直接相连)(影像 4)[66]。MRI检查方案应包括冠状位T1序列。●CT扫描最适合用于评估胸部的转移性疾病，这是至关重要的，因为约80%的骨肉瘤转移灶会累及肺部[60,67]。由于可能存在假阳性结果，如果病变不确定但被视为代表“可能的”转移灶，则或许需要进行组织学检查来证实。然而，CT可能会低估转移瘤累及肺部的范围[68,69]。在一项研究中，除开胸手术期间用手触诊肺部以外，任何其他检查方法均会导致超过1/3病例的转移瘤被漏诊[68]。由此人们开始怀疑，当目标是切除肺部的所有转移瘤时，使用微创手术(如，胸腔镜转移瘤切除术)是否可取[70-72]。 (参见“肺转移瘤手术切除的效果、指征、术前评估及手术技术”)区别转移灶与良性结节可能比较困难，尤其是对于肉芽肿性疾病患病率较高的成人，以及生活在真菌病(尤其是组织胞浆菌病)流行地区的儿童。 (参见“肺组织胞浆菌病的诊断和治疗”，关于‘何时怀疑组织胞浆菌病’一节)虽然钙化可以是良性病变的一种征象，但也可见于骨肉瘤转移瘤中[73]。欧洲和美国骨肉瘤研究小组制定了评估疑似肺转移瘤的指导标准，EURAMOS 1(AOST0331)试验正在使用该标准(表 2)[74]。●锝放射性核素骨扫描是评估全身骨是否存在多发性病灶的优选方法。尽管PET对评估术前化疗疗效的效用可能更大，但至少1项研究表明，该检查对于发现骨肉瘤骨组织转移的作用不及放射性核素骨扫描[75]，发现肺转移瘤的作用不及螺旋CT[76]。PET和PET/CT联合影像学检查对于骨肉瘤患者的作用尚未完全了解，其应用也未达成共识[76,77]。美国国家综合癌症网络(National Comprehensive Cancer Network, NCCN)的指南建议使用PET扫描和/或骨扫描作为疑似骨肉瘤的诊断性检查[78]。来自美国儿童肿瘤专家组骨肿瘤委员会的影像学检查指南推荐，采用放射性核素骨扫描和/或PET扫描进行全身分期评估(表 1)[64]。不论选用哪一种检查，在整个治疗过程中和治疗后监测期间，均应使用同一种影像学检查方法。活检—一旦疑诊为原发骨肿瘤，就应将患者转诊至在治疗此类肿瘤方面具有专业技能的医疗机构做进一步处理，包括诊断性活检。若选择开放性活检，应由骨肉瘤处理方面经验丰富的骨外科医生进行，理想情况下还应由这名医生进行根治手术。如果介入放射科医生计划进行针芯穿刺活检，则放射科医生应与骨外科医生商讨活检穿刺路径。在仔细考虑日后根治性手术后合理制定活检计划很重要，以免危及到后续治疗，尤其是保肢手术[79]。这一专题将会单独详细讨论。 (参见“骨肿瘤的诊断与活检技术”)分期系统—MSTS分期系统最常用于骨组织肉瘤分期，由弗罗里达大学的Enneking制定[80,81]。这是一个手术分期系统，不用于决定骨肉瘤患者的内科治疗(化疗)。MSTS分期系统通过分级[低级别[(Ⅰ期) vs 高级别(Ⅱ期)]来描述非转移性恶性骨肿瘤的特征，并根据病灶的局部解剖学范围[间室内(A型) vs 间室外(B型)]进一步细分。对于骨肿瘤，通过肿瘤是否延伸穿过受累骨的皮质来判定间室状态；大多数高级别骨肉瘤属于间室外型。有远处转移的患者归为Ⅲ期。组织学分类—骨肉瘤的组织学诊断依据是，存在恶性肉瘤性间质，并产生肿瘤性类骨质和骨。目前认为骨肉瘤起源于间充质干细胞，该干细胞可分化为纤维组织、软骨或骨。因此，骨肉瘤与软骨肉瘤和纤维肉瘤具有很多共同的特征(表 3)[14]，后两者属于同一骨组织肉瘤家族，骨肉瘤很容易与它们混淆。然而，软骨肉瘤和纤维肉瘤没有诊断骨肉瘤所必需的编织骨基质，据此可以与骨肉瘤鉴别。由于一些骨肉瘤仅生成有限程度的类骨质，且组织形态学多样，可能需要免疫组织化学来证实诊断。与尤文肉瘤和许多软组织肉瘤不同，骨肉瘤与任何特征性的染色体易位无关[82]。 (参见“尤文肉瘤家族肿瘤的流行病学、病理学和分子遗传学”和“软组织与骨肉瘤的致病因素”)普通型骨肉瘤—最大的一组骨肉瘤是普通型(髓内高级别)骨肉瘤，约占所有骨肉瘤的90%[14,83]。这类肿瘤通常累及长骨干骺端(图 3)，最常见于青少年和年轻成人。根据主要的细胞成分，可将普通型骨肉瘤再细分为：成骨细胞型(约占普通型骨肉瘤的50%)、软骨母细胞型(25%)或成纤维细胞型(25%)骨肉瘤(表 3)[62]。尽管组织学表现不同，但这些肿瘤的临床行为和处理相似。●成骨细胞型骨肉瘤的特征是恶性肿瘤细胞产生大量骨样基质，在其周围形成精细或粗糙的花边；大量的骨样基质可能会导致恶性间质细胞变形(图片 1)。一些肿瘤含有较厚的骨样基质小梁，形成不规则的吻合网。其矿化程度不一。●成纤维细胞型骨肉瘤主要由高级别的梭形细胞间质构成，此间质中仅有局灶区域产生骨(图片 2)。更具多形性的肿瘤可能与以前称为骨恶性纤维组织细胞瘤(malignant fibrous histiocytoma, MFH)的未分化型高级别多形性骨组织肉瘤相似，但前者有肿瘤产生的骨样基质，后者有骨膜反应性宿主编织骨(可能存在于肿瘤周围)，可通过这些特点进行鉴别。●在软骨母细胞型骨肉瘤中，大部分肿瘤中均有明显的软骨基质产生。虽然大多数肿瘤往往级别较低，但软骨样区域可能含有在细胞学上非典型的细胞，是高级别肿瘤的特征。这些软骨母细胞型病灶混合产生骨性小梁的恶性梭形细胞(图片 3)。组织学变异型—除这3种普通型骨肉瘤的亚分类以外，还有几种变异型：●小细胞型●血管扩张型●多病灶型●MFH亚型最初认为这些变异型的预后较差。然而，采用现代的积极治疗，这些变异型的生物学行为似乎相似。其他亚型(近皮质骨旁骨肉瘤和骨膜骨肉瘤)的生物学行为更具惰性。骨旁骨肉瘤更常见于年龄较大的患者，骨膜骨肉瘤与典型骨肉瘤的年龄分布相似。小细胞型骨肉瘤—小细胞型骨肉瘤值得注意的地方在于，在常规光学显微镜下观察苏木精和伊红(hematoxylin and eosin, H&E)染色的切片时，可能与其他“小圆蓝色细胞肿瘤”(如，尤文肉瘤)混淆[84,85]。确诊可能需要进行免疫组织化学染色、细胞遗传学和分子遗传学检测[86,87]。 (参见“尤文肉瘤家族肿瘤的治疗”)血管扩张型骨肉瘤—血管扩张型骨肉瘤是一种高级别的血管性肿瘤，含极少量的类骨质[88]。因为其在普通X线摄影上仅有溶骨表现，因此可能与动脉瘤样骨囊肿或骨巨细胞瘤(giant cell tumor of bone, GCTB)相混淆。其肉眼看似“多囊性血袋”，通常无实性肿瘤肿块[83]。因此，在活检时可能难以获得诊断性组织。在组织学上，极少量的类骨质形成和大量的多核巨细胞(图片 4)，使人联想到良性GCTB。然而，这些细胞具有高度多形性。 (参见“骨巨细胞瘤”)该型骨肉瘤的年龄分布及治疗与典型高级别骨肉瘤相同。对化疗的反应及生存情况与普通型骨肉瘤相似[89,90]。多病灶型骨肉瘤—罕见情况下，患者在诊断时表现为同步发生多处病灶，且均像是原发性肿瘤。很难确定这些病变是同步发生的多处原发灶，还是转移瘤。无论是哪一种判定结果，预后通常较差。多中心性骨肉瘤也可能具有异时性，治疗首个病灶后数年才出现其他骨性病灶。未分化型高级别多形性骨组织肉瘤—未分化型高级别多形性骨组织肉瘤(以前称为骨MFH)与骨肉瘤相似，但无类骨质产生[91]。尽管这类肿瘤在诱导化疗后的肿瘤坏死率较低，但长期生存率与普通型骨肉瘤相近[92]。表面(近皮质)骨肉瘤—表面骨肉瘤与这些髓内变异型骨肉瘤相比，在预后和治疗方面不同。这类骨肉瘤包括低级别骨旁骨肉瘤、中等级别骨膜骨肉瘤和高级别表面骨肉瘤[92-94]。对于低级别和中级别变异型，只要未侵入骨髓腔且无去分化成分，单纯手术就可能治愈[95,96]。●骨旁骨肉瘤–这类肿瘤中最常见的通常为骨旁骨肉瘤，是低级别成纤维细胞(可产生编织骨或板层骨)形成的一种表面病变。与普通型髓内骨肉瘤相比，该型发生于年龄较大(通常是20-40岁)的人群。股骨远端后侧是最常受累的部位，但也可能累及其他长骨。肿瘤起源于皮质，形成基底较宽的病变。然而，随着时间推移，病变可能侵入皮质进入骨内膜腔。常规骨旁骨肉瘤的治疗方法为单纯性手术切除，预期生存率约为90%[97,98]；然而，对于有去分化成分的骨旁骨肉瘤患者，可能采用辅助化疗。●骨膜骨肉瘤–骨膜骨肉瘤是一种中等级别的软骨母细胞性表面骨肉瘤，常位于胫骨近端，与普通型髓内骨肉瘤的年龄分布相同(影像 4)。其转移的可能性高于低级别的骨旁肿瘤，但低于典型的髓内骨肉瘤。辅助化疗对骨膜骨肉瘤的作用尚有争议。由于该型骨肉瘤的转移率估计为20%，很多中心推荐行辅助化疗。然而，回顾性报告表明，该型骨肉瘤比典型骨肉瘤的结局更好(一项研究中的10年生存率为84%[99])，接受辅助化疗的患者与接受单纯手术的患者相比无获益[99,100]，以及接受辅助化疗的患者中出现了数量令人担忧的第二恶性肿瘤[99]。部分由于骨膜骨肉瘤罕见，目前尚未针对这类问题进行随机试验，从而限制了可从现有文献中得出的结论。●高级别表面骨肉瘤–普通型高级别骨肉瘤也可能发生于骨表面，可能与骨旁骨肉瘤或骨膜骨肉瘤相混淆。其治疗方法与普通型髓内骨肉瘤相似。颌部骨肉瘤—另一种独特的变异型是颌部骨肉瘤，其往往发生于年龄较大的患者、呈惰性病程，相比远处转移更容易局部复发。骨外骨肉瘤—骨外骨肉瘤是一种发生于软组织的恶性肿瘤，不累及骨和骨膜，可产生类骨质、骨或软骨样物质(影像 5和影像 6)[101-106]。大多数发生于既往接受过放疗的情况下。与骨组织骨肉瘤不同，骨外骨肉瘤发生于年龄较大的患者人群，其好发的解剖学部位不同(最常见的部位为股部)，且对基于多柔比星的化疗显示出相对化学抵抗[102-104,107]。通常按照具有侵袭性行为的软组织肉瘤进行治疗。 (参见“肢体和胸壁原发性软组织肉瘤的局部治疗”和“局部复发和不能切除的局部晚期四肢软组织肉瘤的治疗”和“软组织肉瘤的临床表现、组织病理学、诊断性评估及分期”和“四肢软组织肉瘤的辅助化疗与新辅助化疗”和“转移性软组织肉瘤的全身性治疗”)患者教育—UpToDate提供两种类型的患者教育资料：“基础篇”和“高级篇”。基础篇通俗易懂，相当于5-6年级阅读水平(美国)，可以解答关于某种疾病患者可能想了解的4-5个关键问题；基础篇更适合想了解疾病概况且喜欢阅读简短易读资料的患者。高级篇篇幅较长，内容更深入详尽；相当于10-12年级阅读水平(美国)，适合想深入了解并且能接受一些医学术语的患者。以下是与此专题相关的患者教育资料。我们建议您以打印或电子邮件的方式给予患者。(您也可以通过检索“患者教育”和关键词找到更多相关专题内容。)●基础篇(参见“患者教育：骨癌(基础篇)”)总结●骨肉瘤是一种少见的原发性恶性骨肿瘤，特征是恶性肿瘤细胞产生类骨质或不成熟的骨。 (参见上文‘引言’)●骨肉瘤的发病年龄呈双峰分布，分别出现于青春期早期和65岁以上。骨肉瘤是儿童和年轻成人最常见的原发性骨肿瘤；发病高峰年龄为13-16岁。 (参见上文‘儿童’)●大多数儿童骨肉瘤是散发性的。少数病例与遗传性易感综合征有关，例如遗传性视网膜母细胞瘤、Li-Fraumeni综合征、Rothmund-Thomson综合征(RTS)，以及相关的Bloom综合征和Werner综合征。 (参见上文‘危险因素’)●通常认为成人骨肉瘤是继发性肿瘤，来自Paget骨病或一些其他良性骨病变的肉瘤性转化。美国60岁以上患者的所有骨肉瘤中半数以上为继发性，而在亚洲，Paget病相对少见，原发性骨肉瘤比例较高。 (参见上文‘成人’和‘Paget病和其他良性骨病变’)●大多数骨肉瘤患者表现为局限性疼痛，通常持续数月。体格检查中最重要的发现是软组织肿块，通常较大且触诊有压痛。就诊时，10%-20%的患者有明确的转移性疾病，最常累及肺部。 (参见上文‘临床表现’)●需要活检确诊。在仔细考虑日后根治性手术的前提下合理制定活检计划很重要，以免危及到后续治疗，尤其是保肢的机会。 (参见上文‘活检’)●骨肉瘤的组织学诊断依据是存在恶性肉瘤性间质并伴有肿瘤性类骨质和骨的产生。普通型(高级别髓内)骨肉瘤约占所有骨肉瘤的90%。其他较少见的组织学变异型包括：小细胞型、血管扩张型、多病灶型、表面(近皮质)型和骨外骨肉瘤，未分化型高级别多形性骨组织肉瘤[以前称为骨恶性纤维组织细胞瘤(MFH)]，以及颌部骨肉瘤。颌部骨肉瘤较常见于年龄较大的患者中。 (参见上文‘组织学分类’)●一旦确立骨肉瘤的诊断，则分期评估应包括受累骨全段的MRI、胸部CT、锝放射性核素骨扫描和/或PET。 (参见上文‘分期诊断性检查’)致谢—UpToDate公司的编辑人员感谢对这一专题的早期版本做出贡献的Murali Chintagumpala, MD。

引言—20世纪早期，尤文肉瘤(Ewing sarcoma, ES)和外周原始神经外胚叶肿瘤(primitive neuroectodermal tumor, PNET)(以前被称为外周神经上皮瘤)最初被当成两种不同的临床疾病。现已证明它们实际上属于尤文肉瘤家族肿瘤(Ewing sarcoma family of tumors, EFT)，EFT还包括骨外尤文肉瘤(extraosseous Ewing sarcoma, EES)、PNET、胸肺部的小细胞恶性肿瘤(Askin肿瘤)和非典型尤文肉瘤。由于具有相似的组织学和免疫组化特征和共同的非随机染色体易位，这些肿瘤被认为是同一细胞起源。虽然其组织发生的来源已争论多年，但越来越多来自免疫组织化学、细胞遗传学和分子遗传学研究的证据支持所有EFT均来源于间充质祖细胞[1]。 (参见“尤文肉瘤家族肿瘤的流行病学、病理学和分子遗传学”和“胸壁疾病和限制性生理”)EFT可发生在几乎所有的骨和软组织中，但最常发生于骨盆、中轴骨和股骨；患者通常表现为局部疼痛和肿胀。尽管在诊断时在不到25%的患者中会发现显性转移性病变，但由于在仅做局部治疗的患者中复发率高达80%-90%，我们推测几乎所有患者都存在亚临床转移性病变。因此，全身性化疗已成为治疗的重要组成部分[2]。近30年来在EFT多学科治疗的进展已使得生存率显著提高，且做保肢手术而不是截肢术的可能性增大[3-6](参见“骨源性肉瘤的术前评估、组织学分型和外科治疗原则”)。来自美国国立癌症研究所的监测、流行病学与最终结果(Surveillance, Epidemiology and End Results, SEER)项目的数据表明，在1975-1984年以及1985-1994年期间，尤文肉瘤患者的5年生存率从36%增至56%[3]。采用现代多学科治疗时，70%-80%无转移性病变的患者可实现长期生存[4,5,7]。在此，我们将讨论EFT的临床表现、诊断和分期。这些肿瘤的流行病学、病理、分子遗传学和治疗，进行诊断性骨活检的原则以及中枢性(幕上)PNET将在别处讨论。 (参见“尤文肉瘤家族肿瘤的流行病学、病理学和分子遗传学”和“骨肿瘤的诊断与活检技术”和“尤文肉瘤家族肿瘤的治疗”和“尤文肉瘤家族肿瘤的放射治疗”和“罕见的脑肿瘤”，关于‘幕上原始神经外胚叶肿瘤’一节)临床表现原发部位—EFT最常出现在四肢长骨(主要是股骨，但也可以是胫骨、腓骨及肱骨)和骨盆骨。脊柱、手和足受累相当少见[8,9]。欧洲组间合作尤文肉瘤研究(European Intergroup Cooperative Ewing Sarcoma Studies, EI-CESS)试验中975例患者的资料汇总显示，原发部位分布如下[9]：●中轴骨–54%(骨盆25%、肋骨12%、脊柱8%、肩胛骨3.8%、颅骨3.8%及锁骨1.2%)●附肢骨骼–42%(股骨16.4%、腓骨6.7%、胫骨7.6%、肱骨4.8%、足骨2.4%、桡骨1.9%、手骨1.2%)●其他骨–0.7%少数尤文肉瘤出现在软组织。相较于骨的未分化尤文肉瘤，EES患者年龄往往更大、女性更多见，更常出现在中轴骨而不是附肢骨骼[8,10-12]。症状和体征—EFT患者通常表现为持续数周或数月的局部疼痛或肿胀[13-15]。创伤(常轻微)可能是最先引起对病变注意的事件。疼痛开始时可能较轻，但迅速加重；运动可能加剧疼痛，往往晚上更甚。有时可察觉到一个明显的软组织肿块，常常牢固地贴附于骨上，触诊时有中等到明显的压痛[16,17]。患肢肿胀伴肿块表面红斑并不少见。病变临近关节的患者可能表现为关节活动性丧失，而累及肋骨的病变可直接扩散至胸膜并形成大的骨外肿块[18]。若病变累及脊柱或骶骨，神经根刺激或受压可导致背痛、神经根病或脊髓压迫的症状(如，无力或排便和/或排尿控制丧失)。 (参见“肿瘤性硬膜外脊髓压迫症(包括马尾综合征)的临床特征和诊断”)10%-20%的患者就诊时存在全身症状或体征，如发热、乏力、体重减轻或贫血[13]。发热(与肿瘤细胞产生的细胞因子有关)连同其他全身症状，与晚期病变有关。大约80%的患者表现为临床局部病变，但如前所述，据推测几乎所有患者均存在亚临床转移性病变。如不进行有效治疗，显性转移可能在数周到数月内变得十分明显。其意义在于，从出现症状到诊断的时间常被延迟，在一项报道中平均为9个多月[15,19]。原发性骨盆肿瘤患者较其他部位肿瘤患者明显更可能发生转移性病变(25% vs 16%)[9]。可能与就诊时临床明显转移性病变相关的其他因素包括：高水平的乳酸脱氢酶(lactic dehydrogenase, LDH)、有发热，出现症状到诊断的时间间隔小于3月和年龄大于12岁[20]。在一项病例系列研究中，没有上述任何危险因素的患者就诊时转移性病变率仅4%，有2个危险因素者为23%，而存在3个或4个危险因素时发生率几乎翻倍(44%)。诊断时转移性病变部位与复发性病变相似；以肺和骨/骨髓转移为主，比例大致相等。脊柱是最常累及的骨[21,22]。肺转移为70%-80%病例远处转移的首发部位，是EFT患者死亡的主要原因。而淋巴结、肝脏和脑转移不常见[14,23]。分期评估—初步评估的目标是确定诊断、评估局部病变范围，及确定是否存在转移扩散及扩散部位。临床分期需参考所有在根治性治疗前获得的资料，包括影像学检查、实验室检查、体格检查和组织活检的结果。放射影像学检查—诊断性检查通常是首先对受累部位进行X线平片摄影。累及骨的尤文肉瘤通常表现为边界不清的破坏性病变，伴有软组织肿块的情况最常见。肿瘤往往较大，在长骨中的位置常位于干骺端或骨干(影像 1和图 1)。放射影像学表现被描述为“侵蚀样”或“虫蚀样”，表明先是一系列细小的破坏性病变，后来逐渐融合。病变部位的皮质常膨胀，并且骨膜下的肿瘤使骨膜移位，造成骨膜三角的临床征象。特征性的骨膜反应产生了数层反应骨，积累成为“洋葱皮样”外观(影像 2)。肿瘤的软组织成分极少显示有任何钙化或骨化。如果有硬化，则表明是继发性骨反应而非骨肉瘤特征的原发骨形成。10%-15%的病例在诊断时有病理性骨折[13,15]。相对于X线平片摄影，原发部位的计算机断层扫描(computed tomography, CT)可以更好地显示皮质破坏和软组织病变的范围(影像 3)。一项包括387例儿童和成人患者的多机构研究得出结论认为，CT和MRI在骨和软组织肿瘤的局部分期方面具有同等的准确度[24]。然而，在大多数情况下优选MRI，因为它能更好地分辨肿瘤的大小，局部骨内和骨外病变的范围，以及筋膜面、血管、神经和器官与肿瘤的关系(影像 4)。有必要对整个受累骨进行影像学检查以排除存在跳跃式病变的可能性(即，同一骨内的髓质病变，但并不直接与原发病变相连)。鉴别诊断—对于表现为原发性骨肿瘤的EFT，鉴别诊断包括多种良、恶性疾病。最常见的非恶性疾病是亚急性骨髓炎，可能与EFT表现相似(特别是都存在发热及血沉升高)，并且骨扫描显示放射性示踪剂摄取增强，其他影像学检查显示软组织肿块[25]。肿瘤穿刺抽吸可能会得到脓样物质；然而，培养结果显示无菌。可表现为溶骨性病变的“良性”骨肿瘤包括骨嗜酸性肉芽肿和巨细胞瘤。破坏性嗜酸性肉芽肿常发生在较年轻时，不伴有相当大的软组织肿块。鉴别中应该考虑的恶性肿瘤包括儿童期的其他常见实体肿瘤，包括骨肉瘤、骨原发性淋巴瘤、骨未分化高级别多形性肉瘤(以前被称为骨恶性纤维组织细胞瘤或梭形细胞肉瘤)、急性白血病以及其他非骨肿瘤的转移瘤(尤其是神经母细胞瘤)(表 1)。影像学检查可能难以区分主要是溶骨性的骨肉瘤与尤文肉瘤。然而，骨肉瘤最常位于干骺端，并且通常有一个骨形成的边缘，这在尤文肉瘤中非常少见。骨原发性淋巴瘤的发病年龄比尤文肉瘤大，且骨质破坏通常比尤文肉瘤少。软骨肉瘤在这个年龄段并不常见；此外，软组织肿块通常含有钙化成分。 (参见“骨肿瘤的诊断与活检技术”和“原发性骨淋巴瘤”，关于‘影像学检查’一节和“软骨肉瘤”)EES和软组织外周性PNET必须与各种良性和恶性软组织肿瘤相鉴别。 (参见“软组织肉瘤的临床表现、组织病理学、诊断性评估及分期”，关于‘组织病理学’一节)对转移病变的诊断性检查—美国儿童肿瘤协作组(Children's Oncology Group, COG)骨肿瘤委员会提供了针对EFT患者的影像学检查指南(表 2)[26]：●转移病变的诊断性检查应包括胸部CT扫描以评估胸部是否有转移性病变。COG有关疑似肺转移的评估标准采纳了国家协作组尤文肿瘤研究1999的欧洲尤文肿瘤工作组倡议(European Ewing Tumor Working Group Initiative of National Groups Ewing Tumour Studies 1999, EURO-E.W.I.N.G 99)(表 3)[27,28]。●推荐进行放射性核素骨扫描以评估全身骨骼是否存在多发性病变。●尚不清楚正电子发射计算机断层扫描(positron emission tomography, PET)或联合PET-CT用于初始分期的效果[29-34]。至少有3项病例系列研究观察到，对于检测骨转移，PET比骨扫描和其他传统影像学方法的敏感性更高[32,34,35]。然而，一个潜在的问题是：由于联合PET-CT时通常的扫描范围是从颈部到股骨，不能像骨扫描一样显示所有的骨骼。在很多机构中，PET还没有取代放射性核素骨扫描用于初始分期。与检测骨转移的情况相比，PET检测肺转移的敏感性似乎比胸部CT低[32,33]，但在这方面联合PET/CT优于单纯CT[36]。一项回顾性研究探讨了放射性核素骨扫描在已进行了PET/CT用于初始分期患者中的实用性，得出结论认为，当原发肿瘤为溶骨性时，骨扫描对氟脱氧葡萄糖(fluorodeoxyglucose, FDG)PET/CT分期没有额外益处，并认为在这种情况下可不做骨扫描[37]。而如果EFT为硬化性，放射性核素骨扫描能检测到FDG PET/CT不能检测到的骨转移。PET在监测化疗和/或放疗(特别是新辅助化疗[38,39])的反应时以及术后评估可能的复发时作用更大。(参见“尤文肉瘤家族肿瘤的治疗”，关于‘疾病复发’一节)尽管如此，PET或PET/CT越来越多地被用于尤文肉瘤患者的初始分期。美国国家综合癌症网络(National Comprehensive Cancer Network, NCCN)基于共识的指南推荐PET扫描和/或骨扫描用于初始诊断性检查[40]，COG推荐就诊时如果骨闪烁成像显示原发性骨肿瘤为阴性，可行基线PET(表 2)[26]。分期系统—EFT不像其他实体肿瘤那样有通用的分期系统。尽管肌肉骨骼肿瘤学会和美国癌症联合会(American Joint Committee on Cancer, AJCC)/国际抗癌联盟 (International Union Against Cancer, UICC)提供了骨[41,42]和软组织(表 4)[43]原发性肿瘤的TNM(tumor node metastasis)分期系统，但未广泛应用于EFT。这些分期系统的一个明显缺陷是没有专门指明原发部位，而这是最重要的预后因素之一。 (参见下文‘预后因素’)此外，至少对软组织肿瘤而言，2002年版原发肿瘤分类特征在2010版未被保留。具体内容是，将肿瘤大小相同的浅表肿瘤和深部肿瘤归入相同预后组，这样就不再需要之前患者的风险分层标准，但没有支持性数据提示该标准没有必要。 (参见“软组织肉瘤的临床表现、组织病理学、诊断性评估及分期”，关于‘分期’一节)实验室检查—初始实验室检查应包括全血细胞计数、血清化学检查以及LDH，其中LDH是EFT患者的已知预后因素[9,44,45](参见下文‘预后因素’)。在神经母细胞瘤也属于鉴别诊断的情况下，检测尿儿茶酚胺水平可能有用，因为其在神经母细胞瘤患者中会升高，而在EFT患者中是正常的。 (参见“神经母细胞瘤的流行病学、发病机制和病理学”)骨髓穿刺抽吸与活检—由于EFT倾向扩散至骨髓[46]，一些临床医生主张对所有患者均行骨髓活检(至少单侧)以排除广泛转移性病变。MRI和骨扫描均不足以评估骨髓转移的可能性。尽管MRI对骨髓的改变很敏感，但不具特异性。骨髓脂肪含量的任何程度减少都可能改变信号，导致难以鉴别肿瘤和活动性造血。肿瘤活检—对软组织或骨肿块进行恰当活检的注意事项与其他软组织及骨肉瘤相似(参见“骨肿瘤的诊断与活检技术”)。在进行任何活检之前都应请外科医生会诊，并且应谨慎计划活检操作过程以获取足够的诊断组织而不影响后续手术，尤其是存在保肢机会时。应在完成原发部位的影像学检查后进行活检，而且外科医生、放射肿瘤科医生、内科或儿科肿瘤医生，以及病理科医生都应详细回顾这些检查，以便团队中的每个成员都能够充分了解诊断的注意事项。有必要获取足量的组织以供诊断。为了在“蓝色小圆细胞肿瘤”组中确定正确诊断常需要进行广泛的病理学评估，这意味着通常需要对组织进行特殊检查，这些标本需要特殊处理。该专题将在别处详细讨论。 (参见“骨肿瘤的诊断与活检技术”，关于‘样本的处理’一节)最常通过CT引导的空心针穿刺活检来确诊(影像 3)。如果空心针穿刺活检仅得到坏死物质，可能需要进行开放性活检。不论是穿刺活检还是开放性活检，都应获取标本进行微生物学检测以排除骨髓炎(参见上文‘鉴别诊断’)。不能仅采用细针抽吸活检进行诊断，这种活检只能在已知组织学诊断时用于对转移部位或可疑复发区域取样。此问题将在别处详细讨论。 (参见“骨肿瘤的诊断与活检技术”，关于‘活检技术’一节)预后因素—一些临床和生物学特征可帮助确定预后及指导治疗的强度[47]。这些特征包括是否存在转移、原发瘤的位置和大小、年龄、对治疗的反应，及存在某些染色体易位。病变范围—尤文肉瘤的关键预后因素是有无转移。局部病变患者的5年生存率大约为70%，而诊断时有显性转移的患者5年生存率平均为33%。 (参见“尤文肉瘤家族肿瘤的治疗”，关于‘局限期肿瘤的治疗’一节和“尤文肉瘤家族肿瘤的治疗”，关于‘转移性疾病的治疗’一节)远处病变的部位也影响结局。根据欧洲组间(European Intergroup)经验，就诊时局部病变和转移性病变患者5年无复发生存率分别为55%和21%[9]。有肺转移和骨转移的患者比单纯骨转移患者情况显著更差，而单纯骨转移的患者比有孤立肺转移的患者更差。大约30%转移局限于肺的患者可以存活5年，相比之下，有骨或骨髓受累的患者5年生存率仅10%。适合切除术的局限性肺转移患者，治愈机会尚可。 (参见“尤文肉瘤家族肿瘤的治疗”，关于‘肺转移’一节)肿瘤部位和大小—对于表现为局部病变的患者，中轴骨原发肿瘤(即，骨盆、肋骨、脊柱、肩胛骨、颅骨、锁骨和胸骨)患者比有四肢原发病变的患者治疗结局更差[9,48]。在一项病例系列研究中，以上两类患者的5年无复发生存率分别是40%和61%[9]。此外，原发肿瘤小(<100mL)的患者比肿瘤较大的患者情况要好[9,49]。发热、贫血和血清LDH升高都与肿瘤体积更大、预后更差相关[9,20,44,45]。较大的原发肿瘤以及累及骨盆和脊柱的原发肿瘤预后更差，这至少部分是由于难以得到宽的阴性切缘，以及对较大的病变放疗后局部失败率较高。 (参见“骨源性肉瘤的术前评估、组织学分型和外科治疗原则”，关于‘非肢体病变’一节和“尤文肉瘤家族肿瘤的放射治疗”)与骨源性肿瘤相比，骨外来源的肿瘤对生存率没有不良影响。肿瘤起源对结局有显著不良影响[11,50,51]。事实上，出现在皮肤或皮下部位的EFT通常都有着良好的预后[51-53]。对治疗的反应—对于看似局部病变的患者，若仅接受手术或放疗，治愈可能性仅为10%-20%；当加入化疗后治愈可能性将大大提高(参见“尤文肉瘤家族肿瘤的治疗”)。手术切除是否完全和对诱导治疗的反应都是重要的预后因素。新辅助化疗后切除的标本中残留大量活肿瘤的患者比极少或没有残留肿瘤的患者预后要差[9,54-58]。这些专题将在别处详细讨论。 (参见“骨源性肉瘤的术前评估、组织学分型和外科治疗原则”，关于‘新辅助化疗’一节和“尤文肉瘤家族肿瘤的放射治疗”，关于‘辅助放疗’一节)组织学—大多数研究发现，存在神经分化(如，在外周性PNET中)对生存率没有不利影响[10,59-61]。年龄—在有些报告中年龄较大者预后不良[62-64]，但其他报告未得出该结论[65,66]。例如，在一项报告中，年龄小于10岁的儿童比年龄更大的儿童5年无复发生存率显著更高(86% vs 55%)[63]。与之类似，来自3项连续COG研究的数据表明，年龄大于18岁、骨盆部肿瘤、肿瘤大于8cm，以及无依托泊苷/异环磷酰胺的化疗都与结局明显更差相关[67]。成年人的情况尚不明确。许多病例系列研究已报道成人(尤其年龄较大者[62])与儿童相比结局较差，而成人肿瘤体积更大或使用的烷化剂剂量更低[68]可能是部分原因。其他研究已观察到成人和儿童的病情一样，尤其是当应用足剂量化疗方案时[69]。分子学发现—EFT的特点是独特的非随机染色体易位，均涉及22号染色体上的尤文肉瘤基因。这些易位导致了不同染色体上的不同基因融合，有学者认为这些融合基因编码的杂交蛋白参与了肿瘤发生。 (参见“尤文肉瘤家族肿瘤的流行病学、病理学和分子遗传学”，关于‘分子遗传学’一节)据报道在这些肿瘤中基因融合至少有18种不同的结构可能性。差异主要来源于两个因素：EWS的融合伙伴(如，FLI1、ERG、ETV1、E1A或FEV)以及基因内部的断点位置。这种分子异质性可能对EFT的预后有一定影响[70-73]。例如，与其他融合类型相比，表达最常见的嵌合转录产物(所谓Ⅰ型转录产物，其中EWS外显子7与FLI1外显子6融合，约见于60%的病例中)的局部肿瘤患者的结局更好[71,72]。然而，较新的治疗方案似乎已消除了基于融合类型的预后差异[74]。仅少量量的研究对EFT中其他细胞遗传学及分子学改变的预后意义进行评估。然而，1号染色体短臂(1p)缺失、CDKN2A和p16/p14ARF纯合性缺失，及p53突变均与化疗效果差和预后更差相关[70,75,76]。EFT的遗传变异型与有临床意义表现的相关性还需要进一步的研究。应用预后因素进行治疗分层—如前所述，尚无公认的正式EFT分期系统。分期系统最重要的应用之一就是根据预期结局来对患者进行以治疗为目的的分层。由于存在转移性病变对预后有着非常大的影响，大多数EFT研究都通过是否存在转移性病变对患者分层。尽管原发部位(即，四肢 vs 骨盆或脊柱)也有预后意义，但仅有少数研究根据原发部位来决定治疗激进程度。 (参见“尤文肉瘤家族肿瘤的治疗”)有些研究者认为有局部病变但却显示预后不良特征(如，骨盆部位原发灶、年龄较大)的患者是“晚期”或“高危”患者，于是出于治疗目的将他们与有显性转移性病变的患者分到同一组。根据各个预后因素选择治疗被称为风险适应性治疗[54]。除了转移性病灶，还有学者使用一些预后指示变量，并结合SEER数据库数据开发出一种预后模型，用于1680例入组COG试验治疗尤文肉瘤的患者[77]。这些研究者根据年龄、骨盆病灶部位、族群以及是否存在转移性病灶，能够确定5种不同的预后组。 (参见“尤文肉瘤家族肿瘤的治疗”，关于‘转移性疾病的治疗’一节)资料表明有不同融合基因的患者预后存在差异，说明也有可能利用嵌合转录产物结构的异质性进行临床风险分组。例如，治疗效果和EWS融合类型的直接对比可能揭示某些嵌合体在治疗抵抗中的作用。然而，才刚开始进行前瞻性临床研究来探讨该假说。将确定EWS融合类型纳入将来的临床试验是恰当的。其他预后因素—一项报告发现可以根据体质指数(body mass index, BMI)异常来预测出化疗后肿瘤坏死情况不佳和总体生存情况较差[78]。患者教育—UpToDate提供两种类型的患者教育资料：“基础篇”和“高级篇”。基础篇通俗易懂，相当于5-6年级阅读水平(美国)，可以解答关于某种疾病患者可能想了解的4-5个关键问题；基础篇更适合想了解疾病概况且喜欢阅读简短易读资料的患者。高级篇篇幅较长，内容更深入详尽；相当于10-12年级阅读水平(美国)，适合想深入了解并且能接受一些医学术语的患者。以下是与此专题相关的患者教育资料。我们建议您以打印或电子邮件的方式给予患者。(您也可以通过检索“患者教育”和关键词找到更多相关专题内容。)●基础篇(参见“患者教育：尤文肉瘤(基础篇)”和“患者教育：骨癌(基础篇)”)总结—尤文肉瘤(ES)和外周原始神经外胚叶肿瘤(PNET)由同一谱系，被称为尤文肉瘤家族肿瘤(EFT)的肿瘤疾病组成，EFT还包括胸壁的小细胞恶性肿瘤(Askin肿瘤)。由于它们相似的组织学和免疫组化特征和共有的非随机染色体易位，这些肿瘤被认为是同一细胞起源，但其组织来源存在争议。 (参见上文‘引言’)EFT最常出现于四肢长骨(主要是股骨，但也可以是胫骨、腓骨及肱骨)和骨盆骨。脊柱、手和足受累相当少见。 (参见上文‘原发部位’)EFT患者常表现为持续数周或数月的局部疼痛或肿胀。创伤一般很轻微，但可能是最先引起对病变注意的事件。10%-20%的患者在就诊时存在全身症状或体征，如发热、乏力、体重减轻或贫血。 (参见上文‘症状和体征’)初步评估的目标是确定诊断、评估局部病变范围，及确定是否存在转移扩散及扩散部位。 (参见上文‘分期评估’)诊断性检查通常是先对受累部位进行X线平片摄影。累及骨的EFT常表现为边界不清的破坏性病变，呈“侵蚀样”或“虫蚀样”外观，最常伴有软组织肿块。虽然CT能够更好地显示皮质破坏和软组织病变的范围，但通过MRI可最好地分辨肿瘤的大小，局部骨内和骨外病变的范围，以及筋膜面、血管、神经和器官与肿瘤的关系。 (参见上文‘放射影像学检查’)转移性病变的诊断性检查包括：进行胸部CT以评估胸部是否有转移性病变，进行放射性核素骨扫描以评估全身骨骼是否存在多发性病变。正电子发射计算机断层扫描(PET)或PET/CT越来越多地被应用于EFT的初始分期和疗效评估，在某些有溶骨性病变的患者中它们也许能够替代需要放射性核素扫描的骨转移检测。一些临床医生主张对所有患者均行骨髓活检(至少单侧)以排除广泛转移性病变。 (参见上文‘对转移病变的诊断性检查’和‘骨髓穿刺抽吸与活检’)应谨慎计划活检以获取足够的诊断组织而不影响后续手术，尤其是存在保肢机会时。 (参见上文‘肿瘤活检’)一些临床和生物学因素可帮助确定预后及指导治疗的强度，这类因素包括是否存在转移、原发肿瘤的位置和大小、年龄、对治疗的反应，及存在某些染色体易位。 (参见上文‘预后因素’)

引言自引入前列腺特异性抗原(prostate specific antigen, PSA)筛查以来，前列腺癌诊断时的临床表现已明显改变。虽然就诊时大部分患者为局限于前列腺的病变，但仍有相当一部分患者就诊时已出现转移，转移会影响患者的生活质量，同时也是患者死亡的原因，因此转移性前列腺癌仍是重要的临床问题。最常见的转移为成骨性骨转移。这些转移通常有症状，可引起疼痛、体弱和功能障碍。前列腺癌骨转移的治疗为姑息性治疗。治疗的目标为改善生存、缓解疼痛、改善患者的活动能力以及防止并发症(如，病理性骨折、硬膜外脊髓压迫症)。本专题将总结晚期前列腺癌骨转移的治疗。治疗方法包括特异针对骨骼转移的治疗，破骨细胞抑制以防止骨受累并发症，以及针对癌症的全身性治疗。骨转移的临床表现和评估以及晚期前列腺癌患者的总体治疗策略详见其他专题。(参见“成人肿瘤患者骨转移的流行病学、临床表现及诊断”和“晚期前列腺癌骨转移：临床表现及诊断”和“播散性去势敏感性前列腺癌治疗概述”)有症状骨转移患者的治疗外照射 — 对于骨痛局限于1个部位或数量有限部位的去势抵抗性前列腺癌患者，首选治疗方法为外照射。外照射的内容详见其他专题。(参见“骨转移痛的放射治疗”)骨靶向放射性同位素 — 骨扫描发现骨转移部位存在异常核素吸收，且与骨痛密切相关，这是采取骨靶向放射性同位素治疗的先决条件。这些放射性同位素具有不同的物理特性(表 1)，主要用于有症状的成骨性骨转移晚期前列腺癌患者。镭-223是一种发射α粒子的放射性物质，是唯一在经恰当选择的患者中可延长OS和减少症状性骨骼事件(symptomatic skeletal event, SSE)的放射性药物(参见下文‘镭-223’)。虽然发射β粒子的放射性同位素可缓解疼痛，但不会显著延长OS。(参见下文‘发射β粒子的放射性同位素’)镭-223 — 镭-223(223Ra)是一种发射α粒子的亲骨性元素，其衰减产生的高能量辐射距离比发射β粒子的放射性同位素短得多，因此可在治疗肿瘤时最大程度减少对正常骨髓的毒性。在多灶性症状性骨转移前列腺癌患者中，镭-223可以延长OS，并降低骨病导致的SSE。镭-223适用于治疗去势抵抗性前列腺癌、有症状骨转移和无内脏转移的患者。但是，尚未确定适合镭-223治疗患者的最佳选择标准[1]。关于在临床试验之外镭-223联合其他系统性疗法治疗去势抵抗性前列腺癌的作用，目前尚未进行系统研究，故不推荐将其与任何其他药物联合使用。(参见下文‘基于镭-223的联合治疗’)ALSYMPCA试验 — 在Ⅲ期ALSYMPCA试验中，镭-223使总体生存期和初次发生SSE的时间都有所延长[2,3]。SSE的定义是需要进行外照射来减轻骨骼症状、新发症状性病理性骨折、出现脊髓压迫或肿瘤相关的骨科手术干预。在ALSYMPCA试验中，所有患者都存在去势抵抗性前列腺癌伴多发性骨转移，且在接受多西他赛化疗后疾病仍进展或不适合接受多西他赛化疗。纳入条件还包括存在2处或更多处骨转移且没有已知内脏转移。该试验将921例患者按2:1的比例随机分配至接受最佳支持治疗加镭-223(每4周1剂，持续6个周期)或最佳支持治疗加安慰剂。可选择的最佳支持治疗包括各种二线激素疗法和双膦酸盐。骨扫描发现，大约80%的患者存在至少6个转移灶，40%存在至少20个转移灶。近60%的患者既往接受过多西他赛化疗。关键的研究结果包括[2-5]：●镭-223组的总体生存期(该试验的主要终点)显著长于安慰剂组(中位14.9个月 vs 11.3个月，HR 0.70，95%CI 0.58-0.83)[2]。所有患者亚组在生存获益方面一致，包括曾接受过和没有接受过多西他赛化疗的患者。●两组对比，首次出现SSE的时间延长且具有统计学意义(中位数为15.6个月 vs 9.8个月，HR 0.66，95%CI 0.52-0.83)，SSE包括第一次需要使用外照射缓解症状、新发病理性骨折、脊髓压迫或肿瘤相关骨科手术干预[3]。如果单独分析SSE，在使用外照射缓解症状(HR 0.67)和脊髓压迫(HR 0.52)方面，两组的差异都具有统计学意义。而在新发病理性骨折(0.62)或骨科手术干预(0.72)方面，两组的差异没有统计学意义，但此类事件的数量有限。该试验进行过程中未进行常规X线摄影，因此所有SSE都为临床检查发现。●一项预先设定的亚组分析显示，对于有多西他赛用药史的患者和没有多西他赛用药史的患者，镭-223的效果相似[4]。无论既往是否使用过多西他赛，治疗的耐受性都较好，但在既往用过多西他赛的患者中，3-4级血小板减少症的发生率较高(9% vs 3%)。●与安慰剂相比，镭-223治疗的安全性良好，所有不良事件的发生率均较低；3-4级不良事件的发生率差异没有临床意义。一项最终分析考察了患者接受最后一剂镭-223后3年的长期安全性数据，证实该疗法的耐受性良好且没有出现新的安全性问题。在405例接受长期随访的患者中，1例患者发生了再生障碍性贫血，没有患者出现急性髓系白血病、骨髓增生异常综合征或新发原发性骨肿瘤[5]。在研究药物给药期间，接受镭-223治疗的患者的生活质量较好[2]。该临床试验使用了6剂镭-223(每4周1剂)，这也是获得批准的镭-223给药方案。一项随机试验表明，使用更大剂量的镭-223或使用多达12个周期的延长方案并无任何益处[6]。来自有限数量患者的数据表明，给予第二个周期的镭-223(注射6剂)，血液系统毒性不大且对限制疾病进展具有一些早期效果[7]。还需进行其他试验以进一步评估再治疗的作用。目前尚无随机试验比较了镭-223与其他已知可延长去势抵抗转移前列腺癌患者总生存期的药物(表 2)。目前尚未确定适合镭-223治疗的患者的最佳选择标准[1]。影响不同治疗方法的先后顺序和组合的因素见其他专题。(参见“播散性去势敏感性前列腺癌治疗概述”)基于镭-223的联合治疗 — 有学者研究了镭-223联合其他药物治疗去势抵抗性前列腺癌的作用。然而，尚未确定这种联合治疗的益处，且至少有部分数据表明，镭-223+阿比特龙会导致有害结局。鉴于这些资料，对于大部分患者，我们建议不要同时启用镭-223和阿比特龙。对于已使用阿比特龙的患者，加用镭-223是否安全以及是否有临床获益，目前还不清楚。若采取这种方案，则最好确保患者还接受骨改良药物，如唑来膦酸或地诺单抗。●两项非随机研究中，共有299例患者接受了镭-223+阿比特龙或恩杂鲁胺[8,9]。有部分患者同时接受了地诺单抗治疗，两项研究均未发现其有任何新的安全性问题，且结果提示患者的生存期有所改善。●但后来一项关于阿比特龙+镭-223或安慰剂的Ⅲ期安慰剂对照试验未能确认联合治疗的益处；而且联合治疗增加了骨折率[10]。该试验中，806例骨转移为主的去势抵抗性前列腺癌患者基本没有症状且未接受过化疗，他们接受了阿比特龙+泼尼松/泼尼松龙治疗，然后被随机分配至接受镭-223或安慰剂。中位随访22个月时，与安慰剂组相比，镭-223组中有更多的患者发生了至少1种SSE或死亡(49% vs 47%)。该研究未达到主要终点，镭-223+阿比特龙组中无SSE中位生存期为22.3个月，而单纯阿比特龙组为26个月，即使用镭-223使骨骼事件风险升高了22%。联合治疗组中的骨折发生率为29%，而对照组为11%。有一点值得注意，两组中都只有大约40%的患者接受了破骨细胞抑制剂。镭-223组中的总体生存期缩短并不具有统计学意义(30.7个月 vs 33.3个月，HR 1.195，95%CI 0.950-1.505)，但可能具有临床意义。基于这些发现，加拿大卫生部(Health Canada)推荐不要将镭-223与醋酸阿比特龙+泼尼松/泼尼松龙联合应用，而欧洲药品管理局(European Medicines Agency)规定只对以下患者使用镭-223：之前接受了至少2次治疗的骨转移前列腺癌患者或不能接受任何其他治疗的患者。基于已发布的资料，我们认同这些限制，不推荐镭-223+阿比特龙的联合治疗。●值得注意的是，在后续一项随机试验中发现破骨细胞抑制剂具有降低骨折率的作用，这项PEACE Ⅲ期试验比较了恩杂鲁胺+镭-223与单用恩杂鲁胺治疗无症状或轻度症状的转移性去势抵抗性前列腺癌患者。在公布ERA 223结果后，修订了临床试验方案，强制要求所有患者使用破骨细胞抑制剂。有关其中一部分治疗患者(n=146)的初步报告显示，联合治疗与单用恩杂鲁胺(无破骨细胞抑制剂)的骨折风险分别为33%和13%，而通过强制要求持续使用破骨细胞抑制剂，上述骨折升高风险几乎全部消除，联合治疗组骨折风险变为3%，单用恩杂鲁胺组风险变为0[11]。●一项Ⅱ期试验纳入了53例存在2处或更多骨转移且未接受过化疗的去势抵抗性前列腺癌患者，将其随机分配至多西他赛+镭-223组或单独用多西他赛组[12]。联合治疗组的血清肿瘤标志物(PSA和骨碱性磷酸酶)下降更持久。单用多西他赛组的发热性中性粒细胞减少发生率更高(15% vs 0)。然而，目前尚无这种联合方案的长期安全数据，其应用仍处于试验阶段。该试验仍在进行中，更多信息可查询DORA 试验(DORA trial) (多西他赛每3周1次vs镭-223+多西他赛每6周1次)。发射β粒子的放射性同位素 — 在开发镭-223之前，临床上已对多种发射β粒子的放射性同位素评估和应用(表 1)。研究最广泛的药物为锶-89和钐-153。其他研究过的同位素包括磷-32、铼-186和铼-188[13]。●有多项临床试验评估了锶-89治疗前列腺癌骨转移的疗效[14-17]。其中最大的一项试验(757例患者)将锶-89与多西他赛化疗相联合[17]。意向治疗分析发现，各组的总体生存期和临床无进展生存期的差异均无统计学意义。●两项小型Ⅲ期随机试验比较了钐-153与安慰剂。这两项试验均发现，钐-153缓解疼痛的作用比安慰剂有效[18,19]。发射β粒子的放射性同位素的主要毒性为骨髓抑制，锶的骨髓抑制作用比钐更显著。这种毒性限制了此类物质的使用，没有证据表明使用发射β粒子的放射性同位素可延长患者生存期。双膦酸盐 — 对于尚未使用破骨细胞抑制剂的前列腺癌患者，静脉用伊班膦酸或其他双膦酸盐可能替代外照射来治疗骨转移所致疼痛。然而，美国并未批准将这些药物用于该适应证。(参见“破骨细胞抑制剂治疗乳腺、前列腺及其他部位实体瘤的骨转移”，关于‘双膦酸盐’一节)一项多中心试验纳入了470例骨转移所致疼痛的前列腺癌患者，将其随机分配至接受单次静脉用伊班膦酸(6mg)或放疗(8Gy，一次给予)[20]。4周时疼痛未缓解的患者可转为接受另一种治疗。4周和12周时，两个治疗组中疼痛缓解的差异并无统计学意义。两个治疗组的治疗转变率差异没有统计学意义(初始接受伊班膦酸的患者中为31%，初始接受放疗的患者中为24%)；总体生存期的差异也没有统计学意义(中位值12.9个月 vs 12.2个月)。虽然放疗仍是大多数骨转移所致局限性骨痛患者的标准治疗方法，但对于放疗无效的患者以及特殊临床状况(如患者存在放疗禁忌证)，静脉用伊班膦酸是一种有效的治疗方法。聚焦超声 — 对于标准放疗无效或不适合接受放疗的患者，采用磁共振引导聚焦超声可缓解疼痛性骨转移[21]。聚焦超声波可提高成像焦点的温度，从而引起热组织消融。一项国际多中心试验证实该方法有效且安全，因此监管机构批准了这种设备的使用[22]。(参见“骨转移瘤的影像引导下消融”，关于‘结局’一节)手术 — 一般仅对发生病理性骨折或硬膜外脊髓压迫症的转移性前列腺癌患者进行手术或椎体后凸成形术，以治疗其骨病变。(参见“肿瘤性硬膜外脊髓压迫症(包括马尾综合征)的治疗和预后”和“骨转移、多发性骨髓瘤和淋巴瘤患者中完全性病理性骨折和病理性骨折倾向的评估和处理”)镇痛药 — 若专门针对转移性疾病的措施不能充分控制癌症相关骨痛，现有多种药物可用于治疗。癌症患者中的疼痛治疗详见其他专题。(参见“阿片类药物治疗癌症疼痛：镇痛最优化”和“癌症疼痛治疗：对乙酰氨基酚和非甾体类抗炎药的使用”和“癌症疼痛治疗：辅助镇痛药(协同镇痛药)”和“癌症疼痛的心理、康复和整合治疗”)全身性抗癌治疗 — 对于转移性前列腺癌引起骨转移的患者，全身性抗癌治疗为其治疗的重要组成部分。雄激素剥夺治疗(androgen deprivation therapy, ADT)作为初始治疗以及去势抵抗性前列腺癌的多种其他治疗方式参见其他专题(参见“播散性去势敏感性前列腺癌治疗概述”)。全身性治疗还会影响SSE或SRE(skeletal-related events, SRE)的发生频率。SSE是临床上可检测到的事件，并不依赖于常规影像学检查获得的结果。SSE为临床上明显的事件，而不是临床上不明显但放射学检查可检测到的事件。已证实可降低骨骼事件发生频率的药物包括镭-223、恩杂鲁胺和阿比特龙，以及破骨细胞抑制剂地诺单抗和唑来膦酸(表 3)。(参见“去势抵抗性前列腺癌的雄激素通路靶向治疗”和‘破骨细胞抑制’)骨转移并发症的预防镭-223 — 镭-223除了可治疗骨转移引起的症状外，研究证实其还可显著降低症状性骨转移患者中的SSE发生率。SSE包括首次使用外照射缓解症状、新发病理性骨折、脊髓压迫或肿瘤相关骨科手术干预。(参见上文‘镭-223’)针对镭-223的确定性临床试验仅限于有症状骨转移患者，尚未评估其治疗无症状性骨转移患者的作用。破骨细胞抑制 — 前列腺癌患者的骨转移主要为成骨性骨转移，但也有由破骨细胞介导的显著溶骨性成分。此类患者确实会发生病理性骨折，但发生频率通常低于以溶骨性转移为主的其他癌症。此外，ADT可引起骨吸收和骨丢失增加，这会增加发生骨质疏松性骨折的风险。(参见“雄激素剥夺治疗的副作用”，关于‘骨质疏松和骨折’一节和“破骨细胞抑制剂治疗乳腺、前列腺及其他部位实体瘤的骨转移”和“骨转移的机制”，关于‘溶骨性骨转移vs成骨性骨转移’一节)骨转移所致SRE的预防 — 对于去势抵抗性前列腺癌骨转移患者，破骨细胞抑制(双膦酸盐或地诺单抗)可降低骨相关并发症的发生率，可推荐使用这些药物。然而，在激素敏感性转移性前列腺癌患者中进行的试验表明，破骨细胞抑制并不会显著降低SRE的发生率；因此，这种情况下不适合使用此类药物。去势抵抗性前列腺癌双膦酸盐 — 对于去势抵抗性前列腺癌骨转移患者，双膦酸盐可延迟SRE的发生；SRE是一个复合终点，包括病理性骨折、骨骼放疗、骨骼手术以及脊髓压迫症。对于去势抵抗性前列腺癌患者，现有充分数据支持将大多数患者的唑来膦酸剂量定为每12周1次，而非每4周1次。然而，对于存在广泛或高度症状性骨转移的患者(包括所有正在接受镭-223的患者)，我们仍然倾向于采用每4周1次的剂量方案，至少最初采用该方案。(参见“破骨细胞抑制剂治疗乳腺、前列腺及其他部位实体瘤的骨转移”，关于‘给药间隔’一节)一项试验纳入了643例在接受ADT时疾病进展的患者，并证实了唑来膦酸对发生骨转移的去势抵抗性前列腺癌患者有益[23]。该试验将这些患者随机分配至接受两种唑来膦酸剂量之一(4mg或8mg)或安慰剂，各组都是每3周给药1次。由于肾毒性风险升高，研究者在试验早期将8mg剂量的唑来膦酸减至4mg。随访24个月时，唑来膦酸组的SRE发生率显著低于安慰剂组(38% vs 49%)，且发生SRE的中位时间显著更长(488日 vs 321日)[24]。