Association of sarcopenia with osteoporosis: research and application

doi:10.3969/j.issn.2095-4344.0380

Abstract

Abstract:

BACKGROUND: As the increase in number of older adults, sarcopenia has drawn more and more attention. Importantly, high relevance exists in bone and muscle, osteoporosis and sarcopenia.
OBJECTIVE: To review the relationship between sarcopenia and osteoporosis in order to remind when preventing and treating one of the diseases cannot neglect the important role of another disease.
METHODS: Databases of WanFang, CNKI, VIP, PubMed, Embase and Medline were searched with the keywords of “sarcopenia, muscular atrophy, osteopenia and osteoporosis” in English and Chinese, respectively for the literature concerning sarcopenia and osteoporosis published before December 2017. The types of literature included journal article, conference literature, dissertation and review. Initially 1 479 articles were retrieved involving in 1 374 English and 105 Chinese articles, and finally 50 eligible articles were enrolled for summation based on the inclusion and exclusion criteria.
RESULTS AND CONCLUSION: (1) Muscles and bones are co-regulated by various factors, and the muscle mechanical stress plays an important role in the development and maintenance of the bone. (2) Skeletal system possesses a regulatory effect on muscle, also includes osteoblasts and cytokines secreted by osteocytes. (3) Except for vitamin D, testosterone and corticosteroids, muscle and bone are collectively regulated by oestrogen and growth hormone, suggesting that abnormal changes in these hormones will lead to bone and muscle dysfunction. (4) The mechanism between osteoporosis and sarcopenia is very complex, including the effect of muscle contraction on bone, and endocrine regulation between bone and muscle. (5) Studying on the relevance between osteoporosis and sarcopenia is of instructive significance for the prevention of fractures following falls in older adults.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Muscle, Skeletal, Osteoporosis, Fractures, Bone, Bone Density, Tissue Engineering

CLC Number:

R318

Ma Jian-xiong1, 2, 3, Kuang Ming-jie1, 2, He Wei-wei1, 2, Chen Heng-ting1, 2, Wang Ying1, 2, Sun Lei1, 2, Lu Bin1, 2, Tian Ai-xian1, 2, Wang Yan1, 2, Dong Ben-chao1, 2, Bo Hao-hao1, 2, Cui Yu-hong3, Ma Xin-long1, 2. Association of sarcopenia with osteoporosis: research and application[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(32): 5222-5227.

Figures/Tables 3

2.2 肌肉与骨骼的相互联系肌肉骨骼均起源于中胚层，有着共同的间质前体，因此肌肉和骨骼会受到某些相同的遗传因素的调控；二者在运动功能上紧密关联，肌肉是骨与骨连接的纽带，与骨的生长和发育密切相关。肌肉和骨骼作为运动系统的两大重要组成部分，共同受机体多种因素的调节[10]。在生长发育过程中肌量与骨量密切相关，骨量和肌力的增加几乎同步进行，人体生长期时二者均增加，青壮年时期步入停滞期，最后进入减少期[11]。在一项对双胞胎的研究中，发现体质量和骨密度之间的关系被是受遗传因素的影响，而脂肪量和骨密度之间的关系不受遗传因素影响[12]。骨和肌肉间不仅在解剖上联系紧密，而且在功能和发育上密不可分。 2.3 肌肉与骨的相互调控 2.3.1 肌肉对骨的调控 1960年前，认为骨的生理模式主要是刺激-效应细胞-健康/疾病，决定人体骨骼强度的主要是非机械性因素对成骨细胞和破骨细胞这两个效应细胞的作用，进而发生成骨和骨吸收；显然，这种模式不仅忽视了机械性因素对骨质和骨强度的作用，也未重视组织和器官对骨骼的影响。认识到该模式的缺陷与不足，犹他大学医学院组织研究者们对骨生理模式进行研讨并改进，创立犹他骨生理模式[13]。使骨组织变形的外力作用中，主要由肌肉收缩产生[14]；当骨应变超过骨重建阈值时，骨就会进入保留模式使骨吸收和形成平衡，骨得以保留；而当其低于骨重建阈值时，比如肌肉减少症患者，骨就会进入废用模式，骨的吸收多于形成，使骨量减少。也就是说，骨骼所承受的肌肉力学刺激对其发育和维持有着重要的作用。有文献对涉及肌肉和/或骨骼机械转导的分子通路进行总结，通过表1可以看出骨骼与肌肉这两种组织在力学传递方面有许多相似之处[15]。"