唑来膦酸组患者的疼痛和镇痛评分显著低于安慰剂组，但在病情进展、体能状态和生活质量评分方面，各组均无差异。其他双膦酸盐并非同样有效[25]。针对氯膦酸二钠的临床研究并未得出确定结果[26-28]，两项针对帕米膦酸二钠的试验并未发现其在SRE或疼痛控制方面的益处具有统计学意义[29]。美国批准将唑来膦酸用于存在骨转移的去势抵抗性前列腺癌患者。欧洲专利药品委员会已批准将唑来膦酸用于所有发生骨转移的前列腺癌患者。地诺单抗 — 地诺单抗是一种完全人源化的单克隆抗体，该抗体可与RANK配体结合，该配体是破骨细胞形成和活化途径的关键因素。(参见“地诺单抗治疗骨质疏松”和“骨转移的机制”)研究者已在一系列的临床情况中评估了地诺单抗。地诺单抗被批准用于预防前列腺癌骨转移患者SRE的发生，以及用于治疗接受ADT前列腺癌患者的骨丢失。对于已确定存在骨转移的去势抵抗性前列腺癌患者，地诺单抗预防发生SRE的作用比唑来膦酸有效，但并不能延长总体生存期或延迟疾病进展。一项双盲Ⅲ期试验纳入了1901例至少存在一处骨转移灶的去势抵抗性前列腺癌患者，将其随机分配至接受地诺单抗(120mg)或唑来膦酸(4mg)，各组都为每4周给药1次[30]。两个治疗组的患者都被建议使用钙和维生素D补充剂。该研究的主要目的是确定首次发生SRE(病理性骨折、需要进行放疗或手术或脊髓压迫症)的时间。中位随访约12个月时，得到了以下结果：●与唑来膦酸组相比，地诺单抗组首次发生SRE的时间显著更迟(中位时间20.7个月 vs 17.1个月，HR 0.82，95%CI 0.71-0.95)。●两组总体生存期(19.4个月 vs 19.8月，HR 1.03)或疾病进展时间(两组均为8.4个月，HR 1.06)的差异并无统计学意义。●两种治疗的耐受性都较好。与唑来膦酸组相比，地诺单抗组有颌部骨质坏死(osteonecrosis of the jaw, ONJ)更频繁(2.3% vs 1.3%)的趋势，但这些差异并无统计学意义。地诺单抗组中低钙血症的发生率也显著更高(13% vs 6%)。此外，地诺单抗组患者中低磷血症的发生率超过25%[31]。去势敏感性前列腺癌 — 与去势抵抗性前列腺癌患者中的结果相比，对于存在骨转移的去势敏感性前列腺癌患者，在ADT初始治疗期间开始使用唑来膦酸并无任何益处。CALGB 90202试验将645例患者随机分配至接受唑来膦酸或安慰剂[32]。该试验由于企业赞助商撤回资金支持而过早终止。中位随访24个月时，就首次发生SRE的时间而言，两组的差异并无统计学意义(中位值为31.9个月 vs 29.8个月，HR 0.97)。总体生存期差异也无统计学意义(中位数38个月 vs 36个月，HR 0.88，95%CI 0.70-1.12)。关于地诺单抗预防去势敏感性前列腺癌患者发生SRE的作用，目前尚无相关数据。预防ADT相关骨丢失 — 在接受ADT治疗前列腺癌的患者中，双膦酸盐和地诺单抗都可显著降低骨转化率以及增加骨密度。这种情况下的随机试验结果参见其他专题。(参见“雄激素剥夺治疗的副作用”，关于‘地诺单抗’一节和“雄激素剥夺治疗的副作用”)预防或延迟骨转移 — 对于未转移的去势抵抗性前列腺癌患者，随机试验并未证实双膦酸盐和地诺单抗有较好的风险/收益比。双膦酸盐 — 虽然临床前资料表明双膦酸盐对前列腺癌具有抗肿瘤作用，但对于没有骨转移的去势抵抗性前列腺癌患者，没有研究证实辅助使用双膦酸盐可显著降低骨转移的发生率。Ⅲ期ZEUS试验纳入了1433例高危前列腺癌患者(PSA≥20ng/mL、Gleason评分为8-10或存在淋巴结转移)，并将其随机分配至接受唑来膦酸(每3个月4mg)或安慰剂，持续4年[33]。中位随访4.8年后，两组的骨转移(4年发病率，唑来膦酸组14.7% vs 对照组13.2%)发生率差异并无统计学意义。一项规模较小的试验采用了氯膦酸二钠，也未证实可降低骨转移的发生率[34]。地诺单抗 — 虽然地诺单抗可延迟未转移的去势抵抗性前列腺癌患者首次出现骨转移的时间，但其并不能延长总生体存期或总体无进展生存期，且会引起相当多的病例出现ONJ。地诺单抗尚未被批准用于此适应证。但对于没有骨转移但PSA升高且PSA倍增时间不到6个月的患者，可考虑使用地诺单抗。一项Ⅲ期临床试验纳入了1432例未转移的去势抵抗性前列腺癌患者，将其随机分配至接受地诺单抗或安慰剂组[35]。所有患者都接受了双侧睾丸切除术或至少持续6个月的促性腺激素释放激素激动剂或拮抗剂的连续治疗。如果连续3次测定都显示PSA升高，则确定患者为去势抵抗性。如果血清PSA≥8.0μg/L或PSA倍增时间<10个月，则将患者归类为骨转移高风险。与安慰剂相比，地诺单抗显著延长了患者的无骨转移生存期(29.5个月 vs 25.2个月，HR 0.85，95%CI 0.73-0.98)。首次发生骨转移的时间也显著推迟了4个月。然而，总体生存期的差异并无统计学意义(中位44个月 vs 45个月，HR 1.01)。该试验的一项后续探索性分析发现，PSA快速倍增的患者较短时间内出现了骨转移[36]。此外，地诺单抗对延迟骨转移发生的作用比安慰剂更明显。对于PSA倍增时间≤6个月的患者，地诺单抗组中骨转移的中位时间为25.9个月，安慰剂组为18.7个月(HR 0.77，95%CI 0.64-0.93)。地诺单抗治疗组中有5%的患者出现ONJ，而安慰剂组中没有患者出现。地诺单抗组中低钙血症的发生率更高(1.7% vs 0.3%)。钙和维生素D — 开始破骨细胞抑制剂治疗前，应评估钙和维生素D的水平，如果较低应在用药前予以纠正。如果没有禁忌证(如，之前存在高血钙症、复发性肾结石)，所有接受破骨细胞抑制剂的患者都应接受钙和维生素D补充治疗，以防止发生继发性甲状旁腺功能亢进症和低钙血症，以及确保有足够的钙用于骨修复/愈合。副作用 — 虽然一些大型随机临床试验已明确使用破骨细胞抑制有益，但这些药物可引起极少数病例出现严重毒性。重要的潜在副作用包括：●ONJ●低钙血症●肾功能受损(双膦酸盐有该副作用但地诺单抗没有)并发症的潜在风险不应妨碍破骨细胞抑制剂的应用。仔细选择患者、避免对高风险患者使用这些药物以及在治疗期间持续警惕并发症，这对最大程度降低严重并发症的风险很重要[37,38]。破骨细胞抑制剂(双膦酸盐和地诺单抗)相关并发症的预防和治疗参见其他专题。(参见“抗骨吸收药物在晚期恶性肿瘤患者中的治疗风险”)学会指南链接部分国家及地区的学会指南和政府指南的链接参见其他专题。(参见“Society guideline links: Diagnosis and management of prostate cancer”和“Society guideline links: Cancer pain”)总结与推荐●中轴骨的成骨性转移是晚期前列腺癌最常见的转移部位。优选姑息治疗，目标是缓解疼痛、改善患者活动能力以及预防并发症(如，病理性骨折或硬膜外脊髓压迫)。●全身性治疗是患者综合治疗的重要部分，以控制症状并延缓骨转移进展。(参见“播散性去势敏感性前列腺癌治疗概述”)●对于全身性治疗不能控制疼痛且只有1个或数量有限的局灶性症状性骨转移的患者，我们建议行外照射而非给予静脉用伊班膦酸(Grade 2B)。(参见上文‘外照射’和‘双膦酸盐’)对于接受外照射的患者，我们建议对受累区域给予单次照射，剂量为8Gy(Grade 2A)。(参见“骨转移痛的放射治疗”，关于‘外照射’一节)●对于去势抵抗性前列腺癌患者，如果存在全身性治疗或外照射无法控制的多灶性症状性成骨性骨转移，则发射α粒子的骨靶向放射性同位素(如，镭-223)可能提供显著的姑息性治疗益处。(参见上文‘骨靶向放射性同位素’)镭-223应仅用于特定的去势抵抗性前列腺癌患者：有症状性骨转移且无内脏转移。(参见上文‘ALSYMPCA试验’)尚未证实镭-223联合全身性治疗的益处，至少有部分数据表明，同时启用镭-223+阿比特龙会导致有害结局。对于大部分患者，我们建议不要同时启用镭-223和阿比特龙(Grade 2B)。对于已使用阿比特龙的患者，加用镭-223是否安全以及是否临床有效目前还不清楚。若选用这种方案，患者还应接受骨改良药物，如唑来膦酸或地诺单抗。(参见上文‘基于镭-223的联合治疗’)●对于存在骨转移的去势抵抗性前列腺癌患者，我们推荐使用破骨细胞抑制剂(地诺单抗或唑来膦酸)来降低骨转移患者发生骨骼并发症的风险(Grade 1A)。一项大型随机试验显示地诺单抗的疗效更好，因此我们建议大多数患者使用地诺单抗而非唑来膦酸(Grade 2A)。对于费用和/或报销为重要考虑因素的患者，唑来膦酸是一种合适的替代选择。(参见上文‘去势抵抗性前列腺癌’)如果选择唑来膦酸，现有充分证据支持将大多数去势抵抗性前列腺癌患者的剂量定为每12周1次，而非每4周1次。然而，对于存在广泛或高度症状性骨转移的患者(包括所有正在接受镭-223的患者)，我们仍然倾向于采用每4周1次的剂量方案，至少最初采用该方案。(参见上文‘双膦酸盐’)●控制癌症相关骨痛是患者整体治疗的一项重要内容，尤其对于已经实施了特异针对骨转移的各项措施仍无法有效控制的情况。(参见“阿片类药物治疗癌症疼痛：镇痛最优化”和“癌症疼痛治疗：对乙酰氨基酚和非甾体类抗炎药的使用”和“癌症疼痛治疗：辅助镇痛药(协同镇痛药)”和“癌症疼痛的心理、康复和整合治疗”)

Tibial Plateau FractureRelated SummariesShin painGeneral InformationDescriptionany fracture of the proximal tibia, ranging from simple lateral split to complex comminuted fracture with severe soft tissue injury1,2,3,4TypesSchatzker classification1,2,4type I - pure cleavage (split) of lateral tibial plateau type II - cleavage (split) with depression of lateral tibial plateau type III - pure central depression of lateral tibial plateau type IV - fracture of medial plateau type V - bicondylar fractures type VI - fracture with dissociation of tibia metaphysis and diaphysis Muller AO classification (also adopted by Orthopedic Trauma Association [OTA])1,2type A - extra-articular fractures A1 - avulsion A2 - metaphyseal simple A3 - metaphyseal multifragmentary type B - partial articular fractures B1 - pure split B2 - pure depression B3 - split-depression type C - complete articular fractures (with detachment of fragments from diaphysis) C1 - articular simple, metaphyseal simple C2 - articular simple, metaphyseal multifragmentary C3 - articular multifragmentary each subtype further divided into 3 additional subtypes denoting lateral (.1), medial (.2), or bilateral (.3) type often preceded by 41, with 4 denoting tibial fracture, and 1 denoting proximal location Moore classification1type I - coronal split fracture of medial tibia plateau which displaces distally type II - fracture of entire condyle type III - rim avulsion fracture type IV - rim fracture displaced distally or impacted and crushed type V - 4-part fracture where tibial eminence separates from diaphysis and condyles Definitionsknee-specific patient-reported outcome measuresInternational Knee Documentation Committee (IKDC) subjective knee evaluation formassesses improvement or deterioration in symptoms, function, and sports activities due to knee impairmentappropriate for use in patients with a variety of knee conditions, including ligament injuriesmeniscal injuriesarticular cartilage lesionspatellofemoral pain18-item scale with 3 domains assessingsymptoms, including pain, stiffness, swelling, locking/catching, and giving way (7 items)sport activities (1 item) and daily activities (9 items)current knee function (1 item) and knee function prior to knee injury (not included in the total score) responses vary for individual items, including yes/no responses, 5-point Likert scales, and 11-point numerical rating scalespossible score range is 0-100, where 100 indicates no limitation with daily or sporting activities and absence of symptoms References 22588746Arthritis Care Res (Hoboken) 2011 Nov;63 Suppl 11:S208full-textoriginal scale can be found in 11573919Am J Sports Med 2001 Sep-Oct;29(5):600, commentary can be found in 11799013Am J Sports Med 2002 JanWestern Ontario and McMaster Universities Osteoarthritis (WOMAC) Indexself-administered or interview-administered questionnaire assessing disease course or response to therapeutic intervention in patients with hip and/or knee OAconsists of 24 items divided into 3 subscales, includingpain (severity during various positions or movements; 5 items)function (difficulty performing daily functional activities; 17 items)stiffness (severity after periods of inactivity; 2 items)available in 5-point Likert scale, 11-box numerical rating scale, and 100-mm visual analog scale (VAS) formatsLikert scale - scale ranges from 0 indicating "none" to 4 indicating "extreme"11-box numerical rating scale - horizontal scale, with left end box indicating "none" and right end box indicating "extreme"100-mm VAS - scale ranges from 0 indicating "none" to 100 indicating "extreme"Reference - 22588746Arthritis Care Res (Hoboken) 2011 Nov;63 Suppl 11:S208full-textKnee injury and Osteoarthritis Outcome Score (KOOS) questionnairedeveloped as an extension of the WOMAC Index (questions from the WOMAC Index version 3.0 are included in the KOOS questionnaire)42-item questionnaire evaluating short- and long-term symptoms, and function in patients with knee injury and osteoarthritis5 KOOS subscales includepain frequency and severity during functional activities (9 items)other symptoms (7 items), such asseverity of knee stiffnesspresence of swelling, grinding or clicking, catching, and/or range of motion restrictionactivities of (function in) daily living (equivalent to function subscale in WOMAC; 17 items)function in sport and recreation (5 items)knee-related quality of life (4 items)Likert scale-based scoring system, each item has 5 possible answer options with scores ranging from 0 (no problems) to 4 (extreme problems)scores are transformed to a 0-100 scale, with higher scores indicating fewer knee problemsno aggregate score is calculated; each subscale is analyzed separatelyvalidated for anterior cruciate ligament reconstruction, meniscectomy, and total knee replacementReference - 14613558Health Qual Life Outcomes 2003 Nov 3;1:64full-textLysholm knee scoreevaluation of function in patients with knee ligament injury and anteromedial, anterolateral, combined anteromedial/anterolateral, posterolateral rotatory, or straight posterior instability8 domains of revised scale includelimpsupport (using cane or crutches)locking (locking sensation of knee)painstair climbinginstability (giving way sensation of knee)swellingsquattingscores range from 0 to 100excellent outcome 95-100 pointsgood outcome 84-94 pointsfair outcome 65-83 pointspoor outcome < 65 pointsReferences22588746Arthritis Care Res (Hoboken) 2011 Nov;63 Suppl 11:S208full-textoriginal scale can be found in 4028566Clin Orthop Relat Res 1985 Sep;(198):43Tegner activity scoreassesses ability of patients with knee ligament injuries to perform various functions related to work and sporting activitiesdeveloped to complement the Lysholm knee scale1 activity level is selected from a range of 11 levels that best represents the patient's activity levellevels range from 0 to 10, with higher levels representing participation in higher-level activitiesactivity level 0 indicates the patient is on sick leave and receiving disability due to knee problemactivity level 10 indicates the patient participates in national elite competitive sportsReferences22588746Arthritis Care Res (Hoboken) 2011 Nov;63 Suppl 11:S208full-textoriginal scale can be found in 4028566Clin Orthop Relat Res 1985 Sep;(198):43Western Ontario Meniscal Evaluation Tool (WOMET)health-related quality of life tool for patients with meniscal tears, or meniscal repair or resection16-item scale with 3 domains assessingphysical symptoms (9 items)sports/recreation/work/lifestyle (4 items)emotions (3 items)each item is scored using a VAS (100-mm lines anchored at ends by extremes of dimension being measured)total possible score ranges from 0 to 1,6000 is best or least symptomatic score1,600 is highest and most symptomatic scoremay be reported as a total overall score, score for each domain, or as a percentage of normal (to calculate percentage of normal the total score is subtracted from 1,600, divided by 1,600, then multiplied by 100)Reference - 17873546Clin J Sport Med 2007 Sep;17(5):349Oxford knee scoreassesses symptoms directly related to kneeconsists of 12 questions that are rated on a Likert scale, with values from 0 to 4a summative score is calculated, with 48 as best possible score (least symptomatic) and 0 as worst possible score (most symptomatic)Reference - 24253376Knee Surg Sports Traumatol Arthrosc 2014 Aug;22(8):1933Hospital for Special Surgery (HSS) knee scoreassessment for suspected injury to ≥ 1 knee ligamentmaximum score is 50 points, indicating normal knee functionif all subjective questions are answered as normal, 18 points are awarded; questions focus on presence of pain or swelling, difficulty with stair-climbing or cutting maneuvers, other functional impairment, and loss of confidence in kneeif all objective questions are answered as normal, 32 points are awarded; questions focus on presence of tenderness, effusion, soft tissue swelling, muscle weakness, loss of motion, or ligament laxityoutcome grading scale41-50 points considered good to excellent outcome30-40 points considered fair outcome< 30 points considered poor outcomeReferences6826594J Bone Joint Surg Am 1983 Mar;65(3):323original scale can be found in 856512Clin Orthop Relat Res 1977 Mar-Apr;(123):115EpidemiologyWho is most affectedpatients > 50 years old reported to account for > 50% of tibial plateau fractures (9531914Am Fam Physician 1998 Mar 15;57(6):1314) low-energy injury with unilateral depression fractures most common in elderly patients who have simple fall1,5high-energy injury with comminuted fracture and soft tissue damage most common in young and middle-aged patients involved in motor vehicle accident or fall from height1,5rare in young adults and children before closure of epiphyseal plate1reported to be more common in males than females1Incidence/Prevalencetibial plateau fractures reportedly account for 1.3% of all fractures18% of fractures in the elderly2Possible risk factorsosteoporosis in elderly patients1,4Associated conditionshigh-energy fractures may be associated with damage to other bony structures or solid organs1Etiology and PathogenesisCausesvehicular and vehicular-pedestrian accidents1,2,3falls1,2,3,4sporting or recreational activities (for example, tackle football, rugby)1,2medial tibial plateau fracture after medial Oxford unicompartmental knee arthroplasty in case series (mnh17549863pcxh25311315pmdc17549863pOrthopedics 2007 May;30(5 Suppl):28EBSCOhost Full Text) Pathogenesismechanisms of injury1,2,4sideways bending force (varus or valgus stress) vertical compression of lower limb (axial loading) combination of both shearing or compression from femoral condyles causing split or depression fractures History and PhysicalHistory and PhysicalHistoryChief concern (CC)knee pain or swelling4inability to bear weight on injured leg4History of present illness (HPI)knee pain secondary to trauma (such as fall or traffic accident)1,2,3,4rapid onset (within 2 hours) of large, tense, joint effusion may indicate tibial plateau fracture and hemarthrosis (mnh13678139p t ccxh10786308t c pmdc13678139p t cAm Fam Physician 2003 Sep 1;68(5):907EBSCOhost Full Textfull-text) Past medical history (PMH)ask about comorbidities that increase risk of complications3coronary artery disease emphysema heavy smoking poorly controlled diabetes PhysicalGeneral physicalexamine for associated injuries such as damage to other bony structures or solid organs, especially with high-energy injuries1confirm inability to bear weight on injured leg4Extremitiesgive appropriate analgesia before examining injured limb4assess soft tissue for1,2,3,4swelling (may be secondary to hemarthrosis) and bruising (conditions which may indicate need for staged management) abrasions, lacerations, and blisters relation of open wounds to fracture site assess for tenderness distal to knee4examine for joint effusion (mnh13678139p t ccxh10786308t c pmdc13678139p t cAm Fam Physician 2003 Sep 1;68(5):907EBSCOhost Full Text) assess neurologic and vascular status of limb1,2,4distal pulses peroneal nerve function (sensation over first web space and ankle and toe dorsiflexion) assess joint stability (examine collateral and cruciate ligaments)4assess for compartment syndrome5perform serial leg compartment exams for minimum 24 hours note tenderness on palpation note skin pallor over compartment see also Acute limb compartment syndromeDiagnosisDiagnosisDiagnosisMaking the diagnosissuspect tibial plateau fractures in patients with4knee pain and swelling secondary to trauma rapid onset of large, tense joint effusion (within 2 hours of injury) suggests hemarthrosis secondary to tibial plateau fracture (mnh13678139p t ccxh10786308t c pmdc13678139p t cAm Fam Physician 2003 Sep 1;68(5):907EBSCOhost Full Text) inability to bear weight on injured leg fracture confirmed by x-rayDifferential diagnosiscommon causes of knee pain in children and adolescents patellar subluxation patellar tendinopathy Osgood-Schlatter diseasereferred pain osteochondritis dissecans in adults patellofemoral pain syndrome medial plica syndromeanserine tendinopathy (pes anserine bursitis) ligamentous sprains meniscus tears inflammatory arthropathy septic arthritisin older adults knee osteoarthritisgoutcalcium pyrophosphate dihydrate deposition diseasepopliteal cystReference - mnh13678140p t ccxh10786314t c pmdc13678140p t cAm Fam Physician 2003 Sep 1;68(5):917EBSCOhost Full Textfull-textTesting overviewx-rays of knee (anteroposterior, lateral, and oblique) computed tomography (CT) - used when more detailed examination of bony architecture required, especially to aid surgical planning magnetic resonance imaging (MRI) - used when ligamentous or meniscal injuries are suspected if impaired limb perfusion suspected, perform duplex ultrasound or angiography1Imaging studiesx-ray anteroposterior1,2,3,4angled 10 degrees in craniocaudal direction to approximate posterior slope of plateau allows evaluation of fracture lines extending into joint and inspection of tibial spines lateral - to identify coronal plane split fractures1,2,3,4oblique - may provide more information about fracture pattern1,2,3,4see also Decision rules for x-ray use in knee injuriescomputed tomography (CT) used when more detailed examination of bony architecture required, especially to aid surgical planning1,2axial, sagittal, and coronal reconstructions can provide information about2,3,53-dimensional fracture pattern articular involvement degree of comminution can help diagnosis bony ligament avulsions2less useful with gross tibial displacement, angulation or shortening, and often beneficial to wait until leg length has been restored with external fixator before performing for clearer images of fracture fragments3,5magnetic resonance imaging (MRI) used when ligamentous or meniscal injuries are suspected1,2,5cannot be done after fixation with metal devices5comparative efficacy use of CT scan or MRI in addition to x-rays may change treatment plan in up to a quarter of patientsbased on 2 diagnostic cohort studies 52 tibial plateau fractures evaluated using knee x-rays (anteroposterior, lateral, 2 oblique views), CT scan, and MRI 3 surgeons were randomly assigned to evaluate x-rays alone vs. x-rays with CT vs. x-rays with MRI (including soft tissue injuries documented by experienced MRI radiologist) compared to x-rays alone, fracture classification changed with addition of CT scan in 6% of cases addition of MRI in 21% of cases MRI changed treatment plan in 23% of cases CT scan changed treatment plan in 9% of cases Reference - 12368643J Orthop Trauma 2002 Oct;16(9):63221 tibial plateau fractures evaluated using knee x-rays and CT scans 2 orthopedic traumatologists, 2 orthopedic residents, and 2 skeletal radiologists evaluated fractures using x-rays alone vs. x-rays in combination with CT scan addition of CT scan changed treatment plan in mean 26% of cases Reference - 9334949J Orthop Trauma 1997 Oct;11(7):484American College of Radiology (ACR) Appropriateness Criteria for acute trauma to knee can be found at ACR 2014 PDFdiscussion of radiologic evaluation of the lower extremity can be found in 9531914Am Fam Physician 1998 Mar 15;57(6):1314full-textManagementTreatmentTreatmentManagement overviewstable, minimally displaced fractures may be treated conservatively with splint, long leg cast, or cast brace for 8-12 weeks1,2medical managementopen fractures require antibiotic prophylaxis check tetanus immunization and update as needed consider deep vein thrombosis prophylaxis assess for compartment syndrome5perform serial leg compartment exams for minimum 24 hours note tenderness on palpation note skin pallor over compartment see also Acute limb compartment syndromesurgical managementsurgery indicated for intra-articular fractures with > 2 mm joint depression or separation significantly displaced metaphyseal components or metaphyseal components angulated > 5 degrees open injuries fractures with vascular injury fractures with associated ligamentous injuries requiring stabilization surgical options include external fixation with or without limited internal fixation internal fixationscrew fixationpercutaneous screw fixation - used for Schatzker type I (AO type B1) or low-energy type IV fractures raft screw construct - used for pure depression fractures (Schatzker type III) staged management - external fixation used to allow soft tissue injuries to recover before definitive internal fixation give first-generation cephalosporin within 1 hour prior to surgical incision and continue for 24 hours Activityundisplaced fractures can be treated with immobilization1,2splint, long leg cast, or cast brace for 8-12 weeks brace initially locked in extension progressive range of motion may be increased up to 90 degrees by 4 weeks bed rest appropriate for short period patient may begin knee range of movement exercises after 4-6 weeks 4-8 weeks of nonweight bearing with crutches Medicationsfor open fractures1give antibiotic prophylaxis cephalosporin antibiotic appropriate as first-line treatment aminoglycoside may be added in case of motor vehicle accident with mild contamination add anaerobe cover in case of farm-yard injury make sure tetanus immunization is current or give booster if needed consider deep vein thrombosis prophylaxis1in children with uncomplicated extremity fractures, oral ibuprofen is as effective as oral morphine for pain reduction and has fewer adverse events (level 1 [likely reliable] evidence)Randomized Trialmnh25349008pmdc25349008pCMAJ 2014 Dec 9;186(18):1358studySummary1based on randomized trial Randomized Trial183 children (mean age 11 years) presenting to emergency department with uncomplicated extremity fracture that did not require surgery were randomized to ibuprofen 10 mg/kg vs. morphine 0.5 mg/kg orally up to 4 doses every 6 hours as needed for 24 hours after discharge fracture locations included radius, ulna, clavicle, humerus, elbow, forearm, tibia, and fibula 26.8% did not have severe enough pain to require analgesics and were excluded from modified intention-to-treat analysis pain assessed immediately before and 30 minutes after every dose on Revised Faces Pain Scale (range 0-5, with higher score indicating more severe pain), minimal clinically important difference was ≥ 1-point difference patients in both groups had median pain score of 2 at discharge comparing ibuprofen vs. morphine mean reduction in pain score after first dose 1.3 vs. 1.5 (not significant) adverse events in 30.9% vs. 56.1% (p < 0.01, NNH 4) consistent results for pain reduction after each subsequent dose in subgroups of children taking multiple doses PubMed25349008CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne20141209CMAJ1861813581358 Reference - mnh25349008pmdc25349008pCMAJ 2014 Dec 9;186(18):1358EBSCOhost Full TextSurgery and proceduresPresurgery considerationssurgical indications include1intra-articular fractures with > 2 mm joint depression or separation significantly displaced metaphyseal components or metaphyseal components angulated > 5 degrees open injuries fractures with vascular injury fractures with associated ligamentous injuries requiring stabilization open fractures may require debridement1to prevent infection, begin first-generation cephalosporin within 1 hour prior to surgical incision and continue for 24 hours3optimal surgical results achieved by3providing stable fixation restoring coronal tibial alignment using soft tissue sparing techniques current surgical options focus on indirect reduction techniques and soft tissue preservation methods rather than anatomic reconstruction with rigid fixation5staged management (external fixation followed by internal fixation) may be required for fractures associated with significant soft tissue injuries2,3,5allows resolution of soft tissue injuries before definitive surgery while preventing further cartilaginous or soft tissue damage definitive fracture surgery may be delayed for up to 3 weeks1,2,3reduces risk of wound breakdown, infection, loss of knee function, or loss of limb due to early operation in presence of soft tissue damage1knee-spanning external fixation devices used for maximum 3 weeks3,5staged management reportedly effective with low complication rate in treatment of patients with high-energy tibial plateau fractures (level 3 [lacking direct] evidence)Case Series16056075J Orthop Trauma 2005 Aug;19(7):448studySummary3based on case series Case Series53 patients (mean age 47 years) with 57 high-energy tibial plateau fractures treated with immediate knee-spanning external fixation followed by definitive repair with plates and screw constructs or conversion to ring fixator mean follow-up 15.7 months mean Western Ontario McMaster (WOMAC) functional knee score 91 range of knee motion at final follow-up 1 degree to 106 degrees complications included deep wound infections in 5% nonunions in 4% significant knee stiffness (< 90 degrees) in 4% need for additional surgery in 16% PubMed16056075Journal of orthopaedic trauma20050801J Orthop Trauma197448448 Reference - 16056075J Orthop Trauma 2005 Aug;19(7):448limited evidence for negative wound pressure therapy in patients with grade III B tibial fracturesSystematic Review25595096Clin Orthop Relat Res 2015 May;473(5):1802studySummarylimited evidence for negative wound pressure therapy in patients with grade III B tibial fractures (Clin Orthop Relat Res 2015 May)04/27/2015 07:16:00 AMHospital_MedicineMusculoskeletal_DisordersOrthopedic_DisordersSurgery_and_ProceduresHospital_Medicine Musculoskeletal_Disorders Orthopedic_Disorders Surgery_and_Procedureslimited evidence for negative wound pressure therapy in patients with grade III B tibial fractures (Clin Orthop Relat Res 2015 May)04/27/2015 07:16:00 AM255950964based on systematic review of mostly observational studies Systematic Reviewsystematic review of 13 studies (1 randomized trial and 12 observational studies) evaluating negative wound pressure therapy in patients with grade III B tibial fracturesno study provided information regarding timing of internal fixation or duration of external fixation statistical analysis not performed, statistical analyses of individual studies not reported comparing negative wound pressure therapy to gauze dressings, negative wound pressure therapy associated with decreased infection rates in 2 of 4 studies negative wound pressure therapy associated with longer time (> 72 hours) to wound coverage without increase in infection rates in 8 of 10 studies decreased rates of flap surgery in 6 of 6 studies PubMed25595096Clinical orthopaedics and related research20150501Clin Orthop Relat Res473518021802 Reference - 25595096Clin Orthop Relat Res 2015 May;473(5):1802negative pressure wound therapy may decrease rate of deep infections compared to gauze dressing in patients with severe open fractures (level 2 [mid-level] evidence)based on small randomized trial 59 patients with severe open fractures were randomized to negative pressure wound therapy vs. standard fine mesh gauze dressing prior to wound closure and followed for 9 months all patients had repeat irrigation and debridement every 48-72 hours until wound closure interventions applied to wounds between irrigation and debridement procedures most common fractures included tibial (42%), pilon (13%), and femur (16%) fractures comparing negative pressure wound therapy vs. gauze dressing, deep infections in 5.4% vs. 28% overall (p = 0.024, NNT 5) 8% vs. 36% (no p value reported) in subgroup of patients with tibial fractures in patients with wound infections, negative pressure wound therapy associated with significantly improved health-related quality of life Reference - 19704269J Orthop Trauma 2009 Sep;23(8):552, commentary can be found in 20418741J Orthop Trauma 2010 May;24(5):329External fixationbenefits over internal fixation include earlier knee movement and preservation of soft tissues2risks include pin site infection and septic arthritis2may be used as definitive treatment in patients with extensive soft tissue damage requiring flap coverage or with other contraindications to internal fixation1,2,3often used in conjunction with limited internal fixation2,5circular external fixator application with limited internal fixation associated with shorter hospital stay and fewer complications but similar long-term outcomes compared to open reduction and internal fixation in patients with bicondylar tibial plateau fractures (level 2 [mid-level] evidence)Randomized Trial17142411J Bone Joint Surg Am 2006 Dec;88(12):2613studySummary2based on randomized trial with blinding of outcome assessors not stated Randomized Trial82 patients with 83 bicondylar tibial plateau fractures (Schatzker types V and VI; Orthopedic Trauma Association [OTA] types C1, C2, and C3) randomized to circular external fixator application vs. open reduction and internal fixation and followed for 2 years comparing circular fixator vs. open reduction and internal fixation mean hospital stay 9.9 days vs. 23.4 days (p = 0.024) percentage of patients who returned to preinjury activity 20% vs. 2.8% (p = 0.031, NNT 6) at 6 months 27% vs. 5.7% (p = 0.024, NNT 5) at 1 year 30% vs. 12% (p = 0.128) at 2 years total number of complications and reoperations 0.37 per patient vs. 0.93 per patient (p = 0.001) no significant difference in range of motion or knee function as measured by Hospital for Special Surgery (HSS) knee score PubMed17142411The Journal of bone and joint surgery. American volume20061201J Bone Joint Surg Am881226132613 Reference - 17142411J Bone Joint Surg Am 2006 Dec;88(12):2613no further randomized trials identified in systematic review (mnh18175135pcxh34454227pmdc18175135pArch Orthop Trauma Surg 2008 Oct;128(10):1169EBSCOhost Full Text) hybrid fixators hybrid or ring external fixation plus minimal internal fixation reportedly leads to high rate of united fractures in patients with severe tibial plateau fracture (level 3 [lacking direct] evidence)Case Seriesmnh16628996przh106316486pcxh20643996pmdc16628996pOrthopedics 2006 Apr;29(4):355studySummary3based on case series Case Series110 patients with 112 severe intra-articular fractures of the upper tibia (Schatzker type IV, V, and VI) treated with external fixation with wire rings or hybrid frames and minimal internal fixation and followed for mean 5 years fracture united in 99% at mean 13.5 weeks subjective patient assessment excellent or good in 83% functional score excellent or good in 74% no significant difference in clinical results between patients with knee bridging or nonbridging fixation PubMed16628996Orthopedics20060401Orthopedics294355355 Reference - mnh16628996przh106316486pcxh20643996pmdc16628996pOrthopedics 2006 Apr;29(4):355EBSCOhost Full Textexternal circular fixation and limited internal fixation reportedly leads to excellent or good results in patients with complex tibial plateau fractures (level 3 [lacking direct] evidence)Case Series17993949J Trauma 2007 Nov;63(5):1043studySummary3based on case series Case Series59 patients aged 23-63 years with complex tibial plateau fractures (Schatzker types V, VI; OTA types 41-C1.3, C2.3, C3.1, or C3.3) treated with limited internal fixation and circular fixation (hybrid Ilizarov method) used in 1 of 3 ways frame confined to tibia if fixation stable enough to allow knee bending frame extended to distal femur with proximal tibial ring located at level of tibial plateau if joint surface severely unstable frame extended onto distal femur with proximal tibial ring located more distally if skin and soft tissue compromised and no suitable bone for wires or pins placement 30 patients had results evaluated as excellent 27 patients had results evaluated as good PubMed17993949The Journal of trauma20071101J Trauma63510431043 Reference - 17993949J Trauma 2007 Nov;63(5):1043hybrid fixation with or without minimal internal reduction reportedly leads to high rate of union in patients with bicondylar tibial plateau fracture (level 3 [lacking direct] evidence)Case Seriesa9h65278975pmdc21756337pJ Orthop Surg Res 2011 Jul 14;6:35Full TextstudySummary3based on case series Case Series33 patients with 33 bicondylar tibial plateau fractures (Schatzker type V or VI) were treated all patients had hybrid external fixator 19 patients also had open reduction using cannulated screws fracture united in 32 patients (97%) mean time to radiographic evidence of union 3.4 months functional use of knee regained in 26 patients (78.8%) minor complications occurred in 5 patients (15.1%) 1 patient (3%) had major complications including septic nonunion and osteomyelitis requiring revision surgery PubMed21756337Journal of orthopaedic surgery and research20110714J Orthop Surg Res63535 Reference - a9h65278975pmdc21756337pJ Orthop Surg Res 2011 Jul 14;6:35EBSCOhost Full Textfull-textmodified hybrid fixator reported to result in union of high-energy tibial plateau fracture at mean 14 weeks (level 3 [lacking direct] evidence)Case Series21589678Strategies Trauma Limb Reconstr 2011 Apr;6(1):21Full TextstudySummary3based on case series Case Series33 patients with high-energy tibial plateau fractures (Schatzker type V or VI) treated with hybrid fixator combining Ilizarov ring with modified external fixator all fractures united at mean 14 weeks 8 patients developed pin track infection 1 patient developed septic arthritis of the knee PubMed21589678Strategies in trauma and limb reconstruction (Online)20110401Strategies Trauma Limb Reconstr612121 Reference - 21589678Strategies Trauma Limb Reconstr 2011 Apr;6(1):21full-textindirect reduction using traction table and hybrid external fixator reportedly effective for treatment of comminuted tibial plateau fractures (level 3 [lacking direct] evidence)Case Series21846003Acta Orthop Belg 2011 Jun;77(3):349studySummary3based on case series Case Series28 patients (mean age 35 years) with high-energy tibial plateau fractures (Schatzker type V or VI) treated by indirect reduction using traction table and hybrid external fixation mean time to healing 3.2 months mean range of knee movement 110 degrees Rasmussen knee functional score satisfactory in 23 cases unsatisfactory in 5 cases PubMed21846003Acta orthopaedica Belgica20110601Acta Orthop Belg773349349 Reference - 21846003Acta Orthop Belg 2011 Jun;77(3):349small wire external fixation with or without internal fixation reported to result in near full range of motion after high-energy tibial plateau fractures (level 3 [lacking direct] evidence)Case Seriesmnh17709848pmdc17709848pJ Orthop Surg (Hong Kong) 2007 Aug;15(2):137PDFstudySummary3based on case series Case Series38 patients aged 18-60 years with high-energy tibial plateau fracture (Schatzker type V or VI) had small wire external fixation with or without internal fixation at follow-up ≥ 2 years postsurgery mean range of knee movement 132 degrees mean Rasmussen radiological score 14 (on 18 point scale) mean Rasmussen functional score 26 (on 30 point scale) complications included 2 superficial infections, 3 pin site infections, and 4 peroneal nerve palsies PubMed17709848Journal of orthopaedic surgery (Hong Kong)20070801J Orthop Surg (Hong Kong)152137137 Reference - mnh17709848pmdc17709848pJ Orthop Surg (Hong Kong) 2007 Aug;15(2):137EBSCOhost Full TextPDFEBSCOhost Full Textmajority of patients with high-energy tibial plateau fractures treated with fine-wire fixation and limited internal fixation reported to have fair or poor clinical rating scores (level 3 [lacking direct] evidence)Case Series16243333Injury 2005 Dec;36(12):1467studySummary3based on case series Case Series18 patients with complex tibial plateau fractures (14 Schatzker type VI and 4 Schatzker type V) were treated with fine-wire fixation with or without limited internal fixation and followed for mean 28.2 months all fractures united, although 3 cases of delayed union required additional procedures and bone grafting excellent or good Knee Society Clinical Rating scores in 38.9% fair or poor Knee Society Clinical Rating scores in 61.1% PubMed16243333Injury20051201Injury361214671467 Reference - 16243333Injury 2005 Dec;36(12):1467monolateral external fixation with limited internal fixation reported to result in satisfactory knee function and low rate of arthrosis in patients with tibial plateau fracture (level 3 [lacking direct] evidence)Case Series12208910J Bone Joint Surg Am 2002 Sep;84-A(9):1541studySummary3based on case series Case Series30 patients with 31 tibial plateau fractures were treated with monolateral external fixation and limited internal fixation 23 patients with 24 fractures were evaluated at mean 98 months no patient required further reduction surgery 19 patients rated outcome as excellent or good mean knee range of motion 87% compared to contralateral knee mean Iowa knee score 90 points (on 100 point scale) mean articular step off 3.3 mm grade-2 or grade-3 arthrosis in 21% PubMed12208910The Journal of bone and joint surgery. American volume20020901J Bone Joint Surg Am84-A(915411541 Reference - 12208910J Bone Joint Surg Am 2002 Sep;84-A(9):1541knee-spanning (knee-bridging) external fixation (vs. knee-sparing or nonknee-bridging) knee-spanning fixation increases stability in comminuted and osteoporotic bones beneficial for soft tissue healing required if major arterial disruption repaired indications for knee-spanning extension include extensive fracture comminution severe soft tissue damage anterior cruciate ligament deficiency knee extensor damage popliteal artery repair Reference - mnh16628996przh106316486pcxh20643996pmdc16628996pOrthopedics 2006 Apr;29(4):355EBSCOhost Full Texttibiofemoral extension of external fixation associated with similar clinical outcome as nonbridging fixation in patients with tibial plateau fracture (level 2 [mid-level] evidence)based on 2 retrospective cohort studies 112 patients with severe intra-articular fractures of the tibia plateau treated with minimal internal fixation and external fixation with ring or hybrid frames and followed for mean 5 years 82 patients (73.2%) had knee-bridging external fixation no significant difference in clinical or radiological results Reference - mnh16628996przh106316486pcxh20643996pmdc16628996pOrthopedics 2006 Apr;29(4):355EBSCOhost Full Text48 patients with tibial plateau fractures (Schatzker type V or VI) treated with minimally invasive internal and small wire external fixation and followed for mean 38 months 30 patients (62.5%) had extension of external fixation to distal femur (joint spanning fixation) 47 patients (98%) healed at mean 13.5 weeks 36 patients (76%) had excellent or good final clinical result no significant difference between bridging and nonbridging external fixation Reference - 15795572J Orthop Trauma 2005 Apr;19(4):241, correction can be found in J Orthop Trauma. 2006 Jan;20(1):69 pin site care different pin site care regimens may have similar effect on infection rates (level 2 [mid-level] evidence)Cochrane ReviewchhCD004551Cochrane Database Syst Rev 2013 Dec 3;(12):CD004551studySummary2based on Cochrane review of trials with methodological limitations Cochrane Reviewsystematic review of 11 randomized trials evaluating cleansing or dressing regimens for orthopedic percutaneous pin sites in 572 patients with orthopedic fractures all trials lacked blinding of outcome assessors or had unclear allocation concealment no significant differences in infection rates comparing cleansing vs. no cleansing in analysis of 3 trials with 295 patients, results limited by significant heterogeneity sterile antiseptic vs. sterile nonantiseptic solutions in analysis of 3 trials with 920 patients different cleansing methods in analysis of 2 trials with 691 patients different types of dressing in 4 trials CochraneCD004551The Cochrane database of systematic reviews20131203Cochrane Database Syst Rev12CD004551CD004551 Reference - chhCD004551Cochrane Database Syst Rev 2013 Dec 3;(12):CD004551evidence-based guideline on skeletal pin site care from National Association of Orthopaedic Nurses can be found in rzh106623751t pc8h106623751t pOrthop Nurs2005 Mar-Apr;24(2):99Internal fixationscrews, dual plating, or locked plates/fixed-angle devices may be used to stabilize fracture3surgical approaches1anterior-lateral and postero-medial approaches most commonly used, often combined in bicondylar fractures posterior approach with patient in prone position may be used, but may be more challenging for surgeon and has higher risk of neurovascular complications traditional ventral midline incision rarely used due to high risk of wound complications open reduction and internal fixation reportedly allows good alignment and soft tissue injury repair with low complication rates in patients with tibial plateau fracture (level 3 [lacking direct] evidence)Case Seriesmnh15633959pmdc15633959pOrthopedics 2004 Dec;27(12):1281studySummary3based on retrospective case series Case Series114 patients (mean age 43 years) with 117 tibial plateau fractures treated with open reduction and internal fixation and followed for mean 29 months fixation methods included K-wires, screws, buttress plates, compression plates, and combination of multiple methods according to Rasmussen functional score excellent results in 68% good result in 13% fair result in 11% poor result in 9% complications included compartment syndrome in 23% wound infection in 4% deep vein thrombosis in 1.8% PubMed15633959Orthopedics20041201Orthopedics271212811281 Reference - mnh15633959pmdc15633959pOrthopedics 2004 Dec;27(12):1281EBSCOhost Full Textless invasive stabilization system (LISS) fixation allows less disruption of soft tissue compared to traditional plating techniques2LISS fixation associated with similar union rate and knee function as conventional double plating in patients with bicondylar tibial plateau fracture, but may cause higher incidence of postoperative malalignment (level 2 [mid-level] evidence)Randomized Trial18215801Knee 2008 Mar;15(2):139studySummary2based on randomized trial without intention-to-treat analysis Randomized Trial96 patients with