人体运动时，以肌肉收缩产生的力为主的应力系统开始对骨产生影响，在保证骨骼的健康方面有着重要的作用。Qin等[16]通过对脊柱损伤患者进行电刺激诱导肌肉收缩，进而减少骨质丢失的研究，提出肌肉收缩可减少破骨细胞生成，促进成骨细胞增殖，其机制可能与血清Ⅰ型胶原蛋白c端端肽、核因子kB活性受体的量相关。与之相对应的是Edwards等[17]发现，如若习惯性的运动缺失，像卧床、瘫痪等则会引起快速大量的骨矿质的丢失。骨骼肌不仅通过力学作用对骨骼产生影响，还能通过化学作用对骨骼发挥作用。化学作用主要是指肌肉产生的化学物质可能通过旁分泌或内分泌机制作用于成骨(前体)细胞破骨细胞或骨细胞，促进成骨和/或抑制破骨。MyoD和Myf5基因敲除小鼠由于缺乏骨骼肌，小鼠胚胎在母体子宫内无自主活动能力，出生后难以存活，骨骼表现为矿化不良，且新生骨中的破骨细胞数量增多，提示肌肉可能促进骨骼发育的作用[18]。由肌肉产生的骨诱导因子和FAM5C是重要的分泌型骨形成因子，肌肉产生的其他内分泌因子包括类胰岛素1号增长因子、白细胞介素6、白细胞介素7、白细胞介素15、脑源性神经营养因子和成纤维细胞生长因子2等均可能影响骨代谢[19]。肌肉运动后产生的鸢尾素则可能通过Wnt-catenin 通路促进成骨细胞分化和RNKL/RNK途径抑制破骨细胞形成[20]。 2.3.2 骨骼对肌肉的调节骨骼系统具有调节肌肉的作用，如成骨不全的患者表现为肌肉萎缩。成骨细胞或骨细胞分泌的因子，如骨钙素、类胰岛素1号增长因子、硬骨素、成纤维细胞生长因子23、前列腺素E2等，均可能对肌肉有调节作用[14]。骨钙素对肌肉会产生同化作用，骨骼中产生的骨钙素可能通过GPR6A/AMPK/ mTOR/S6激酶途径调节肌量和功能[21]。骨钙素还可能影响糖脂和能量代谢进而影响肌肉功能。异性因子羧基化骨钙素可部分修复功能受损的肌肉[21]。类胰岛素1号增长因子不仅可由肌细胞产生，骨细胞和成骨细胞也可生成，它可激活骨骼肌PI3K/Akt 通路[22]。在敲除骨细胞类胰岛素1号增长因子的小鼠中，类胰岛素1号增长因子的mRNA表达在骨骼和肌肉中分别中减少了65%和59%，虽然其在肌肉中的减少并不是关键性的，肌纤维形态并未改变，但是细胞核的大小和数量却发生改变[23]。经典的Wnt信号通路的激活是肌肉分化所必需，骨细胞分泌的硬骨素和Ihh等对Wnt信号通路有调控作用，表明骨细胞可能远程调节肌细胞的分化[24]。骨细胞和成骨细胞分泌的成纤维细胞因子23具有抑制肾小管重吸收磷和降低1α羟化酶活性的作用，可导致低磷血症和活性维生素D水平过低，由此会影响肌肉的代谢和功能[25]。此外，骨骼细胞中的特异性间隙连接蛋白Connexin43可直接参与肌肉生长和功能的调控[26]。但究竟骨骼对肌肉的影响是如何通过机械应力和生物因子共同协调发挥作用的，仍有待深入研究。 2.4 肌肉与骨骼的激素调节 2.4.1 维生素D 又称为抗佝偻病维生素，属于脂溶性维生素。它对骨盐代谢的调节及保持肌肉和骨骼的正常功能有重要作用。