bicondylar tibial plateau fractures (AO/OTA type C) randomized to plate fixation by LISS vs. plate fixation by classic double plates and followed for ≥ 24 months 84 patients included in analysis comparing LISS vs. double plates union at 6 months in 100% vs. 97.7% (not significant) postoperative malalignment occurred in 14.6% vs. 2.3% (p = 0.041, NNH 8) mean HSS score (measure of knee function) at 12 months 81.8 vs. 80.3 (not significant) LISS associated with trend toward increased hardware irritation (12.2% vs. 0%, p = 0.057) no significant difference in other complications PubMed18215801The Knee20080301Knee152139139 Reference - 18215801Knee 2008 Mar;15(2):139LISS fixation reportedly effective for treatment of complex tibial plateau fracture (level 3 [lacking direct] evidence)based on 3 case series 38 patients with complex tibial plateau fracture (OTA type 41C) treated with LISS and followed for mean 15 months fracture united in 36 patients (95%) at 4 months postsurgery 2 patients (5%) had prophylactic autogenous bone grafting and fracture united 3 months postgrafting significant loss of knee range of motion (< 90 degrees) occurred in 5 patients (13%) Reference - 15345983J Trauma 2004 Aug;57(2):34033 patients with 34 tibial plateau fractures (OTA type 41C) treated with LISS and followed for ≥ 12 months all fractures healed without further surgery or bone grafting mean time to complete union 15.6 weeks articular step-off average 0.8 mm no cases of deep infection or osteomyelitis Reference - 15475852J Orthop Trauma 2004 Sep;18(8):55225 patients with 26 tibial plateau fractures (AO type A2, A3, C1, C2, or C3) treated with LISS and followed for 3 years varus malalignment occurred in 1 patient with intra-articular fracture severe knee arthrosis and total knee replacement occurred in 2 patients with type AO 41 C3.3 fractures delayed union occurred in 1 patient implants removed from 2 patients Reference - 16456310Clin Orthop Relat Res 2006 Apr;445:222Screw fixationpercutaneous screw fixation1,2fixation of fracture with 2 cancellous screws across fracture2can be used for Schatzker I (AO B1) or low-energy type IV fractures2less suitable for fractures with comminution or significant joint depression2closed reduction and percutaneous screw fixation reported to be effective in patients with displaced tibial plateau fractures (level 3 [lacking direct] evidence)Case Series1428164Injury 1992;23(6):387studySummary3based on case series of 13 patients with displaced tibial plateau fractures Case Series11 of 13 had satisfactory results 1 patient had persistent pain 1 patient had failed fixation PubMed1428164Injury199201Injury236387387 Reference - 1428164Injury 1992;23(6):387raft screw construct may be used for pure depression fractures (Schatzker type III)2depressed fracture elevated, then supported by raft of screws2residual defects may require grafting2four 3.5 mm screws reported to result in statistically significantly stronger repair compared to two 6.5 mm screws in biomechanical study (16647262Knee 2006 Jun;13(3):231) Arthroscopymay be used for assessment of soft tissue injuries and management of articular surface2arthroscopic management associated with similar functional outcome and faster postoperative rehabilitation compared to conventional open reduction in patients with tibial plateau fracture (level 2 [mid-level] evidence)Cohort Studymnh12720016pcxh16922510pmdc12720016pArch Orthop Trauma Surg 2003 Nov;123(9):489studySummary2based on retrospective cohort study Cohort Study28 patients with tibial plateau fracture (Schatzker type II, III or V) treated with arthroscopically-assisted management (19 patients) or conventional open reduction (9 patients) and followed for ≥ 1 year comparing arthroscopic management vs. open reduction mean time to achieve 120 degrees of flexion 4.6 weeks vs. 9.1 weeks (p < 0.05) anatomical reduction (< 2 mm residual displacement postsurgery) in 84% vs. 55% (no p value reported) mean flexion of knee at follow-up 151.3 degrees vs. 148.9 degrees (not significant) PubMed12720016Archives of orthopaedic and trauma surgery20031101Arch Orthop Trauma Surg1239489489 Reference - mnh12720016pcxh16922510pmdc12720016pArch Orthop Trauma Surg 2003 Nov;123(9):489EBSCOhost Full TextBone graft and bone graft substitutesused in cases where depressed fractures have been elevated, leaving bone defect2calcium phosphate cement associated with similar functional outcomes (level 2 [mid-level] evidence), but higher rate of articular subsidence (level 3 [lacking direct] evidence) compared to autogenous bone graft in patients with unstable tibial plateau fracturesRandomized Trial18829901J Bone Joint Surg Am 2008 Oct;90(10):2057studySummarybased on randomized trial with differential loss to follow-up Randomized Trial119 patients aged 16-77 years with acute, closed, unstable tibial plateau fractures (Schatzker types I-VI) undergoing open reduction and internal fixation randomized to subarticular grafting with calcium phosphate cement vs. subarticular grafting with autogenous bone graft follow-up exams at 6 weeks, 3 months, 6 months, and 12 months 13.4% of calcium phosphate cement patients vs. 31.6% of autogenous bone graft patients lost to follow-up before 6-month exam no significant differences in range of motion measurements at 6 or 12 months subsidence of ≥ 2 mm on anteroposterior x-rays occurred in 9% of calcium phosphate cement group vs. 30% of autogenous bone graft group (p = 0.009, NNT 5) PubMed18829901The Journal of bone and joint surgery. American volume20081001J Bone Joint Surg Am901020572057 Reference - 18829901J Bone Joint Surg Am 2008 Oct;90(10):2057bioactive glass granules associated with similar outcomes compared to autogenous bone graft in patients with depressed, comminuted tibial plateau fracture (level 2 [mid-level] evidence)Randomized Trialcxh60278475pmdc21431354pJ Mater Sci Mater Med 2011 Apr;22(4):1073studySummary2based on small randomized trial Randomized Trial25 patients with depressed unilateral comminuted tibial plateau fracture (AO type B2 and B3) randomized to bioglass vs. autogenous bone graft and followed for 1 year no significant difference in redepression of articular surface, functional outcomes, valgus alignment, or patients' subjective evaluation PubMed21431354Journal of materials science. Materials in medicine20110401J Mater Sci Mater Med22410731073 Reference - cxh60278475pmdc21431354pJ Mater Sci Mater Med 2011 Apr;22(4):1073EBSCOhost Full TextPostsurgery carepostsurgical analgesia considerations3morphine or hydromorphone IV (patient-controlled) for 1-2 days after day 2, transition to oral pain control avoid peripheral nerve blocks (may mask signs of compartment syndrome) avoid nonsteroidal anti-inflammatory drugs (NSAIDS) for 6 weeks following surgery (may inhibit bone healing) activity restrictions and weight bearing specific to individual patient and based on3fracture pattern type of stabilization used presence of other injuries patient's ability to mobilize safely physical therapy may be possible at postoperative day 1 with focus on range of motion exercises to regain movement and nourish articular cartilage2,3Consultation and referralorthopedic surgeon Complications and PrognosisComplications and PrognosisComplicationssoft tissue bruising or swelling1,3compartment syndrome1knee stiffness (may be due to initial injury, surgery, scarring, or immobilization)2,3infection2,3osteoarthritis (may be due to initial chondral damage, residual articular discontinuity, or postoperative disrupted mechanical axis)2malunion or nonunion2wound dehiscence3deep vein thrombosis (DVT)2peroneal nerve injury2avascular necrosis of articular fragments2loss of limb3Prognosisneed for total knee arthroplasty at 10 years about 7.3% for patients having fixation surgery for tibial plateau fracture and about 1.8% for general populationCohort Study24430414J Bone Joint Surg Am 2014 Jan 15;96(2):144studySummarybased on retrospective cohort study Cohort Study8,426 patients ≥ 16 years old (median age 49 years) who had fixation surgery for tibial plateau fracture were matched to 33,698 controls (without fracture) matching was by age (same calendar year), sex, income quintile, and urban/rural residence rates of total knee arthroplasty comparing surgery vs. controls (p < 0.0001 for trend, no pairwise comparisons reported) 0.32% vs. 0.29% at 2 years 5.3% vs. 0.82% at 5 years 7.3% vs. 1.8% at 10 years surgery associated with increased risk of total knee arthroplasty after adjustment for comorbidities (hazard ratio 5.3, 95% CI 4.6-6.1) PubMed24430414The Journal of bone and joint surgery. American volume20140115J Bone Joint Surg Am962144144 Reference - 24430414J Bone Joint Surg Am 2014 Jan 15;96(2):144in most patients treated surgically, fractures appear to have uneventful union by 1 year, but approximately one-third have secondary osteoarthritis at mean 14 years (level 2 [mid-level] evidence)Cohort Study17211262J Orthop Trauma 2007 Jan;21(1):5studySummary2based on retrospective cohort study Cohort Study202 patients (mean age at injury 46 years) with surgically treated tibial plateau fracture were followed for 1 year at 1 year uneventful union occurred in 95% mean range of motion 130 degrees in 109 patients with additional follow-up at mean 14 years (range 5-27 years) mean range of motion 135 degrees functional results significantly better for monocondylar fractures compared to bicondylar fractures 31% of patients developed secondary osteoarthritis patients with malalignment > 5 degrees developed moderate-to-severe osteoarthritis more often than patients with anatomic knee axis (27% vs. 9.2%, p = 0.02) no correlation between age and functional results PubMed17211262Journal of orthopaedic trauma20070101J Orthop Trauma21155 Reference - 17211262J Orthop Trauma 2007 Jan;21(1):5, correction can be found in J Orthop Trauma. 2007 Mar;21(3):218 secondary osteoarthritis may be common in patients with tibial plateau fracture, especially after removal of meniscus (level 2 [mid-level] evidence)Cohort Study7562147J Orthop Trauma 1995;9(4):273studySummary2based on cohort study Cohort Study131 patients with tibial plateau fracture evaluated at mean 7.6 years follow-up secondary osteoarthritis occurred in 44% overall 74% of cases with removal of meniscus 37% of cases without removal of meniscus PubMed7562147Journal of orthopaedic trauma199501J Orthop Trauma94273273 Reference - 7562147J Orthop Trauma 1995;9(4):273smoking associated with increased risk of nonunion in tibial and other long-bone fracturesSystematic Review24740664J Bone Joint Surg Am 2014 Apr 16;96(8):674studySummarybased on systematic review of observational studies Systematic Reviewsystematic review of 19 cohort studies evaluating the effect of cigarette smoking on long-bone fracture healing in 6,356 adults with 6,374 fractures compared to no smoking, smoking associated with increased risk of nonunion of tibial fracture (odds ratio [OR] 2.16, 95% CI 1.55-3.01) in analysis of 7 studies with 925 fractures nonunion of any long-bone fracture (OR 2.32, 95% CI 1.76-3.06) in analysis of 10 studies with 1,221 fractures open fracture nonunion (OR 1.95, 95% CI 1.3-2.9) in analysis of 4 studies with 658 fractures no significant differences in healing time or infections PubMed24740664The Journal of bone and joint surgery. American volume20140416J Bone Joint Surg Am968674674 Reference - 24740664J Bone Joint Surg Am 2014 Apr 16;96(8):674Prevention and ScreeningPrevention and Screeningnot applicable Quality ImprovementMedicare Hospital Outpatient Department Quality MeasuresOP-21 Median Time to Pain Management for Long Bone Fracture measured as time (in minutes) from emergency department arrival to time of initial oral, intranasal, or parenteral pain medication administration for emergency department patients with a diagnosis of a long bone fracturesee Medicare Hospital Outpatient Department Quality Measures for additional informationGuidelines and ResourcesGuidelinesGuidelinesGuidelinesAmerican College of Radiology/Society of Pediatric Radiology/Society of Skeletal Radiology (ACR/SPR/SSR) practice parameter on performance and interpretation of magnetic resonance imaging (MRI) of knee can be found at ACR 2015 Oct PDFMusculoskeletal_DisordersACR Appropriateness Criteria for acute trauma to knee (National Guideline Clearinghouse 2015 Jul 27)07/28/2015 02:00:00 PMAmerican College of Radiology (ACR) Appropriateness Criteria for acute trauma to knee can be found at ACR 2014 PDFEast Practice Management Guidelines Work Group practice management guideline on prophylactic antibiotic use in open fractures can be found in 21610369J Trauma 2011 Mar;70(3):751Review articlesreview can be found in 11401171Am J Knee Surg 2001 Spring;14(2):125review can be found in 20345023Zhongguo Gu Shang 2010 Feb;23(2):81[Chinese] Emergency_Medicine Musculoskeletal_Disorders Orthopedic_DisordersCochrane review evaluating surgical fixation methods for tibial plateau fracture (Cochrane Database Syst Rev 2015 Sep 15)12/22/2015 03:40:00 PM263702683Cochrane review evaluating surgical fixation methods for tibial plateau fracture can be found in chhCD009679Cochrane Database Syst Rev 2015 Sep 15;(9):CD009679review of open reduction and internal fixation of fractures of tibial plateau can be found in 19336799J Bone Joint Surg Br 2009 Apr;91(4):426review of osteoporotic tibial plateau fracture can be found in 15913173Am J Orthop (Belle Mead NJ) 2005 Apr;34(4):186review of complications after tibia plateau fracture surgery can be found in 16118010Injury 2006 Jun;37(6):475review of evaluation of patients with knee pain (parts I and II) can be found in mnh13678139p t ccxh10786308t c pmdc13678139p t cAm Fam Physician 2003 Sep 1;68(5):907EBSCOhost Full Textfull-text, mnh13678140p t ccxh10786314t c pmdc13678140p t cAm Fam Physician 2003 Sep 1;68(5):917EBSCOhost Full Textfull-textreview of principles of casting and splinting can be found in mnh19145960pcxh35896095pmdc19145960pAm Fam Physician 2009 Jan 1;79(1):16EBSCOhost Full Textfull-textMEDLINE searchto search MEDLINE for (Tibial plateau fracture) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosisPatient InformationPatient Infohandout on fractures of the proximal tibia from American Academy of Orthopaedic Surgeonstechnical information on tibial and fibular fractures from Patient PlusICD CodesICD CodesICD-10 codesS82.1 fracture of upper end of tibia use optional subclassification codes to indicate 0 closed 1 open ReferencesGeneral references usedThomas Ch, Athanasiov A, Wullschleger M, Schuetz M. Current concepts in tibial plateau fractures. Acta Chir Orthop Traumatol Cech. 2009 Oct;76(5):363-73.Fenton P, Porter K. Tibial plateau fractures: a review. Trauma. 2011 July;13(3):181-87.Dirschl DR, Del Gaizo D. Staged management of tibial plateau fractures. Am J Orthop (Belle Mead NJ). 2007 Apr;36(4 Suppl):12-7.Young CF, Haddad F. Fractures around the knee. Br J Hosp Med (Lond). 2006 May;67(5):M96-8.Berkson EM, Virkus WW. High-energy tibial plateau fractures. J Am Acad Orthop Surg. 2006 Jan;14(1):20-31.DynaMed Editorial ProcessDynaMed topics are created and maintained by the DynaMed Editorial Team and Process.All editorial team members and reviewers have declared that they have no financial or other competing interests related to this topic, unless otherwise indicated.DynaMed provides Practice-Changing DynaMed Updates, with support from our partners, McMaster University and F1000.Special acknowledgementsDynaMed topics are written and edited through the collaborative efforts of the above individuals. Deputy Editors, Section Editors, and Topic Editors are active in clinical or academic medical practice. Recommendations Editors are actively involved in development and/or evaluation of guidelines.Editorial Team role definitionsTopic Editors define the scope and focus of each topic by formulating a set of clinical questions and suggesting important guidelines, clinical trials, and other data to be addressed within each topic. Topic Editors also serve as consultants for the DynaMed internal Editorial Team during the writing and editing process, and review the final topic drafts prior to publication.Section Editors have similar responsibilities to Topic Editors but have a broader role that includes the review of multiple topics, oversight of Topic Editors, and systematic surveillance of the medical literature.Deputy Editors are employees of DynaMed and oversee DynaMed internal publishing groups. Each is responsible for all content published within that group, including supervising topic development at all stages of the writing and editing process, final review of all topics prior to publication, and direction of an internal team.How to citeNational Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. T116325, Tibial Plateau Fracture; [updated 2018 Nov 30, cited place cited date here]. Available from https://www.dynamed.com/topics/dmp~AN~T116325. Registration and login required.

Overview and RecommendationsBackground·Osteoporosis (compromised bone strength and bone quality) is common withprevalenceof 20%-40% in postmenopausal women and 6%-8% men ≥ 50 years old.·Osteoporosis can occur as part of the aging process orsecondarilydue to nutritional deficiency, metabolic disorders, or medication side effects.·Certain endocrine, gastrointestinal, hematologic, autoimmune, and central nervous system (CNS) disorders increase the risk of osteoporosis.·Medications such as long-term anticoagulation, hormonal therapies, glucocorticosteroids, some immunosuppressants, lithium, thiazolidinediones (glitazones), and long-term proton pump inhibitor use may also cause osteoporosis.Evaluation·Thediagnosisis made in adults with fragility fracture, regardless of any test results (Strong recommendation).·If no fragility fracture, considerscreeningfor osteoporosis with bone mineral density testing (usually dual-energy x-ray absorptiometry measurement [DEXA] at posterior-anterior spine and hip) in:·all women ≥ 65 years old, and all men ≥ 70 years old·postmenopausal women < 65 years old, perimenopausal women, and men aged 50-69 years with clinical risk factors for fracture (or use arisk calculatorto predict 10-year risk of fracture)·any adult with fracture after age 50 years·any adult with condition (such as rheumatoid arthritis) or use of medication (such as glucocorticoids for ≥ 3 months) associated with low bone mass or bone loss·Osteoporosis isdefined asa fragility fracture orT-score≤ -2.5 when determined by lowest calculation from lumbar spine (at least 2 evaluable vertebrae), femoral neck, or total femur T-score.·Osteopenia is low normal bone density that is not low enough to be osteoporosis, as defined byT-scorebetween -1 and -2.5 when determined by lowest calculation from lumbar spine, femoral neck, or total femur. The preferred terms are "low bone mass" or "low bone density."·Diagnose osteoporosis in children withz-score≤ -2 plus clinically significant fracture history (≥ 2 long bone fractures by age 10 years or ≥ 3 long bone fractures by age 19 years) (Strong recommendation).·Considertesting(serum calcium, vitamin D, creatinine, and thyroid-stimulating hormone levels) for secondary causes of osteoporosis (Weak recommendation).Management·Encourage all patients with osteoporosis or increased risk of osteoporosis to initiate lifestyle changes including (Strong recommendation):·balanced dietwith adequate calcium and vitamin D intake·regular weight-bearing and muscle-strengtheningexerciseto improve agility, strength, posture, balance, increase bone mineral density, and reduce risk of falls and fractures·smoking cessation·avoiding excessalcohol intake·Offerpharmacologic therapyto reduce fracture risk for (Strong recommendation):·postmenopausal women and men ≥ 50 years old with hip or vertebral fracture (including asymptomatic vertebral fracture)·postmenopausal women and men ≥ 50 years old with T-score ≤ -2.5 at femoral neck, total hip, or lumbar spine by dual-energy x-ray absorptiometry (DEXA)·patients taking long-term glucocorticoids·men with prostate cancer receiving androgen deprivation therapy who have high risk of fracture·Considerpharmacologic therapyto reduce fracture risk for postmenopausal women and men ≥ 50 years old with T-score -1 to -2.5 at femoral neck, total hip, or lumbar spine by DEXA and 10-year risk of hip fracture ≥ 3% or 10-year risk of major osteoporosis-related fracture ≥ 20% (using calculatorsuch as FRAX).·Select abisphosphonateas first-line therapy for most patients (Strong recommendation).·Bisphosphonates include alendronate 10 mg or risedronate 5 mg orally once daily, alendronate 70 mg or risedronate 35 mg orally once weekly, risedronate or ibandronate 150 mg orally once monthly, or zoledronic acid 5 mg IV once yearly.·Dosing is the same for those patients with asymptomatic osteoporosis and those who have had an osteoporotic fracture.·Considerdiscontinuationafter 3-5 years to reduce adverse effects with minimal loss of efficacy.