血清维生素D缺乏对老年人来说是一个常见的健康问题，它可以导致身体活动能力变弱、增加跌倒的概率、同时也使骨折风险增大[27]。人骨骼肌细胞表面有活性维生素D受体，其受体的类型对骨骼肌的收缩力和骨盐密度有重要影响[28]。25-(OH)D是维生素D在体内最主要的循环形式，常作为反映体内维生素D营养状况的指标。有研究发现，25-(OH)D浓度≥20 μg/L的人群下肢骨骼肌肉功能和力量好于25-(OH)D浓度小于20 μg/L的患者[28]。在来自29个国家的多中心试验中也发现，绝经后患有骨质疏松症的女性(1.3%亚裔)，血清25-(OH)D水平和骨密度关系密切[29]。 2.4.2 睾酮睾酮又称睾丸素，由男性的睾丸或女性的卵巢分泌，肾上腺也可分泌少量睾酮。有研究发现性腺功能减退的青年及老年男性睾酮水平降低，继而骨量减少、骨质疏松，骨折发生率也因此明显增加[30]。对前列腺癌患者的研究表明，雄激素阻断治疗可以抑制睾酮产生，因此可控制肿瘤的生长，但却导致骨质疏松并增加骨折的发生[31]。此外，也有研究报道，雄激素阻断也可导致肌量的丢失、肌力减弱、身体活动能力衰退[32]。LeBlanc等[33]通过队列研究，最终测定了1 183名老年男性的性激素水平、身体成分和身体活动能力，发现若体内内源性睾酮含量较高，则老年人肌量的丢失会减少、下肢功能的减退会减缓。 2.4.3 糖皮质激素糖皮质激素影响着肌肉的代谢与生长。Hallangerås等[34]在研究中，给小鼠连续7 d注射皮质醇，每天检测小鼠体质量和肌肉含量，发现实验组小鼠肌肉萎缩，尿中3-甲基组氨酸含量升高，与此相一致的是存在肌蛋白降解，并且发现泛素化mRNA，泛素化蛋白酶体C8亚单位，接合酶E214k等泛素化组分均升高，推测糖皮质激素可能通过泛素化途径来影响肌肉的代谢。并且有研究表示，注射米非司酮的大鼠可以阻断脓毒症引起的肌肉量的升高和肌纤维蛋白质分解[35]。同时糖皮质激素对骨组织细胞的分化、增殖与凋亡发挥着至关重要的作用。在生理浓度下，糖皮质激素调节成骨细胞的分化，刺激成骨细胞分泌Wnt信号通路相关蛋白，来激活经典Wnt信号通路，上调成骨细胞分化相关因子，使多能干细胞成骨分化[36]。而外源性的糖皮质激素则主要会导致骨质疏松的发生。即使小剂量糖皮质激素也会对骨组织造成影响，当每日泼尼松龙的治疗剂量>7.5 mg 则可以引起骨质显著流失[37]。其具体机制虽不清楚，但有研究发现糖皮质激素可抑制成骨细胞分化和功能并且诱导其凋亡，进而抑制骨组织发育[38]。高水平的糖皮质激素通过糖原合成酶激酶3β泛素化功能和蛋白酶β-catenin 蛋白等可溶性拮抗因子致使间充质干细胞成骨分化下降，同时大剂量糖皮质激素也增加了过氧化物增殖物激活受体，促进间充质干细胞的成脂分化[39]。另一方面，成骨分化重要调节因子骨生成蛋白2，糖皮质激素抑制其下游信号，干预成骨分化。糖皮质激素致骨质疏松与骨组织细胞的凋亡机制相关，糖皮质激素还可以中断成骨细胞周期亦或是通过诱导的促凋亡激酶Pyk2和JNK的活化，诱导细胞凋亡[40]。而对于破骨细胞，糖皮质激素诱导的其数量以及活性的上升[41]。综上，糖皮质激素可通过抑制成骨细胞的生长周期，甚至诱导其凋亡来减少骨的生成，同时增加破骨细胞活性，加快骨量减少。除了上述的维生素D、睾酮与皮质激素外，肌肉与骨骼的生长代谢还受着许多激素的共同调节，如生长激素、雌激素等。当体内这些激素的水平发生改变，骨骼和肌肉均可表现出相应症状，但由于骨骼和肌肉对于同一激素的敏感性并不相同，其中一者可能更早地表现出相应症状，这就为临床的早期诊断提供了机会，阻断骨骼和肌肉病变的进程，或是尽早预防、诊治另一者的病变。 2.5 肌肉减少症和骨质疏松相关性肌肉减少症和骨质疏松症是增龄过程中两种较常见的病症，常同时出现。越来越多的证据表明肌肉减少症和骨质疏松症之间有很多相似点，比如：对某些激素分泌减少的反应、炎性因子的活跃性增加[14]。多数大样本横断面研究显示，女性骨骼肌量与骨密度呈正相关，肌肉含量下降是骨质疏松症的重要危险因素。Miyakoshi等[42]调查40-89岁的2 400名日本女性，发现肌肉减少症在骨密度正常、骨量减少、骨质疏松的受试者中的检出率分别为10.4%，16.8%和20.4%，从而得出肌肉减少症和骨质减少以及骨质疏松症存在显著的相关性的结论。在对313名髋骨骨折的女性肌肉状况和骨质疏松状况的检测中发现，肌肉减少症患者为58%，骨质疏松者占74%，试验数据表明肌肉减少症与骨质疏松呈明显正相关关系[43]。肌肉减少症和骨质疏松症具有相关性不仅存在于女性中，男性也不例外。Go等[44]调查了韩国1 397名老年男性，通过检测受试者四肢肌肉量，以及腰椎、股骨和股骨颈的骨密度，发现肌肉减少症和骨密度的减低存在相关。Pereira等[45]通过使用双能X射线吸收仪并以2010年欧洲老年肌肉减少症工作组对肌肉减少症的定义标准诊断肌肉减少症，对198名60岁以上男性的骨密度和是否患有肌肉减少症进行评估，发现肌肉减少症前期和肌肉减少症对骨密度减少存在影响。Verschueren等[46]为了探索肌肉减少症和骨质疏松症之间的关联性，检测了679个40-79岁的欧洲男性，发现患有肌肉减少症的男性较无肌肉减少症男性更易患骨质疏松症。国内有关肌肉减少症和骨密度相关性的研究报道较少。帅波等[47]研究武汉地区中老年男性肌肉减少症与骨密度的相关性，发现武汉地区中老年男性肌肉减少症与低骨密度和骨质疏松症密切相关。 2.6 肌肉减少症和骨折的相关性骨折严重影响患者身心健康，并给家庭和社会带来沉重负担。肌肉减少症与骨质疏松的存在密不可分，而引起的骨密度减低显然会增加骨折风险。此外，肌肉减少症主要是Ⅱ型肌肉纤维的减少，并伴有运动神经元数量减少，显然，这些都影响肌肉含量及功能，从而引起步速减慢身体摇摆性增加，导致机体平衡能力减弱，因而增加跌倒风险，而跌倒往往是骨折的直接诱因[48-49]。同时，越来越多的国内外临床研究证实，肌肉减少症不仅与低骨密度密切关联，也是骨折的重要危险因素[50]。"

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