·Considerparathyroid hormone 1-34(teriparatide 20 mcg subcutaneously once daily) as first-line therapy for patients at particularly high risk for fracture.·Considerdenosumab60 mg subcutaneously every 6 months as alternative first-line therapy (Weak recommendation).·Considerraloxifene60 mg orlasofoxifene0.5 mg orally once daily, but selective estrogen response modulators (SERMs) may be less effective than bisphosphonates and teriparatide, and may increase risk for venous thromboembolism.·Considermonitoringbone mineral density (BMD) with DEXA every 1-2 years after initiating treatment, but monitoring BMD may have little effect on predicting outcomes or changing treatment.Related Summaries·Osteoporosis causes and risk factors·Bisphosphonates for treatment and prevention of osteoporosis·Hormonal replacement therapy (HRT) and osteoporosis·Calcium and vitamin D for treatment and prevention of osteoporosis·Physician Quality Reporting System Quality MeasuresGeneral InformationDescription·generalized skeletal disorder characterized by compromised bone strength and deterioration of bone quality, often leading to fragility fracture2·low bone mass frequently found, but not required, for diagnosis·regardless of bone mass, fragility fracture necessitates diagnosisDefinitions·osteomalacia - softening of bones, usually due to severe lack of vitamin D4·osteopenia1,2·low normal bone density, as defined byT-scorebetween -1 and -2.5 when determined by lowest calculation from lumbar spine (at least 2 evaluable vertebrae), femoral neck, or total femur T-score, not low enough to be osteoporosis·preferred terms are "low bone mass" or "low bone density"·osteoporosis1,2·fragility fracture orT-score≤ -2.5 when determined by lowest calculation from lumbar spine (at least 2 evaluable vertebrae), femoral neck, or total femur T-score·one-third radius site may be used if either lumbar spine or femur is nonevaluable·primary osteoporosis - deterioration of bone mass unassociated with other chronic illness, related to aging and decreased gonadal function (bone loss accelerated during sixth decade of life or perimenopausal period in women) (Am Fam Physician 2001 Mar 1;63(5):897EBSCOhost Full Textfull-text)·secondary osteoporosis - deterioration of bone mass associated with chronic conditions that contribute significantly to accelerated bone loss (Am Fam Physician 2001 Mar 1;63(5):897EBSCOhost Full Textfull-text)·severe osteoporosis - fragility fracture or fractures ANDT-score≤ -2.51,2·osteitis fibrosa - softening and deformity of bones, usually due to complications ofhyperparathyroidism·fragility (low impact) fracture is fracture from minor trauma (for instance, fall from standing height or less)1,2·high-trauma fracture - fracture from high trauma (for instance, from car accident)1,2·clinical fracture - fracture suspected from signs on clinical exam1,2EpidemiologyWho is most affected·postmenopausal women1,2·persons ≥ 65 years old1,2·Caucasians and people of Asian descent1,2·persons with small body frame1,2Incidence/Prevalence·prevalence of osteoporosis in adults aged ≥ 50 years in United States1,2·> 10 million persons overall·> 33 million have low bone density at hip·estimated prevalence of osteoporosis 22 million (21%) women and 5.5 million (6%) men in European Union·based on 7.5 million adults aged 50-84 years in Sweden who had bone mineral density (BMD) data at femoral neck reported as part of third National Health and Nutrition Examination Survey (NHANES III)·prevalence of osteoporosis across 27 countries of European Union was calculated by applying prevalence of osteoporosis in Sweden to population demographic in each country and assuming that mean femoral neck BMD is similar across all countries at age 50 years·3.5 million incidences of fragility fracture (hip, vertebral, forearm, or other fracture) estimated in European Union in 2010·Reference -Arch Osteoporos 2013;8(1-2):136full-text·prevalence of osteoporosis 37% in postmenopausal women ≥ 50 years old and 7.8% in men ≥ 50 years old in Korea in 2008-2010·based on 3,849 postmenopausal women and 3,314 men aged 50-90 years who had bone mineral density data reported as part of Korea National Health and Nutrition Examination Survey (KNHANES) in 2008-2010·Reference -Endocrinol Metab (Seoul) 2013 Sep;28(3):180full-text·osteoporosis in men·osteoporosis detected in 20%-30% of 86 men with chronic obstructive pulmonary disease, 57% of whom were taking glucocorticoids·based on retrospective cohort study·Reference -Chest 2002 May;121(5):1456·17.5%-57.8% incidence of osteoporosis found in men > 50 years old with fractures·based on retrospective chart review of 2,035 men > 50 years old with 2,142 fractures, including 90 men with hip fracture and 143 men with ankle fracture·57.8% with hip fracture and 17.5% with ankle fracture had osteoporosis·Reference -J Bone Joint Surg Br 2008 Jan;90(1):72Etiology and PathogenesisCauses and risk factors·lifestyle factors- low calcium intake, vitamin D deficiency, excess vitamin A intake, inadequate physical activity, smoking, and alcohol abuse·genetic factors- parental history of hip fracture, cystic fibrosis, hemochromatosis, various genetic disorders and gene variants, porphyria, osteogenesis imperfecta, hypophosphatasia·medical conditions·endocrine disorders- hyperparathyroidism, hypogonadal states (such as anorexia nervosa), diabetes mellitus, Cushing syndrome, excess thyroid hormone, endocrine therapies for cancer·gastrointestinal disorders- Celiac disease, gastric bypass, Crohn disease, malabsorption, cirrhosis·hematologic disorders- multiple myeloma, thalassemia, leukemia, lymphoma, mastocytosis·rheumatologic and autoimmune disorders- rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus·central nervous system disorders- epilepsy, multiple sclerosis, Parkinson disease·other medical conditions- HIV infection, amyloidosis, chronic obstructive pulmonary disease (COPD), heart failure, chronic kidney disease, hypercalciuria, weight loss, alcoholism, renal tubular acidosis·medications·including long-term anticoagulation, hormonal therapies, glucocorticosteroids, some immunosuppressants, lithium, thiazolidinediones (glitazones), long-term proton pump inhibitor use·high-dose but not low-dose inhaled steroids may be associated with increased risk of fractures in elderly persons (level 2 [mid-level] evidence)·seeOsteoporosis causes and risk factorsfor detailsPathogenesis·process of bone remodeling maintains healthy bone mass throughout life1,3·in healthy bone, bone resorption (osteoclast cells) is balanced by bone formation (osteoblast cells)·bone loss occurs when bone resorption outpaces bone formation, resulting in decreased bone mass and increased risk of fracture·fracture results from overloading of weakened bones·in primary osteoporosis, bone loss results from factors associated with aging and sex steroid deficiency (for instance, decreased circulating levels of 17beta-estradiol in menopause inhibits bone resorption without increasing bone formation)1,3·in secondary osteoporosis, bone loss results from specific causes, such as1·decreased bone formation and reduced bone quality and integrity with glucocorticoids·antiproliferative effect on osteoblast cells with alcoholHistory and PhysicalHistoryChief concern (CC)·usually asymptomatic until fracture1·may detect with incident radiographic vertebral fractures found during imaging for other clinical indications or during screening imaging in high-risk persons2History of present illness (HPI)·certain fractures appear more likely to be due to osteoporosis·fractures most likely to be due to osteoporosis include·femoral neck fractures·pathologic fractures of vertebrae·lumbar and thoracic vertebral fractures·distal radius fractures·fractures less likely to be due to osteoporosis include·open proximal humerus fractures·skull fractures·facial bone fractures·Reference -J Clin Epidemiol 2011 Jan;64(1):46full-text, editorial can be found inJ Clin Epidemiol 2011 Jan;64(1):45·ask about1·back pain and postural change which may occur with vertebral fractures·dyspnea, constipation, abdominal pain, distention, reduced appetite, and early satiety may be related to loss of height from vertebral collapseMedication history·ask aboutmedications that increase risk for osteoporosis2·including long-term anticoagulation, hormonal therapies, glucocorticosteroids, some immunosuppressants, lithium, thiazolidinediones (glitazones), long-term proton pump inhibitor use·high-dose but not low-dose inhaled steroids may be associated with increased risk of fractures in elderly persons (level 2 [mid-level] evidence)Past medical history (PMH)·ask about medical conditions that increase risk for osteoporosis including2·endocrine disorders - hyperparathyroidism, hypogonadal states, anorexia nervosa, diabetes mellitus, Cushing syndrome, excess thyroid hormone, endocrine therapies for cancer·gastrointestinal disorders - Celiac disease, gastric bypass, Crohn disease, malabsorption, cirrhosis·hematologic disorders - multiple myeloma, thalassemia, leukemia, lymphoma, mastocytosis·rheumatologic and autoimmune disorders - rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus·central nervous system disorders - epilepsy, multiple sclerosis, Parkinson disease·other medical conditions - HIV infection, amyloidosis, chronic obstructive pulmonary disease (COPD), heart failure, chronic kidney disease, hypercalciuria, weight loss, alcoholism, renal tubular acidosisFamily history (FH)·ask about2·genetic factors that increase risk for osteoporosis - cystic fibrosis, hemochromatosis, various genetic disorders and gene variants, porphyria, osteogenesis imperfecta, hypophosphatasia·parental history of hip fractureSocial history (SH)·ask about lifestyle factors that increase risk for osteoporosis including2·alcohol use·diet - low calcium intake, vitamin D deficiency, excess vitamin A intake·low physical activity level·smokingPhysicalGeneral physical·low body mass index or weight < 127 pounds (57.6 kg) is risk factor2·assess for·height loss1,2·signs ofhyperthyroidism1,3,4(such as tachycardia, weight loss, hypertension, goiter)·some physical findings are associated with increased risk of osteoporosis·systematic review of 14 studies of accuracy or precision of physical exam for diagnosing osteopenia, osteoporosis, or spinal fracture·no single finding sufficient to rule in or rule out osteoporosis or spinal fracture without testing·findings with increased likelihood of osteoporosis or spinal fracture·weight < 51 kg (112 lbs) had positive likelihood ratio 7.3·wall-occiput distance > 0 cm had positive likelihood ratio 4.6·rib-pelvis distance < 2 finger breadths had positive likelihood ratio 3.8·tooth count < 20 had positive likelihood ratio 3.4·Reference -JAMA 2004 Dec 15;292(23):2890EBSCOhost Full TextLungs·evaluate for restrictive or obstructive lung disease as comorbid conditionAbdomen·protuberant abdomen may result from kyphosis1,3Back·dorsal kyphosis (abnormal curvature of thoracic spine)1,3,4Extremities·bone deformities may result from fractures1,3Genital exam·assess for testicular atrophy4DiagnosisMaking the diagnosis·make clinical diagnosis of osteoporosis in adults with fragility fracture, regardless of any test results1,2,3·if no fragility fracture·considerscreeningfor osteoporosis with bone mineral density testing (usually dual-energy x-ray absorptiometry [DEXA] measurement at posterior-anterior spine and/or hip) in·all women ≥ 65 years old, and all men ≥ 70 years old·postmenopausal women < 65 years old, perimenopausal women, and men aged 50-69 years withclinical risk factorsfor fracture·any adult with fracture after age 50 years·any adult with condition (such as rheumatoid arthritis) or use of medication (such as glucocorticoids ≥ 3 months) associated with low bone mass or bone loss·risk calculators (Fracture Risk Assessment FRAX,QFracture-2013 Risk Calculator,Garvan Institute Fracture Risk Calculator) predict 10-year risk of fracture·osteoporosis defined as fragility fracture orT-score≤ -2.5 when determined by lowest calculation from lumbar spine (at least 2 evaluable vertebrae), femoral neck, or total femur T-score·osteopenia (preferred terms are "low bone mass" or "low bone density") defined as low normal bone density, as defined byT-scorebetween -1 and -2.5 when determined by lowest calculation from lumbar spine (at least 2 evaluable vertebrae), femoral neck, or total femur T-score, not low enough to be osteoporosis1,2·in children·diagnose osteoporosis in children withz-score≤ -2 plus clinically significant fracture history (≥ 2 long bone fractures by age 10 years or ≥ 3 long bone fractures by age 19 years)5·≥ 1 vertebral compression fracture (in absence of local disease or high-impact trauma) in children is suggestive of osteoporosis and indicates need for bone mineral density testing5Differential diagnosis·seeCauses·homocystinuria/homocysteinemia·hyperparathyroidism·mastocytosis·multiple myeloma·osteomalacia and renal osteodystrophy (adults)·rickets(children)·Paget disease of bone·scurvy·sickle cell anemia·osteitis fibrosa cystica·bone tumors, such as enchondroma andosteochondromaTesting overview·bone mineral density (BMD) testingwith dual-energy x-ray absorptiometry (DEXA)·in adults measure BMD at hip (femoral neck, total hip) and posterior-anterior spine, or 33% radius if unable to use hip and/or spine·in children posterior-anterior spine or total body less head preferred·considervertebral fracture assessment (VFA)in women > 70 years old, men > 80 years old, patients with historical height loss > 4 cm (1.5 inches), or patients taking chronic corticosteroids·tests that may be useful in ruling out secondary causes of bone loss include2·blood tests·for all patients with osteoporosis·25-hydroxyvitamin D·calcium·creatinine·thyroid-stimulating hormone (TSH)·for patients with suspected secondary causes·alkaline phosphatase (ALP)·phosphorus·parathyroid hormone (PTH)·complete blood count·erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)·testosterone (men) or estradiol (women)·luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin·tissue transglutaminase antibody·serum protein electrophoresis·urine tests·24-hour urinary calcium excretion·24-hour urinary free cortisol, if suspect osteoporosis due to glucocorticoid excess·salivary cortisolClinical prediction rules·clinical decision rules appear inaccurate for identifying osteoporosis in patients with rheumatoid arthritis(level 2 [mid-level] evidence)··based on derivation cohort study without validation·287 patients aged 22-72 years with rheumatoid arthritis (RA) and complete data available from Oslo RA register were evaluated·validation of previously published 3-item clinical decision rule was attempted but rule had limited predictive value·62 patients (21.6%) had osteoporosis (T-score ≤ -2.5) at femoral neck and/or spine·5-item clinical decision rule derived with 5 criteria·high disease activity with mean C-reactive protein (CRP) > 20 mg/L and/or mean erythrocyte sedimentation rate (ESR) > 20 mm/hour·age > 50 years in women or > 60 years in men·immobility with Health Assessment Questionnaire (HAQ) score ≥ 1.25·weight < 60 kg (132.3 lbs)·current use of corticosteroids·for detection of osteoporosis, meeting ≥ 3 of 5 criteria had·sensitivity of 82%·specificity of 45%·positive predictive value of 29%·negative predictive value of 90%·positive likelihood ratio of 1.49·negative likelihood ratio of 0.4·Reference -Ann Rheum Dis 2002 Dec;61(12):1085full-text, commentary can be found inAnn Rheum Dis 2004 Mar;63(3):324Blood testsDetermining secondary causes of osteoporosis·consider testing all patients with osteoporosis forsecondary causes(ICSI Strong recommendation, Low-quality evidence)2·initial testing for all patients without prior workup2,3·25-hydroxyvitamin D (25[OH]D) level·optimal level ≥ 30 ng/mL (74.9 nmol/L)·if low (vitamin D deficiency), may indicate inadequate exposure to sunlight, inadequate vitamin D intake, gastrointestinal malabsorption, orceliac disease·serum calcium·if low (hypocalcemia), may indicate malabsorption or vitamin D deficiency·if elevated (hypercalcemia), may indicatehyperparathyroidism·serum creatinine - elevated creatinine suggests renal dysfunction·thyroid stimulating hormone (TSH) - low TSH may indicatehyperthyroidism·further tests to consider2,3·serum alkaline phosphatase, if elevated, may indicatePaget disease of bone, prolonged immobilization, acute fractures, osteomalacia,vitamin D deficiency, gastrointestinal malabsorption,hyperparathyroidism, or liver or biliary diseases·serum phosphorus·may be elevated in renal failure (acuteorchronic)·may be low inhyperparathyroidismor osteomalacia·parathyroid hormone level (PTH), if elevated, suggestshyperparathyroidism·complete blood count may suggest bone marrow malignancy or infiltrative process (anemia, low white blood cells, or low platelets) or malabsorption (anemia, microcytosis, or macrocytosis)·erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), if elevated, may indicate inflammatory process or monoclonal gammopathy·testosterone (total and free) in men and estradiol (total and bioavailable) in women, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and/or prolactin, if low, may indicate hypogonadotropic hypogonadism·free testosterone levels inversely associated with bone mineral density in men, but no association with total testosterone levels··based on cohort study of 792 men aged 51-85 years·mean total hip bone mineral density 0.94 g/cm2in men with free testosterone < 146 pmol/L (4.2 ng/dL) vs. 0.97 g/cm2in men with free testosterone ≥ 146 pmol/L (4.2 ng/dL) (p < 0.01)·Reference -J Clin Endocrinol Metab 2003 Nov;88(11):5240·anti-tissue transglutaminase antibody, if concern forceliac disease·serum protein electrophoresis, monoclonal band may indicatemultiple myeloma·1 in 20 patients with osteoporosis may have monoclonal gammopathy of undetermined significance or multiple myeloma··based on retrospective cohort study·799 adults (685 women) aged 19-94 years newly referred to osteoporosis center with suspected osteoporosis were evaluated·366 had osteoporosis·serum M component found in 18 patients (4.9%) with osteoporosis vs. 9 patients (2.2%) without osteoporosis·multiple myeloma diagnosed in 3 patients (0.8%) with osteoporosis·serum M component had 17.6% positive predictive value for multiple myeloma·monoclonal gammopathy of undetermined significance diagnosed in 13 patients (3.6%) with osteoporosis and 8 patients (2%) with normal bone mineral density or osteopenia·Reference -BMJ 2005 Apr 9;330(7495):818full-textBone turnover markers for diagnosing osteoporosis·serum BTMs of bone resorption include3·N-terminal cross-linking telopeptides (NTX)·C-terminal cross-linking telopeptides (CTX)·deoxypyridinoline (DPD)·serum BTMs of bone formation include3·procollagen type I N propeptide (PINP)·procollagen type I C propeptide (PICP)·osteocalcin (OC)·high bone turnover has been observed in patients with osteoporosis, but currently little consensus on use of serum bone turnover markers (BTMs) to diagnose osteoporosis2·serum BTMs may, however, helpassess risk of fracturein patients with osteoporosis orshow response to therapy1,3·International Osteoporosis Foundation (IOF) and International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) bone marker standards working group recommendations on use of bone turnover markers in clinical practice·bone turnover markers, especially bone resorption markers, may have some utility for predicting fracture outcomes and for monitoring treatment·reference standards recommended for research on use of bone turnover markers·use serum collagen type I crosslinked C-telopeptide (sCTX) as reference standard for bone resorption·use serum procollagen type I N-terminal propeptide (P1NP) as reference standard for bone formation·collect sample in EDTA tube, if possible·use automated analyzers, if available, but if not, use ELISA kit·Reference -Osteoporos Int 2011 Feb;22(2):391EBSCOhost Full Text·elevated levels of serum bone alkaline phosphatase and serum collagen type I crosslinked C-telopeptide may be found in patients with osteoporosis(level 2 [mid-level] evidence)··based on systematic review with wide confidence intervals·133 cohort or case-control studies evaluating use of bone turnover markers to assess bone density in patients with and/or without osteoporosis·increased levels of bone turnover markers in patients with osteoporosis compared to patients without osteoporosis·serum bone alkaline phosphatase (bone ALP), mean difference 7.76 units/L (95% CI 0.17-15.35 units/L) in analysis of 7 studies with 452 patients·serum collagen type I crosslinked C-telopeptide (sCTX), mean difference 523.7 pmol/L (95% CI 134.6-912.8 pmol/L) in analysis of 4 studies with 271 patients·no significant difference in serum osteocalcin (sOC) in analysis of 10 studies with 660 patients or urinary collagen type I crosslinked C-telopeptide (uNTX) in analysis of 2 studies with 148 patients·no significant difference in sOC between patients with osteoporosis with and without vertebral fracture in analysis of 3 studies with 235 patients·no data available to calculate sensitivity, specificity, or predictive values for bone turnover markers in diagnosis of osteoporosis or assessment of fracture risk in osteoporosis·Reference -Joint Bone Spine 2012 Jan;79(1):20Urine studies·initial testing to determinesecondary causesin all patients without prior workup includes 24-hour urine calcium excretion2,3·if low, may indicate state of malabsorption (such as withceliac diseaseor post gastric bypass),vitamin D deficiency, low calcium intake, or use of thiazide diuretics·if elevated, may indicate idiopathichypercalciuria, primaryhyperparathyroidism, renal calcium leak,multiple myeloma, metastatic cancer involving bone, orhyperthyroidismbut also common in patients with excessive calcium intake·additional testing may include2·24-hour urinary free cortisol, elevated with glucocorticoid excess·urine protein electrophoresis, may contain monoclonal light chains withmultiple myelomaImaging studiesDual-energy x-ray absorptiometry (DEXA) scanDEXA testing indications·International Society for Clinical Densitometry/National Osteoporosis Foundation/Institute for Clinical Systems Improvement (ISCD/NOF/ICSI) recommendations on bone mineral density (BMD) testing in adults recommends DEXA for1,2,6·all women ≥ 65 years old and all men ≥ 70 years old·younger postmenopausal women, women in menopausal transition, and men < 70 years old with clinical risk factors for fracture (such as, low body weight or prior fracture)·adults with fragility fracture·adults with conditions (for example, rheumatoid arthritis) or taking medications (for example, prednisone ≥ 5 mg/day or equivalent glucocorticoid for ≥ 3 months) associated with low bone mass or bone loss·anyone considering medication for osteoporosis·anyone being treated for osteoporosis·anyone not being treated but in whom evidence of bone loss would lead to treatment·women discontinuing estrogen who meet any of these indicationsBody site selection for DEXA scan·International Society for Clinical Densitometry/National Osteoporosis Foundation/Institute for Clinical Systems Improvement (ISCD/NOF/ICSI) recommendations on bone mineral density (BMD) testing in adults1,2,6·posterior-anterior spine and hip in all patients·posterior-anterior spine measurement·use L1-L4 for posterior-anterior spine·use maximum number of evaluable vertebrae and only exclude vertebrae if affected by local structural change or artifact·if any nonevaluable vertebrae excluded, use all remaining vertebrae to derive T-score, unless only single vertebra remains, use different valid skeletal site·exclude anatomically abnormal vertebrae if clearly abnormal and nonassessable within resolution of system or ≥ 1 T-score difference between abnormal vertebrae and adjacent vertebrae·do not use lateral spine for diagnosis·hip measurement·use femoral neck or total proximal femur (at either hip), whichever is lowest·insufficient evidence to determine if mean T-scores for bilateral hip BMD can be used for diagnosis·mean hip (preferably total hip) BMD can be used for monitoring·forearm (one-third or 33% radius of nondominant forearm) BMD for diagnosis only if·hip and/or spine cannot be measured or interpreted·patient has hyperparathyroidism·patient is over weight limit for dual-energy x-ray absorptiometry (DEXA) tableT-score and Z-score classification·T-score used in postmenopausal women or men ≥ 50 years old2·T-score - number of standard deviations above or below mean for a gender and ethnicity-matched young adult healthy populationTable 1. T-score Calculation(measured BMD - young adult population mean BMD)/young adult population SD··bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DEXA)·standard deviation (SD)·classification of T-score based on World Health Organization (WHO) international classification·normal - T-score ≥ -1·low bone mass (osteopenia) - T-score -1 to -2.5·osteoporosis - T-score ≤ -2.5·severe or established osteoporosis - T-score ≤ -2.5 and ≥ 1 fractures·Z-score used in premenopausal women, men ≤ 50 years old, and children2·Z-score - number of standard deviations above or below the mean for gender, ethnicity, and age-matched healthy populationTable 2. Z-score Calculation(measured BMD - age-matched population mean BMD)/age-matched population SD··bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DEXA)·standard deviation (SD)·classification based on International Society for Clinical Densitometry rather than WHO classification·within expected range for age - Z-score > -2·low bone mineral density for chronological age (below expected range for age) - Z-score ≤ -2·cannot quantitatively compare BMD or calculate least significant change between facilities without cross-calibration6DEXA scan in children·International Society for Clinical Densitometry/National Osteoporosis Society (ISCD/NOS) recommendations on BMD testing in children5·osteoporosis should not be diagnosed in children based on densitometric criteria alone·DEXA assessment indicated for children with increased risk of fracture·do not perform DEXA on children who cannot be safely and appropriately positioned for testing·perform DEXA when children expected to benefit from intervention to reduce fracture risk and when DEXA results expected to influence intervention·site selection·lumbar spine for children aged ≤ 5 years, or·whole body for children aged ≥ 3 years·forearm and femur measurements are feasible for children aged ≤ 5 years, but methodology, reproducibility, and reference data for this site are lacking·consider impact of growth delay on interpretation of results in children aged ≤ 5 years·DEXA interpretation·DEXA preferred method for assessing bone mineral content (BMC) and areal BMD (grams of mineral per square centimeter scanned)·preferred sites for performing BMC and areal BMD measurements are posterior-anterior spine (PA) and total body less head (TBLH) but other sites may be used depending on clinical need·do not use hip for BMC and areal BMD because of variability in skeletal development·consider soft tissue measures in children with chronic conditions associated with malnutrition or muscle and skeletal disorders·6-12 month minimum interval between scans·adjust spine and TBLH BMC and areal BMD in children with short stature or growth delay (for spine, adjust using either bone mineral apparent density [BMAD] or height Z-score; for TBLH, adjust using height Z-score)·appropriate reference data set includes healthy representatives of general population normal in size for their age·useZ-scorefor reporting BMD in children·classification (Z-score > -2 does not exclude possibility of skeletal fragility and increased fracture risk)·within expected range for age, Z-score > -2·low bone mineral density for chronological age (below expected range for age), Z-score ≤ -2·osteoporosis, Z-score ≤ -2 and clinically significant fracture history (≥ 2 long bone fractures by age 10 years or ≥ 3 long bone fractures by age 19 years)Peripheral dual-energy x-ray absorptiometry (pDEXA)·peripheral dual-energy x-ray absorptiometry (pDEXA) is DEXA measurement of bone density of forearm, finger, or heel2·International Society for Clinical Densitometry/National Osteoporosis Foundation/Institute for Clinical Systems Improvement (ISCD/NOF/ICSI) recommendations on pDEXA in adults1,2,6·may use validated pDEXA device to assess vertebral and global fragility fracture risk in menopausal women, but predictive performance of central DEXA and heel quantitative ultrasound (QUS) better·radius pDEXA plus clinical risk factors may be used to identify population at very low fracture probability who may require no further diagnostic evaluation·pDEXA of peripheral sites not appropriate for diagnosis of osteoporosis; use only femur neck, total femur, lumbar spine, or 33% radius measured by DEXA or pDEXA devices with validated young-adult reference database for WHO diagnostic classification·sufficiently high fracture probability by radius pDEXA plus clinical risk factors can be used to initiate treatment, if central DEXA cannot be performed·do not use pDEXA to monitor skeletal effects of treatments for osteoporosisVertebral fracture assessment (VFA)·vertebral fracture assessment (VFA) densitometric spine imaging to detect vertebral fractures6·VFA has less radiation exposure than standard spine x-rays2·International Society for Clinical Densitometry (ISCD) position statement on VFA with DEXA (or lateral spine radiography) in adults6·VFA indicated for patients with T-score < -1 and at least one of following·women ≥ 70 years old or men ≥ 80 years old·historical height loss > 4 cm (1.5 inches)·self-reported but undocumented prior vertebral fracture·prednisone ≥ 5 mg/day or equivalent glucocorticoid for ≥ 3 months·use Genant visual semiquantitative method for diagnosing vertebral fracture with VFA and include assessment of grade/severity·confirm severity of deformity using morphometry, if desired·follow VFA with another imaging modality if·≥ 2 mild (grade 1) deformities without any moderate or severe (grade 2 or 3) deformities·lesions in vertebrae that cannot be attributed to benign causes·vertebral deformities in patient with known history of relevant malignancy·equivocal fractures·unidentifiable vertebrae between T7 and L4·sclerotic or lytic changes, or findings suggestive of conditions other than osteoporosisQuantitative ultrasound (QUS)·quantitative ultrasound (QUS) measures speed of sound and/or broadband ultrasound attenuation at heel, tibia, patella, or other peripheral skeletal sites1·International Society for Clinical Densitometry/National Osteoporosis Foundation/Institute for Clinical Systems Improvement (ISCD/NOF/ICSI) recommendations on BMD testing using QUS in adults1,2,6·BMD from different devices cannot be directly compared·T-scores from measurements other than dual energy X-ray absorptiometry (DEXA) at femur neck, total femur, lumbar spine, or 33% radius cannot be used according toWHO diagnostic classificationbecause they are not equivalent·heel is only validated skeletal site for clinical use in osteoporosis management·QUS in fracture prediction·validated heel QUS devices predict fragility fracture independently of central DEXA BMD in postmenopausal women (hip, vertebral, and global fracture risk) and in men aged ≥ 65 years (hip and all nonvertebral fractures)·discordant results between heel QUS and central DEXA are common·heel QUS plus clinical risk factors may be used to identify population at very low fracture probability who may require no further diagnostic evaluation·QUS in therapeutic decisions·central DEXA measurements at spine and femur preferred for therapeutic decision making·sufficiently high fracture probability by heel QUS plus clinical risk factors can be used to initiate treatment, if central DEXA cannot be performed·do not use QUS to monitor skeletal effects of treatments for osteoporosis·different calcaneal QUS devices appear to have wide sensitivity and specificity ranges for detection of osteoporosis in women > 45 years old(level 2 [mid-level] evidence)··based on systematic review limited by clinical heterogeneity·systematic review of 31 diagnostic cohort studies evaluating calcaneal QUS devices for detection of osteoporosis in women > 45 years old·QUS devices included Achilles, Achilles Plus, Achilles Express, or Achilles Insight (13 studies), Hologic Sahara (12 studies), CUBA Clinical or CUBA Mark II (6 studies), or other devices (3 studies)·prevalence of osteoporosis ranged from 7.1% to 62% by DEXA (T-score ≤ 2.5) of hip and/or spine (reference standard)·meta-analyses not performed due to heterogeneity in study methodology, device cutoffs, and patient population·diagnostic performance of calcaneal QUS devices for detection of osteoporosisDeviceCutoffStudiesSensitivity (Range)Specificity (Range)Achilles-2.5 to -1 (stiffness index T-score)634.8%-88.4%41.2%-91.8%Achilles Plus-3.7 to 0 (stiffness index T-score)355%-100%10%-100%Achilles Express-2.5 to -1.4 (stiffness index T-score)339.3%-77.5%50%-91.7%Hologic Sahara60.3-115.6 (quantitative ultrasound index)520.8%-100%9.3%-95.8%··Reference -Osteoporos Int 2015 May;26(5):1459EBSCOhost Full Text·QUS of calcaneus may have low to moderate specificity for diagnosis of osteoporosis(level 2 [mid-level] evidence)··based on systematic review limited by clinical heterogeneity·systematic review of 6 diagnostic studies evaluating QUS of calcaneus for detection of osteoporosis in 12,250 adults·reference standard was DEXA with cutoff T-score < -2.5·analysis limited by clinical heterogeneity in QUS equipment (Lunar Achilles, Hologic Sahara) and QUS cutoff T-scores for detection of osteoporosis·QUS of calcaneus for diagnosing osteoporosis·sensitivity ranges 64%-100% in 5 studies, 41%-59% in 1 outlier study·specificity ranges 13%-90%·Reference -Acta Reumatol Port 2011 Oct-Dec;36(4):327EBSCOhost Full TextPDFEBSCOhost Full Text·DynaMed commentary --Sensitivity and specificity ranges reported from Table 3 in article which includes ranges for subpopulations and different comparators (spine DEXA, total hip DEXA) rather than analyzing optimum T-score threshold derived from each article (which may overestimate diagnostic accuracy) to obtain results reported in abstract and discussion.·quantitative heel ultrasound does not appear to have adequate sensitivity or specificity for confirming or ruling out osteoporosis based on DEXA(level 2 [mid-level] evidence)··based on systematic review of 25 studies limited by clinical heterogeneity·quantitative heel ultrasound with T-score threshold of -1 had 79% sensitivity and 58% specificity for identifying individuals with DEXA-determined T-score ≤ -2.5 at hip or spine·Reference -Ann Intern Med 2006 Jun 6;144(11):832EBSCOhost Full Text·calcaneal QUS may be an option for diagnosis of osteoporosis in women aged > 65 years··based on subgroup analysis from prospective cohort study·5,934 women aged ≥ 75 years who took part in EPIDOS cohort study were evaluated at heel with 3 different QUS devices, using DEXA (reference standard) results to determine QUS device thresholds·QUS thresholds were set to identify osteoporosis with both 90% sensitivity (low likelihood) and specificity (high likelihood)·GE-Lunar Achilles, Hologic Sahara, and DMS UBIS-5000 systems evaluated in women aged > 65 yearsTable 3. Diagnostic Thresholds for OsteoporosisDeviceHigh LikelihoodLow LikelihoodGE-Lunar AchillesHeel stiffness index ≤ 57%Heel stiffness index > 78%Hologic SaharaQuantitative index ≤ 59Quantitative index > 83DMS UBIS-5000BUA ≤ 55BUA > 62Abbreviation: BUA, broadband ultrasound attenuation.··diagnostic performance using above diagnostic thresholds·sensitivity 89%·specificity 87%·patients with results below high likelihood threshold have a high probability of having osteoporosis and those with results above low likelihood threshold have low probability of having osteoporosispatients with results that fall between thresholds warrant further evaluation, for instance, with DEXAReference -Salud Publica Mex 2009;51 Suppl 1:S25full-textQuantitative computed tomography-based absorptiometry (QCT)·International Society for Clinical Densitometry/National Osteoporosis Foundation/Institute for Clinical Systems Improvement (ISCD/NOF/ICSI) recommendations on BMD using quantitative computed tomography (QCT) and peripheral QCT (pQCT) testing in adults1,2,6·scan L1-L3 if using single-slice device or L1-L2 if using three-dimensional (3D) device·spinal trabecular BMD may predict vertebral fractures in postmenopausal women with same accuracy as anterior-posterior spinal BMD by DEXA·insufficient data to recommend spine QCT for hip fracture prediction·pQCT of forearm at ultradistal radius predicts hip, but not spine, fragility fractures in postmenopausal women·sufficiently high fracture probability by spine QCT or radius pQCT plus clinical risk factors can be used to initiate treatment, if central DEXA cannot be performed·trabecular BMD of lumbar spine QCT may be used to monitor age, disease, and treatment related BMD changes·trabecular BMD of ultradistal radius pQCT may be used to monitor age-related BMD changes·ISCD position statement on BMD using QCT and peripheral QCT (pQCT) testing in children5·no preferred method for QCT in children·QCT, pQCT, and high resolution (HR)-pQCT may be used clinically in children if appropriate reference data and expertise are available·QCT protocols in children using general computed tomography (CT) scanners require appropriate exposure factors, calibration phantoms, and software to optimize results and minimize radiation exposure·QCT and pQCT associated with greater radiation exposure than DEXA1,2Biomechanical analysis of computed tomography·biomechanical analysis of contrast-enhanced computed tomography enterography identifies osteoporosis in patients with inflammatory bowel disease(level 1 [likely reliable] evidence)··based on retrospective diagnostic cohort study·136 adults (median age 44 years) with inflammatory bowel disease and body mass index < 30 kg/m2who had contrast-enhanced computed tomography (CT) enterography and dual-energy x-ray absorptiometry (DXA) scans within 30 days of each other were assessed·5.1% had osteoporosis (T-score ≤ -2.5) by DXA (reference standard)·bone mineral density (BMD) estimated from CT enterographs by biomechanical CT analysis at femoral neck·diagnostic performance of biomechanical CT analysis for detection of osteoporosis·sensitivity 85.7%·specificity 98.5%·positive predictive value 75%·negative predictive value 99.2%·positive likelihood ratio 57·negative likelihood ratio 0.15·Reference -Am J Gastroenterol 2014 Mar;109(3):401full-text·derivation of biomechanical CT analysis for estimation of BMD can be found inAnn N Y Acad Sci 2010 Mar;1192:57ManagementManagement overview·lifestyle recommendations for all patients·balanced diet with adequatecalcium and vitamin D intake(ICSI Strong recommendation, Moderate-quality evidence)·regular weight-bearing and muscle-strengtheningexerciseto improve agility, strength, posture, and balance, increase bone mineral density, and reduce risk of falls and fractures (ICSI Strong recommendation, Low-quality evidence,level 2 [mid-level] evidence)·smoking cessation (ICSI Strong recommendation, Moderate-quality evidence)·avoid excess alcohol intake·medicationsrecommended in·postmenopausal women and men ≥ 50 years old ifHip or vertebral fracture (including asymptomatic vertebral fracture) without major traumaICSI Strong recommendation, Moderate-quality evidence,Endocrine Society Strong recommendation, Moderate-quality evidenceNNT 19-23 for prevention of any clinical fracture(level 1 [likely reliable] evidence)*Osteoporosis (T-score ≤ -2.5)**ICSI Strong recommendation, Moderate-quality evidence,Endocrine Society Strong recommendation, Low-quality evidenceNNT 47-49 for prevention of nonvertebral fractures(level 1 [likely reliable] evidence)*Osteopenia (T-score -1 to -2.5)** and high risk for fracture***ICSI Strong recommendation, Moderate-quality evidence,Endocrine Society Strong recommendation, Low-quality evidenceNNT 67 for prevention of vertebral fractures (clinical plus radiographic)(level 3 [lacking direct] evidence)** number needed to treat (NNT) based on data from trials evaluatingbisphosphonates** at femoral neck, total hip, or lumbar spine by dual-energy x-ray absorptiometry (DEXA)*** 10-year risk ≥ 3% for hip fracture or ≥ 20% for major osteoporosis-related fracture using Fracture Risk Assessment (FRAX)··patients taking long-term glucocorticoids (ICSI Strong recommendation, Moderate-quality evidence,Endocrine Society Strong recommendation, Low-quality evidence)·men with prostate cancer receiving androgen deprivation therapy who have high risk of fracture (Endocrine Society Strong recommendation, Moderate-quality evidence)·bisphosphonatesare the usual first-line choice when pharmacologic therapy is indicatedTable 4. Bisphosphonates Used to Prevent and Treat Osteoporosis*BisphosphonateRoute of AdministrationType of Fracture Risk ReductionAdverse EffectsOsteoporosis IndicationsAlendronateOral (taken on empty stomach with plenty of water)·Vertebral·Nonvertebral·Hip·Esophagitis·Musculoskeletal pain·Osteonecrosis of the jaw (rare)·Atypical femur fracture (rare)·Postmenopausal osteoporosis: treatment and prevention·Osteoporosis in men: treatment·Glucocorticoid-induced osteoporosis: treatmentIbandronate·Oral (taken on empty stomach with plenty of water)·IV·Vertebral·Acute-phase reaction (intravenous)·Esophagitis·Musculoskeletal pain·Osteonecrosis of the jaw (rare)·Atypical femur fracture (rare)·Postmenopausal osteoporosis: treatment and prevention·Not FDA approved for treatment and prevention of osteoporosis in men or glucocorticoid-induced osteoporosisRisedronateOral (taken on empty stomach with plenty of water)·Vertebral·Nonvertebral·Hip·Esophagitis·Musculoskeletal pain·Osteonecrosis of the jaw (rare)·Atypical femur fracture (rare)·Postmenopausal osteoporosis: treatment and prevention·Osteoporosis in men: treatment·Glucocorticoid-induced osteoporosis: treatment and preventionZoledronic acidIV·Vertebral·Nonvertebral·Hip·Acute-phase reaction (most often after first dose)·Musculoskeletal pain·Osteonecrosis of the jaw (rare)·Atypical femur fracture (rare)·Postmenopausal osteoporosis: treatment and prevention·Osteoporosis in men: treatment·Glucocorticoid-induced osteoporosis: treatment and preventionEtidronateOral (taken on empty stomach with plenty of water)Vertebral·Gastrointestinal·Glossitis·Alopecia·Musculoskeletal pain·Osteomalacia·Neuropsychiatric events·Not approved by FDA for treatment or prevention of osteoporosis·Used for treatment and prevention of osteoporosis outside of United States, such as Canada, Europe, and Japan* Bisphosphonates are contraindicated if creatinine clearance ≤ 30-35 mL/minute.References -1,BMJ 2015 Sep 2;351:h3783EBSCOhost Full Text,N Engl J Med 2016 Jan 21;374(3):254EBSCOhost Full Text,CMAJ 2010 Nov 23;182(17):1864EBSCOhost Full Textfull-text,Curr Osteoporos Rep 2007 Dec;5(4):165EBSCOhost Full Text,FDA DailyMed 2017 Mar 17EBSCOhost Full Text.··parathyroid hormone 1-34 (teriparatide) 20 mcg subcutaneously once daily can be first-line choice for patients at highest risk for fracture (ICSI Strong recommendation, High-quality evidence)·teriparatide may be more effective than alendronate for reducing nonvertebral fractures (NNT 11) in postmenopausal women(level 2 [mid-level] evidence)·teriparatide may be more effective than alendronate for reducing clinical vertebral fractures (NNT 42) in corticosteroid-induced osteoporosis(level 2 [mid-level] evidence)·other licensed medications for osteoporosis include·estrogen receptor modulators in postmenopausal women with osteoporosis·raloxifene(Evista) 60 mg orally once daily may reduce risk for vertebral fracture but not nonvertebral fracture, and may increase risk for venous thromboembolism(level 2 [mid-level] evidence)·lasofoxifene(Fablyn in Europe) 0.5 mg orally once daily may reduce risk of fractures but increase risk of venous thromboembolism(level 2 [mid-level] evidence)·tibolone(Livial in Europe) 1.25 mg orally once daily reduces risk of fractures and some cancers but increases risk of stroke(level 1 [likely reliable] evidence)·abaloparatide(Tymlos), a parathyroid hormone (PTH) 1-34 analog, give as 80 micrograms subcutaneously once daily is FDA-approved for osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies·denosumab(Prolia) 60 mg subcutaneously every 6 months(level 2 [mid-level] evidencefor postmenopausal women,level 3 [lacking direct] evidencefor men)·romosozumabfor 12 months reduces composite risk of fractures at 1 year in women with osteoporosis(level 1 [likely reliable] evidence)·calcitoninbut limited evidence for efficacy(level 3 [lacking direct] evidence)and risks (including cancer) may outweigh benefits·reassessing medication use after 3-5 years suggested; drug holidays (treatment cessation) might reduce adverse effects with minimal loss of efficacy·guidelines suggestbone mineral density monitoringevery 1-2 years, but monitoring appears to have little effect on changing treatment or predicting clinical response to treatmentDiet·balanced diet with adequate nutrition, including dairy products, important in management of osteoporosis (ICSI Strong recommendation, Low-quality evidence)2·adequate calcium and vitamin D intake recommended (ICSI Strong recommendation, Moderate-quality evidence)·calcium·adequate calcium intake should be through diet alone, if possible, and should be maintained throughout lifetime·use a variety of calcium-containing food because calcium absorption from food is compromised by oxalic acid (found in dark, green, leafy vegetables)·2010 Dietary Reference Intakes for calcium·adults aged 19-50 years, 1,000 mg/day·men aged 51-70, 1,000 mg/day·women aged ≥ 51 years, 1,200 mg/day·men aged ≥ 71 years, 1,200 mg/day·pregnant or breast feeding women aged ≥ 18 years, 1,300 mg/day·Reference -Dietary Reference Intakes for Calcium and Vitamin D·see alsoCalcium and Vitamin D for Treatment and Prevention of Osteoporosis·vitamin D·sunlight exposure may not produce adequate vitamin D, so vitamin D intake should be achieved through diet, if possible, and supplementation, if necessary·milk is only dairy source of vitamin D, but levels of vitamin D fortification vary widely·other food sources of vitamin D vary by time of year of harvesting·2010 Dietary Reference Intakes for vitamin D·adults aged 18-70 years, 600 units/day·adults aged ≥ 71 years, 800 units/day·Reference -Dietary Reference Intakes for Calcium and Vitamin D·seeCalcium and Vitamin D for Treatment and Prevention of Osteoporosisfor additional information·phosphorus intake 700 mg/day (United States Recommended Daily Allowances) recommended to prevent hypophosphatemia-induced bone loss (Mayo Clin Proc 2004 Jan;79(1):91)·vitamin K2 supplements may not reduce incidence of fractures(level 2 [mid-level] evidence)but may increase lumbar bone mineral density(level 3 [lacking direct] evidence)in postmenopausal women with osteoporosis in Japan··based on systematic review limited by statistical and clinical heterogeneity·systematic review of 19 randomized trials evaluating oral vitamin K2 supplements for treatment and prevention of osteoporosis in 6,759 postmenopausal women·most trials evaluated menatetrenone 45 mg/day·control group was placebo, bisphosphonates, calcium, vitamin D3, or calcium plus vitamin D3·10 trials evaluated vitamin K2 for treatment of osteoporosis·heterogeneity in intervention regimens, control group, and duration of follow-up limited analyses·majority of trials were conducted in Japan·no significant differences between groups in fracture in analysis of 5 trials with 3,672 women, results limited by significant heterogeneity·vitamin K2 supplements associated with·increased lumbar bone mineral density at 6 months and at 12 months in analyses of 4 trials with 381 women, results limited by significant heterogeneity·increased adverse events in analysis of 5 trials with 4,363 women·odds ratio 1.27 (95% CI 1.01-1.59)·NNH 27-1,537 with adverse events in 7% of control group·adverse events included mostly minor gastrointestinal symptoms and itching·Reference -Osteoporos Int 2015 Mar;26(3):1175EBSCOhost Full Text·alcohol intake2·high alcohol intake associated with decreased bone mineral density (data conflicting on moderate alcohol intake)·Institute for Clinical Systems Improvement (ICSI) recommendations on maximum alcohol intake·women should have ≤ 1 standard drink/day (standard drink is 12 ounces beer, 5 ounces wine, or 1.5 ounces 80-proof distilled spirit)·men should have ≤ 2 standard drinks/day·see alsoAlcohol Use DisorderActivity·recommend regular weight-bearing and muscle-strengthening exercise to improve agility, strength, posture, and balance to increase bone mineral density (BMD) and reduce risk of falls and fractures (ICSI Strong recommendation, Low-quality evidence)1,2·high-impact exercise and weight training stimulate accrual of bone mineral content2·compared to aerobic exercise, resistance training may be more beneficial for site-specific accrual of bone mineral content·high-intensity resistance training improves strength and balance and increases muscle mass, which may especially benefit patients with osteoporosis by increasing bone mass and decreasing risk of falls·three components of exercise program necessary for strong bone health include impact, strengthening, and balance training·addition of exercise to antiresorptive therapy may be associated with increased lumbar spine bone mineral density in adults with osteoporosis(level 3 [lacking direct] evidence)··based on systematic review without clinical outcomes·systematic review of 7 randomized trials comparing effects of exercise plus antiresorptive therapy vs. antiresorptive therapy alone on bone mineral density (BMD) in 420 adults with osteoporosis·type of exercise varied across studies, but included strength or resistance training at least 1 time per week in 6 trials and whole-body vibration in 1 trial·comparing exercise plus antiresorptive therapy to antiresorptive therapy alone, exercise plus antiresorptive therapy associated with increased BMD at lumbar spine in analysis of 7 trials with 420 adults (p < 0.0001)·Reference -Osteoporos Int 2014 May;25(5):1585EBSCOhost Full Text·exercise for improved function and quality of life in postmenopausal women with osteoporosis·exercise programs may improve quality of life in postmenopausal women with osteoporosis(level 2 [mid-level] evidence)··based on systematic review with assessment of trial quality not reported·systematic review of 4 trials evaluating exercise for improving quality of life in 256 postmenopausal women with osteoporosis or osteopenia·exercise associated with significant improvement in physical function, pain, and vitality (p < 0.05)·Reference -Clin Rehabil 2009 Oct;23(10):888·progressive quadriceps strength and proprioception training associated with decrease in falls in postmenopausal women with osteoporosis(level 2 [mid-level] evidence)··based on randomized trial with allocation concealment not stated·100 sedentary postmenopausal women aged 55-75 years with osteoporosis were randomized to 18-week progressive quadriceps strength and proprioception training in addition to osteoporosis drug therapy vs. drug therapy alone·85% completed study·strength and proprioception training associated with decrease in number of falls at 24 weeks posttreatment (incidence rate ratio 0.263, 95% CI 0.1-0.68)·Reference -Osteoporos Int 2010 Apr;21(4):589EBSCOhost Full Text·Pilates associated with greater improvement in pain, functional status, and quality of life compared with home-based exercise program in women with postmenopausal osteoporosis(level 2 [mid-level] evidence)··based on randomized trial with method of randomization and allocation concealment not stated·70 postmenopausal women aged 45-65 years with osteoporosis randomized to Pilates (supervised Pilates exercise program twice weekly for 1 year) vs. home-based exercise program (consisting of thoracic extension exercises)·14% did not complete follow-up at 1 year and were excluded from analyses·Pilates associated with greater improvement in pain, functional status, and quality of life (p < 0.05 for all)·Reference -J Bodyw Mov Ther 2013 Apr;17(2):204·balance training may reduce falls and improve quality of life in older women with osteoporosis(level 2 [mid-level] evidence)··based on small randomized trial without attention control·60 women ≥ 65 years old with senile osteoporosis randomized to balance training vs. no intervention for 12 months·balance training associated with·improved quality of life (p < 0.001)·improved functional balance (p < 0.001)·reduction in falls (50% vs. 26.6% with control) (p < 0.025)·Reference -Maturitas 2010 Jun;66(2):206·weight-bearing exercise may improve walking endurance, leg strength, walking speed, and body sway in older women with low bone mineral density(level 3 [lacking direct] evidence)··based on randomized trial without clinical outcomes·160 women aged 70-73 years with radial and hip BMD > 2 standard deviations below reference value were randomized to impact, balancing, and strengthening exercises vs. no intervention for 30 months·exercise intervention included·1-hour training sessions once weekly for 6 months (October-March) each year·advice to do 20 minutes/day at home for other 6 months each year·control group received general health information at baseline·comparing exercise vs. no intervention·mean change in endurance (distance walked in 2 minutes) was 20.8 meters vs. -2 meters (p < 0.001)·mean change in leg strength was 19.1 kg vs. -8 kg (p < 0.001)·mean change in walking speed was 0.25 meters/second vs. -0.07 meters/second (p < 0.001)·body sway increased more in control group than in exercise group (p < 0.001)·Reference -J Bone Miner Res 2006 May;21(5):772full-text·exercise to improve balance and strength may improve postural control and lower limb strength in older women with osteoporosis(level 3 [lacking direct] evidence)··based on small randomized trial without clinical outcomes·33 women aged ≥ 65 years with osteoporosis randomized to exercises for balance and strength vs. no exercise for 8 weeks·82% adhered to exercise program·exercise associated with improved postural control (p ≤ 0.02) and lower limb strength (p ≤ 0.01)·Reference -Am J Phys Med Rehabil 2010 Jul;89(7):549·exercise for balance in men·tai chi may improve body balance in older men with osteopenia or osteoporosis(level 3 [lacking direct] evidence)··based on small randomized trial without clinical outcomes·49 men aged 60-82 years with osteoporosis or osteopenia were randomized to tai chi exercise class for 45 minutes twice weekly vs. control for 18 weeks·body balance assessed using Computer Posturographic System PE 90·body balance improved from 80.95% to 84.45% (p ≤ 0.01) in tai chi group vs. no significant improvement in control group·Reference -Am J Chin Med 2007;35(1):1Counseling·counsel patients withtobacco use disorderto stop smoking (ISCI Strong recommendation, Moderate-quality evidence)2·counsel patients to achieve or maintain normal body mass index (BMI) of between 20 and 25 kg/m2(ICSI Strong recommendation, Low-quality evidence)2·multifaceted osteoporosis group education might improve health-related quality of life in adults with osteoporosis(level 2 [mid-level] evidence)··based on systematic review limited by clinical heterogeneity·systematic review of 5 randomized trials and 2 observational studies comparing multifaceted osteoporosis group education vs. control in 923 adults ≥ 45 years old with osteoporosis·all interventions included information on osteoporosis and interventions for management (medication, diet, exercise)·some interventions also addressed activities of daily living, pain, and falls prevention·meta-analysis precluded by heterogeneity in interventions and outcome measures·multifaceted osteoporosis group education associated with improved·health-related quality of life in 2 of 3 studies·pain in 2 of 3 studies·Reference -Osteoporos Int 2014 Apr;25(4):1209EBSCOhost Full TextMedicationsMedications licensed for osteoporosis treatment·FDA-approved medications for management of established osteoporosis include (with links to drug topics)·bisphosphonates -alendronate,ibandronate,risedronate,zoledronic acid·parathyroid hormone (PTH) 1-34 (teriparatide)·parathyroid hormone (PTH) 1-34 analog (abaloparatide)·raloxifene(an estrogen agonist/antagonist)·denosumab(a receptor activator of nuclear factor kappa-B ligand [RANKL] inhibitor)·calcitonin·romosozumab·other drugs approved in some countries in Europe include (with links to evidence summaries)·recombinant human parathyroid hormone (rhPTH) (1-84)·lasofoxifene(an estrogen agonist/antagonist)·tibolone(a selective tissue estrogenic activity regulator)·strontium ranelate·osteoporosis treatments that reduce fractures are associated with reduced mortality in elderly persons(level 2 [mid-level] evidence)··based on systematic review without assessment of trial quality·systematic review of 8 trials comparing risedronate, strontium ranelate, zoledronic acid, or denosumab vs. placebo for osteoporosis in 33,090 elderly patients·osteoporosis therapy associated with reduced mortality (relative risk 0.89, 95% CI 0.8-0.99)·Reference -J Clin Endocrinol Metab 2010 Mar;95(3):1174Indications for pharmacologic therapy·National Osteoporosis Foundation recommendations1·medications recommended for treatment of osteoporosis if·hip or vertebral fracture (including asymptomatic vertebral fracture)·T-score ≤ -2.5 at femoral neck, total hip, or lumbar spine by dual-energy x-ray absorptiometry (DEXA), after appropriate evaluation to exclude secondary causes·low bone mass (T-score -1 to -2.5) at femoral neck, total hip, or lumbar spine by DEXA and 10-year risk of hip fracture ≥ 3% or 10-year risk of major osteoporosis-related fracture ≥ 20% based on United States-adapted World Health Organization (WHO) absolute (Fracture Risk Assessment[FRAX])·no pharmacotherapy should be considered indefinite, repeat risk assessment after 3-5 years·Institute for Clinical Systems Improvement (ICSI) recommendations2·treatment withbisphosphonaterecommended for·postmenopausal women and men with osteoporosis to reduce fracture risk (both vertebral and nonvertebral) (ICSI Strong recommendation, Moderate-quality evidence)·patients taking glucocorticoids (ICSI Strong recommendation, Moderate-quality evidence)·men with osteoporosis undergoing androgen deprivation therapy for prostate cancer, particularlyzoledronic acid5 mg IV once per year (ICSI Strong recommendation, High-quality evidence)·following hip fracture - considerzoledronic acid5 mg IV within 90 days of hip fracture for both men and women (ICSI Strong recommendation, Moderate-quality evidence)·anabolic therapy with parathyroid hormone 1-34 (teriparatide) indicated for patients at particularly highriskof future fracture (ICSI Strong recommendation, High-quality evidence)·consider·selective estrogen receptor modulator (SERM) treatment withraloxifenein postmenopausal women to reduce vertebral fracture risk·RANKL inhibitor treatment withdenosumabin postmenopausal women to reduce vertebral and hip fracture incidence·nasalcalcitoninas third-line treatment, particularly for short-term therapy in women ≥ 5 years post menopause with low bone mass·American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) recommendations for use of pharmacological therapy for prevention and treatment of osteoporosis in postmenopausal women·administer pharmacological therapy to women with·osteopenia or low bone mass and a history of fragility fracture of the hip or spine (AACE/ACE Grade A, Level 1)·bone mineral density T-score of ≤ -2.5 in the spine, femoral neck, total hip or 33% (one-third) radius (AACE/ACE Grade A, Level 1)·consider pharmacological therapy for women with T-score between -1 and -2.5 if theFracture Risk Assessment (FRAX)10-year probability for major osteoporosis fracture is ≥ 20% or 10-year probability of hip fracture is ≥ 3% in United States or above country-specific threshold in other countries or regions (AACE/ACE Grade B, Level 2)·DynaMed Commentary --Women meeting these criteria are routinely offered pharmacological therapy.·Reference - AACE/ACE guideline for diagnosis and treatment of postmenopausl osteoporosis (Endocr Pract 2016 Sep 2;22(Suppl 4):1EBSCOhost Full Text)·Endocrine Society recommends administering pharmacological therapy to men ≥ 50 years old at high risk of fracture, including4·men with history of hip or vertebral fracture without major trauma (Endocrine Society Strong recommendation, Moderate-quality evidence)·men without history of spine or hip fracture but with bone mineral density ≤ 2.5 standard deviations below mean of normal young white men at spine, femoral neck, and/or total hip (Endocrine Society Strong recommendation, Low-quality evidence)·men in the United States with T-score between -1.0 and -2.5 in the spine, femoral neck, or total hip plus 10-year risk of any fracture ≥ 20% or 10-year risk of hip fracture ≥ 3% usingFracture Risk Assessment FRAX; for men outside the United States, consult region-specific guidelines (Endocrine Society Strong recommendation, Low-quality evidence)·American College of Rheumatology (ACR) recommendations for use of bisphosphonates for treatment and prevention of glucocorticoid-induced osteoporosis for patients on glucocorticoid therapy·guidance varies according to patient age and results of clinical fracture risk assessment·for all patients on long-term glucocorticoid treatment, consider performing age-appropriate clinical fracture risk assessment within 6 months of initiating glucocorticoid treatment and reassess annually (ACR Good practice recommendation)·patients ≥ 40 years old (women not of child-bearing potential and men)·for high risk patients treat with oralbisphosphonatesovercalcium and vitamin Dalone (ACR Strong recommendation)·for moderate-risk patients, consider oral bisphosphonates (ACR Conditional recommendation)·for low-risk patients consider calcium and vitamin D over oral bisphosphonates (ACR Conditional recommendation) or IV bisphosphonates (ACR Strong recommendation)·patients < 40 years old (women not of child-bearing potential and men)·for moderate to high risk patients consider oral bisphosphonates (ACR Conditional recommendation)·for low risk patients consider optimizing calcium and vitamin D intake and lifestyle modifications rather than treatment with bisphosphonates,teriparatide, ordenosumab(ACR Conditional recommendation), or IV bisphosphonates (ACR Strong recommendation)·for women of child-bearing potential who are at moderate to high risk of fracture and do not plan on becoming pregnant during osteoporosis treatment and are not sexually active or are using effective birth control, consider oral bisphosphonates (ACR Conditional recommendation)·for patients ≥ 30 years old receiving high-dose glucocorticoids (initial dose of prednisone ≥ 30 mg/day and cumulative dose > 5 gm in 1 year), consider oral bisphosphonate (ACR Conditional recommendation)·for patients with organ transplant, glomerular filtration rate ≥ 30 mL/minute and without metabolic bone disease continuing treatment with glucocorticoids, consider treatment according to age appropriate guidelines for adults without transplants and evaluation by metabolic bone disease expert for all patients with renal transplants (ACR Conditional recommendation)·Reference - American College of Rheumatology (ACR) guideline for prevention and treatment of glucocorticoid-induced osteoporosis (Arthritis Rheumatol 2017 Aug;69(8):1521EBSCOhost Full Text) andArthritis Care Res (Hoboken) 2017 Aug;69(8):1095EBSCOhost Full Text·American College of Physicians (ACP) recommendations for pharmacologic treatment in women and men·in women with known osteoporosis (T-scores ≤ -2.5 or history of fragility fractures)·pharmacologic treatment (with bisphosphonates or denosumab) is recommended in women who have known osteoporosis (T scores ≤ -2.5 or history of fragility fractures) to reduce risk of hip and vertebral fractures (ACP Strong recommendation, High-quality evidence)·consider treatment duration of 5 years (ACP Weak recommendation, Low-quality evidence)·women with osteopenia who are ≥ 65 years old and have high risk of fracture may be considered for pharmacologic treatment, depending on patient's preferences, fracture risk profile, risk/benefit and cost analysis, and clinical judgment (ACP Weak recommendation, Low-quality evidence)·men with clinically recognized osteoporosis should be offered pharmacologic treatment with bisphosphonates to reduce risk of vertebral fracture (ACP Weak recommendation, Low-quality evidence)·Reference -Ann Intern Med 2017 Jun 6;166(11):818·similar recommendations from Endocrine Society4Bisphosphonates·bisphosphonates optionsused to prevent or treat osteoporosis include alendronate (oral), ibandronate (oral or IV), risedronate (oral), zoledronic acid (IV), and etidronate (oral); etidronate is not approved by FDA, but is used outside of the United States including Canada, Europe, and Japan (seeBisphosphonates for treatment and prevention of osteoporosisfor additional information)·seeIndications for pharmacologic therapysection for additional information on indications for treatment·guideline recommendations for bisphosphonate therapy·postmenopausal women - American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) recommendations·if decision has been made to offer bisphosphonate therapy·administer alendronate, risedronate, zoledronic as initial therapy to reduce hip, nonvertebral, and spine fractures for most postmenopausal women at high risk of fracture (AACE/ACE Grade A, Level 1)·administer IV zoledronic acid to patients unable to use oral therapy and as initial therapy for patients at especially high fracture risk (AACE/ACE Grade A, Level 1)·administer ibandronate as initial therapy in some cases if only spine-specific efficacy is required (AACE/ACE Grade A, Level 1)·Reference - American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) guideline for diagnosis and treatment of postmenopausl osteoporosis (Endocr Pract 2016 Sep 2;22(Suppl 4):1EBSCOhost Full Text)·men ≥ 50 years old - Osteoporosis Canada suggests alendronate, risedronate and zoledronic acid as first-line therapies for fracture prevention (OC Grade DEBSCOhost Full Text) (CMAJ 2010 Nov 23;182(17):1864EBSCOhost Full Textfull-text), editorial can be found inCMAJ 2010 Nov 23;182(17):1829EBSCOhost Full Text, commentary can be found inCMAJ 2011 Apr 5;183(6):695EBSCOhost Full Text)·American College of Physicians (ACP) recommendations·in women with known osteoporosis (T-scores ≤ -2.5 or history of fragility fractures)·pharmacologic treatment with bisphosphonates (with alendronate, risedronate or zoledronic acid) or denosumab is recommended to reduce risk of hip and vertebral fractures (ACP Strong recommendation, High-quality evidence)·consider treatment duration of 5 years (ACP Weak recommendation, Low-quality evidence)·pharmacologic treatment with bisphosphonates should be offered to men with clinically recognized osteoporosis to reduce risk of vertebral fracture (ACP Weak recommendation, Low-quality evidence)·Reference -Ann Intern Med 2017 Jun 6;166(11):818·considerations for bisphosphonate therapy·bisphosphonates FDA approved for treatment of osteoporosis include·alendronate (Fosamax, Binosto, generic) 10 mg orally once daily or 70 mg orally once weekly; 5 mg once daily is labeled dose for treatment of glucocorticoid-induced osteoporosis·ibandronate (Boniva, generic) 150 mg orally once monthly or 3 mg IV every 3 months; ibandronate not FDA approved for treatment in men or for glucocorticoid-induced osteoporosis·risedronate (Actonel, Atelvia [delayed], generic) 5 mg orally once daily, 35 mg orally once weekly, 75 mg orally on 2 consecutive days each month, or 150 mg orally once monthly·35 mg once week (immediate release) approved dose for treatment of osteoporosis in men·5 mg once daily is labeled dose for treatment of glucocorticoid-induced osteoporosis·zoledronic acid (Reclast) 5 mg IV over at least 15 minutes once yearly (also approved for glucocorticoid-induced osteoporosis)·etidronate - not FDA for treatment or prevention of osteoporosis, however etidronate is used for prevention and treatment in other regions such as Canada, Europe, and Japan·bisphosphonates failure (defined as significant decrease in BMD or recurrent fractures in patient who is compliant to therapy); strategies to address treatment failure may include·replacement of weaker antiresorptive with more potent drug of the same class·replacement of oral drug with injected drug·replacement of strong antiresorptive with an anabolic agent·duration of treatment and drug holiday should be individualized·some patients may be able to discontinue treatment temporarily after several years of therapy (drug holiday)·other patients at risk of high fracture will need to continue treatment·seeBisphosphonates for Treatment and Prevention of Osteoporosisfor details·efficacy of bisphosphonates in postmenopausal women·risk of fractures·bisphosphonatesmay reduce risk of secondary fragility fractures(level 2 [mid-level] evidence)·alendronatereduces clinical vertebral, hip, and wrist fractures(level 1 [likely reliable] evidence)·ibandronatemay reduce vertebral fractures(level 2 [mid-level] evidence)·risedronatemay reduce vertebral and nonvertebral fractures(level 2 [mid-level] evidence)·zolendronic acidannually may reduce any clinical fractures and clinical vertebral fractures(level 2 [mid-level] evidence); however it is unclear if single dose of zolendronic acid reduces clinical fractures inelderly women who are frail·etidronatemay reduce vertebral fractures(level 3 [lacking direct] evidence)but not hip or wrist fractures(level 2 [mid-level] evidence)·change in bone mineral density (BMD)·alendronate·addition of alendronate to cholecalciferol (vitamin D)may increase BMD without affecting serum or urinary calcium levels in postmenopausal women with osteoporosis and normocalcemic primary hyperparathyroidism(level 3 [lacking direct] evidence)·alendronate 70 mg orally every 2 weeks and 70 mg once weeklyassociated with similar increase in BMD in postmenopausal women with osteopenia or osteoporosis(level 3 [lacking direct] evidence)·ibandronate·monthly ibandronate may be as effective as daily ibandronate for increasing BMD, but ibandronate 150 mg monthly associated with greater increase in BMD compared to daily ibandronate(level 3 [lacking direct] evidence)·IV ibandronateassociated with greater increase in lumbar BMD compared to oral ibandronate(level 3 [lacking direct] evidence)·single dose of zoledronic acid 5 mg IVmay improve hip and spine BMD(level 3 [lacking direct] evidence)·comparative efficacy·alendronatemay increase hip and lumbar spine BMD more than risedronate(level 3 [lacking direct] evidence)·daily alendronate, cyclical alendronate, and cyclical etidronatemay be more effective than calcitriol for increasing BMD(level 3 [lacking direct] evidence)·efficacy in men·risk of fractures·alendronateassociated with reduced vertebral fractures in men(level 3 [lacking direct] evidence)·inconsistent evidence for effect ofrisedronateon risk of vertebral fracture in men with osteoporosis or low BMD·insufficient evidence to determine ifzoledronic acid infusionannually compared to placebo reduces clinical fractures in men with hip fracture or with primary or hypogonadism-associated osteoporosis in systematic review·change in BMD·risedronatemay increase lumbar spine BMD in men with osteoporosis(level 3 [lacking direct] evidence)·zoledronic acid 5 mg IV once yearlymay be as effective as daily oral alendronate at increasing BMD in men with osteoporosis(level 3 [lacking direct] evidence)·efficacy for glucocorticoid-induced osteoporosis·bisphosphonatesmay reduce radiographic and symptomatic vertebral fractures in adults treated with glucocorticosteroids for inflammatory disorders(level 2 [mid-level] evidence)·alendronate 70 mg once weeklymay increase BMD in patients on corticosteroids(level 3 [lacking direct] evidence)·etidronatemay increase BMD in patients taking glucocorticosteroids or diagnosed with glucocorticoid-induced osteoporosis(level 3 [lacking direct] evidence)·comparative efficacy -zoledronic acidassociated with greater increase in lumbar spine and femoral neck BMD compared to risedronate in patients receiving bisphosphonates for prevention or treatment for glucocorticoid-induced osteoporosis(level 3 [lacking direct] evidence)·unless at high risk of fracture, assess patients for 3-5 year bisphosphonate holiday after 5 years continuous use1,2·assessment should include interval clinical history (especially intercurrent fracture history and new chronic diseases or medications), height measurement, vertebral imaging if height loss occurred, and BMD testing·fracture prevention effects persist after treatment stopped·decreases incidence of adverse events (such as atypical fractures of femoral shaft and osteonecrosis of jaw) which become more common after 5 years of continuous use·monitor bone density every 2 years during holiday, if can be done on same machine with adequate quality controls·decreased bone density or fracture during holiday necessitates resumption of therapy, otherwise, FDA recommends reassessment for continuation of therapy after 3-5 yearsParathyroid hormone (PTH)Teriparatide·prescribing information and recommendations·anabolic therapy with parathyroid hormone 1-34 (teriparatide) indicated for patients at particularly high risk of future fracture (ICSI Strong recommendation, High-quality evidence), could be first-line therapy in patients at highest risk for fracture2·teriparatide (brand name Forteo) is a biosynthetic fragment of parathyroid hormone (1-34), stimulates bone formation·FDA approved for 3 groups of patients with high risk for fracture·postmenopausal women with osteoporosis·men with primary or hypogonadal osteoporosis·men and women with glucocorticoid-induced osteoporosis·recommended dose 20 mcg subcutaneously into thigh or abdominal wall once daily·teriparatide (Forteo) supplied as injector pen with 750 mcg/3 mL, discard pen after 28 days·safety and efficacy of teriparatide beyond 2 years not established·BLACK BOX WARNING notes osteosarcoma in rats and states do not use if increased baseline risk for osteosarcoma due to Paget disease of bone, unexplained alkaline phosphatase elevations, open epiphyses, or prior radiation therapy of skeleton·other contraindications are metastases, history of skeletal malignancies, metabolic bone diseases (other than osteoporosis), preexisting hypercalcemia·adverse effects include hypercalcemia (may predispose patients to digoxin toxicity), transient orthostatic hypotension, pain, arthralgia, asthenia, nausea, rhinitis, dizziness, headache, hypertension, increased cough, pharyngitis, constipation, diarrhea, dyspepsia·see alsoTeriparatide·efficacy·human parathyroid hormone (1-34) once daily may reduce risk for vertebral (NNT 11) and nonvertebral fractures (NNT 30) in postmenopausal women with prior fractures(level 2 [mid-level] evidence)·based on randomized trial with allocation concealment not stated·systematic review found fracture data mainly from 1 trial·systematic review of 12 randomized trials of human parathyroid hormone for at least 1 year·9 trials involved postmenopausal women, 3 trials involved men·10 trials evaluated human parathyroid hormone (1-34), 2 trials evaluated human parathyroid hormone (1-84)·human parathyroid hormone (1-34) increases bone mineral density at lumbar spine, femoral neck and total hip·human parathyroid hormone (1-34) reduces risk for vertebral and nonvertebral fractures in postmenopausal women with prior fractures, based on 1 trial described below·no comparative efficacy data for fracture risk with human parathyroid hormone (1-34) 20 mcg vs. other active osteoporosis drugs·human parathyroid hormone (1-84) increases lumbar spine bone mineral density·Reference -CMAJ 2006 Jul 4;175(1):52EBSCOhost Full Textfull-text, commentary can be found inACP J Club 2006 Nov-Dec;145(3):71EBSCOhost Full Text·accompanying guidelines from Osteoporosis Canada can be found inCMAJ 2006 Jul 4;175(1):48EBSCOhost Full Textfull-text·randomized trial with allocation concealment not stated·1,637 ambulatory women who were at least 5 years postmenopausal and had at least 2 mild or 1 moderate vertebral fractures were randomized to recombinant human parathyroid hormone (1-34) 20 mcg vs. 40 mcg vs. placebo subcutaneously once daily·all patients given calcium 1,000 mg and vitamin D 400-1,200 units daily·median duration of follow-up 21 months·outcome of new vertebral fractures assessed in 1,326 (81%) women with adequate baseline and follow-up x-rays·comparing parathyroid hormone (1-34) 20 mcg vs. 40 mcg vs. placebo·5% vs. 4% vs. 14% had at least 1 new vertebral fracture (p < 0.001, NNT 10-11)·rates of new nonvertebral fractures were 6.3% vs. 5.8% vs. 9.7% (p = 0.04, p = 0.02, NNT 30)·rates of new nonvertebral fragility fractures were 2.6% vs. 2.5% vs. 5.5% (p = 0.02, p = 0.01, NNT 35)·parathyroid hormone increased bone mineral density·adverse effects·6% vs. 11% vs. 6% withdrawal due to adverse event (NNH 20 for parathyroid hormone 40 mcg)·13% vs. 18% vs. 8% nausea·other adverse effects were headache, dizziness and leg cramps·Reference -N Engl J Med 2001 May 10;344(19):1434, commentary can be found inN Engl J Med 2005 May 5;352(18):1930·reduction in new vertebral fractures persisted for at least 18 months after discontinuation of teriparatide at end of trial (NNT 8) (Arch Intern Med 2004 Oct 11;164(18):2017EBSCOhost Full Text), commentary can be found inArch Intern Med 2005 Mar 14;165(5):588EBSCOhost Full Text·teriparatide may reduce new vertebral fractures and clinical fractures compared to risedronate in postmenopausal women with previous vertebral fracture and T-score ≤ -1.5(level 2 [mid-level] evidence)··based on randomized trial with high-loss to follow-up·1,366 postmenopausal women (mean age 72 years) with previous vertebral fracture were randomized to teriparatide 20 mcg subcutaneously daily plus weekly oral placebo vs. risedronate 35 mg orally weekly plus daily injected placebo for 24 months·all patients had ≥ 2 moderate or ≥ 1 severe vertebral fracture confirmed by x-ray·moderate defined as reduction in vertebral body height 26%-40%·severe defined as reduction in vertebral body height > 40%·all patients had bone mineral density T-score ≤ -1.5 at femoral neck, total hip, or lumbar spine·72% had previous osteoporosis medication use·efficacy analysis included 77% who had at ≥ 1 spinal x-ray after baseline assessment; 99% included in safety analysis·comparing teriparatide vs. risedronate·new vertebral fractures in 5.4% vs. 12% (p < 0.0001, NNT 16)·clinical fractures in 4.8% vs. 9.8% (p = 0.0009, NNT 20)·serious adverse events in 20.1% vs. 16.9% (not significant)·dizziness in 4.4% vs. 1.8% (p < 0.0001, NNH 38)·extremity pain in 5.4% vs. 2.6% (p = 0.013, NNH 35)·teriparatide associated with increase in hypercalcemia, hyperuricemia, and hypomagnesemia (all p < 0.001)·Reference - VERO trial (Lancet 2017 Nov 9 early online)·teriparatide may be more effective than alendronate for reducing nonvertebral fractures in postmenopausal women with osteoporosis(level 2 [mid-level] evidence)··based on randomized trial with early trial termination·146 postmenopausal women with osteoporosis were randomized to teriparatide 40 mcg subcutaneously once daily vs.alendronate10 mg orally once daily for 14 months under double-blind conditions·trial was planned for 2 years but terminated early due to increase in osteosarcoma in rats·bone mineral density significantly higher with teriparatide at lumbar spine and femoral neck but significantly higher with alendronate at distal radius·nonvertebral fracture incidence 4.1% with teriparatide vs. 13.7% with alendronate (p = 0.042, NNT 11)·Reference -J Clin Endocrinol Metab 2002 Oct;87(10):4528, commentary can be found inJ Clin Endocrinol Metab 2003 Mar;88(3):1402·teriparatide may be more effective than alendronate for reducing clinical vertebral fracture incidence (NNT 42) and bone mineral density (BMD) loss due to corticosteroids(level 2 [mid-level] evidence)··based on randomized trial with high dropout rate·428 patients aged 22-89 years with glucocorticoid-induced osteoporosis were randomized to teriparatide 20 mcg injected once daily (plus oral placebo) vs. alendronate 10 mg orally once daily (plus injectable placebo) for 18 months·294 (69%) patients completed 18-month trial·comparing teriparatide vs. alendronate at last measurement·mean increase in BMD of lumbar spine 7.2% vs. 3.4% (p < 0.001)·mean increase in BMD of hip 3.5% vs. 2.1% (p < 0.01)·11.7% in teriparatide group vs. 6.1% in alendronate group dropped out due to adverse events (p = 0.04, NNH 17)·Reference -N Engl J Med 2007 Nov 15;357(20):2028, editorial can be found inN Engl J Med 2007 Nov 15;357(20):2084, commentary can be found inN Engl J Med 2008 Mar 20;358(12):1302·comparing teriparatide vs. alendronate at 36 months·≥ 1 radiographic vertebral fracture in 1.7% vs. 7.7% (p = 0.007, NNT 17) in analysis of 342 patients who had spinal radiographs at baseline·≥ 1 clinical vertebral fracture in 0% vs. 2.4% (p = 0.037, NNT 42)·no significant difference in cumulative nonvertebral fractures·comparing teriparatide vs. alendronate among 294 patients who entered 18-month continuation phase·mean increase in BMD of lumbar spine 11% vs. 5.3% (p < 0.001)·mean increase in BMD of hip 5.2% vs. 2.7% (p < 0.001)·Reference -Arthritis Rheum 2009 Nov;60(11):3346full-text, commentary can be found inArthritis Rheum 2010 Jun;62(6):1837·teriparatide may improve complete bone fusion and reduce bone resorption in women ≥ 50 years old having posterior or transforaminal lumbar interbody fusion for osteoporosis-associated lumbar degenerative disease(level 3 [lacking direct] evidence)··based on nonclinical outcomes from randomized trial without blinding of patients and caregivers·75 women ≥ 50 years old having posterior or transforaminal lumbar interbody fusion for osteoporosis-associated lumbar degenerative disease were randomized to postoperative teriparatide subcutaneously once weekly for 6 months vs. no teriparatide·all women received calcium L-aspartate 1.2 g/day after 1 week of surgery for osteoporosis, wore lumbar soft corset for 3 months, and performed standard physical therapy·osseous union assessed with dynamic radiography and three-dimensional computed tomography scans at 2, 4, and 6 months postoperatively·88% completed trial and were included in per-protocol analysis·complete bone fusion (in 2 grade-1 slices at center cage region) at 6 months in 69% with teriparatide vs. 35.1% with no teriparatide (p = 0.035, adjusted for age)·teriparatide associated with decreased levels of tartrate resistant acid phosphatase 5b (TRACP-5b) compared to no teriparatide (p < 0.001)·no significant differences in disk space narrowing or disk instability on radiographs·clinical and neurological symptoms (including back pain) improved at 6 months in both groups with no significant differences between groups·most common adverse event was nausea in 6 patients treated with teriparatide, among whom 4 discontinued therapy; no severe adverse events reported·Reference -J Bone Joint Surg Am 2017 Mar 1;99(5):365Abaloparatide·abaloparatide (Tymlos) is a parathyroid hormone-related protein analog·approved in April 28, 2017 by the U.S. FDA for treatment of osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies·dosing of 80 micrograms subcutaneously once daily into periumbilical region