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甲状旁腺激素治疗骨质疏松症的研究进展

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世界最新医学信息文摘 2018年第18卷第51期

69

·综述·

甲状旁腺激素治疗骨质疏松症的研究进展

张艺璇,李金源

(华北理工大学口腔医学院,河北󰀁󰀁唐山)

摘要:骨质疏松症(osteoporosis,OP)是一种以骨量减少,骨组织微结构系统性损伤为特点的全身性骨骼疾病,目前临床上对OP的

治疗,主要通过抑制骨吸收和促进骨形成来提高骨密度,目前应用的治疗骨质疏松症的药物中,甲状旁腺激素(PTH)在维持骨稳态的过程中具有独特的双重调节作用,一方面可增加成骨细胞的数量,促进骨生长因子释放,从而促进骨形成,增加骨量,另一方面也可增强破骨细胞活性,促进骨吸收,使骨钙释放入血,因此,PTH 成为骨代谢与治疗骨质疏松症相关研究的热点之一。本文简要介绍了PTH对骨代谢的调节机制,以及在实验动物和临床研究中的作用。

关键词:甲状旁腺激素;骨质疏松症;骨代谢

中图分类号:R681   文献标识码:A   DOI: 10.19613/j.cnki.1671-3141.2018.51.032

本文引用格式:张艺璇,李金源.甲状旁腺激素治疗骨质疏松症的研究进展[J].世界最新医学信息文摘,2018,18(51):69-70,73.

Advances in Treatment of Osteoporosis with Parathyroid Hormone

ZHANG Yi-xuan, LI Jin-yuan

(School of Stomatology, North China University of science and technology, Tangshan Hebei)

ABSTRACT: Osteoporosis osteoporosis (OPO) is a kind of systemic bone disease characterized by the decrease of bone mass and

the systematic damage of bone structure. At present, the treatment of op in clinic mainly increases bone density by inhibiting bone resorption and promoting bone formation. PTH, a parathyroid hormone, plays a unique role in maintaining bone homeostasis. On the one hand, it can increase the number of osteoblasts and promote the release of bone growth factor. Thus promoting bone formation, increasing bone mass, on the other hand, it can also enhance the activity of osteoclasts, promote bone resorption and release bone calcium. Therefore, PTH has become one of the hotspots in the study of bone metabolism and the treatment of osteoporosis. This article briefly introduces the regulatory mechanism of PTH on bone metabolism and its role in experimental animals and clinical studies.KEY WORDS: parathyroid hormone; Osteoporotic

0 引言

骨质疏松症是以骨量减少,骨质量受损及骨强度降低,导致骨脆性增加、易发生骨折为特征的全身性骨病[1]。世界卫生组织调查发现表明,50岁女性约1/6有骨质疏松症,80岁其发病率增加至󰀁50%。骨质疏松症的发生与发展受到各种内外因素的影响。随着年龄的增长,骨吸收的速度超过骨形成的速度,骨组织的平衡状态遭到破坏,从而导致了骨质

[2]

疏松症。另一方面随着年龄的增加,女性卵巢功能减退,从而大致雌激素缺乏,而雌激素有抑制骨吸收的作用,可以使破骨细胞形成活跃,骨吸收速度增快,使全身骨密度降低,导致骨质疏松症。以往骨质疏松症的治疗,多从抑制骨吸收方面着手,常用雌激素、双膦酸盐、降钙素等,这些药物虽可在一定程度上提高骨密度,但疗效一般。近年来,促进骨形成的治疗已引起国内外专家的广泛关注,而甲状旁腺激素的促

[3]

进骨合成作用也受到各界重视。

地生产的生长因子和细胞因子的促分化和促生存作用奠定基础,PPARγ负效应的衰减也可能导致成骨细胞数量增加。每天注射PTH可增加局部甲状旁腺激素的促分化和促生存效果[6]。󰀁

甲状旁腺激素影响骨代谢是一个复杂的过程,首先它可以刺激成骨细胞合成,调节的骨形成,其次它可以刺激破骨细胞,从而调节的骨吸收,多项研究表明间歇性应用甲状旁腺激素可以刺激骨质的形成。其中PTH󰀁1-34󰀁和󰀁PTH󰀁1-84可以通过多条信号传导通路抑制成骨细胞凋亡、促进成骨细胞的分化,来增加骨密度,同时降低骨折发生的风险,治疗骨

[7]

质疏松症。PTH󰀁可以促进软骨内修复,增加骨痂体积、提高骨密度与骨成熟度,增强骨强度,加强形成。加强骨小梁的连续性和增加骨皮质骨厚度,提高骨的生物力学特性,改善骨质量。特立帕肽可以通过增加软骨细胞数量,加快骨折

[8]

愈合成骨和骨矿化过程。

1 甲状旁腺激素对骨代谢的双重调节作用

甲状旁腺激素(󰀁parathyroid󰀁hormone,󰀁PTH󰀁)是由甲状旁腺分泌,是一条由84󰀁个氨基酸所组成的多肽链,其分子量为9500u,甲状旁腺激素在维持机体钙、磷代谢平衡中发挥重要作用,其靶器官主要有骨骼、小肠和肾脏等。甲状旁腺激素不仅能增强破骨细胞的活性,促进骨吸收,升高血钙,降低血磷,还能促进骨髓干细胞分化为成骨细胞,促进骨形成,增加

[4]

骨量,从而改善骨骼生物力学性能。

间歇性使用甲状旁腺激素(PTH)是通过增加成骨细胞数量的形式刺激骨形成,增加骨量,然而其作用机制尚不明确。有研究表明,PTH可直接激活成骨细胞的存活信号通路以及延迟成骨细胞凋亡,这是导致成骨细胞数量增加的主要因素,至少在小鼠体内是如此。这种效果需要Runx2的依赖表达抗凋亡基因如Bcl-2[5]。PTH也会导致细胞中复制祖细胞的周期停止。周期性降低细胞周期蛋白D表达及几种细胞周期依赖性激酶抑制剂的表达。退出细胞周期可能为本

2 甲状旁腺激素治疗骨质疏松症的实验研究

Rafael󰀁Pacheco-Costa等通过建立去卵巢骨质疏松大鼠模型,采用甲状旁腺激素低剂量间歇性给药,测量治疗30天后大鼠骨基质中有机成分的分布,研究表明发每天低剂量注射PTH可改变骨基质中有机成分的分布,增加雌激素缺乏大鼠

[9]

的骨量,有利于骨组织的增加。合成代谢药物PTH可增加骨重塑骨形成对骨吸收和铅的影响增加骨量,改善骨结构[10],󰀁它也被报道增强完整和去卵巢(OVX)的缺损愈合老鼠。总的骨痂面积较大,时间较短。最早的桥接不延迟,骨痂和皮质。密度,生物力学,骨内愈伤率与对照组相比,形成率更高对照组。间歇性甲状旁腺激素的有益作用骨质疏松性骨折愈合的治疗显示增强的皮质和松质骨通过早期刺激增殖和DIF形成骨祖细胞的分化增加生产骨基质蛋白[11-15]。我们以前的研究有表明甲状旁腺激素全身给药有显著意义,明显提高βTCP降解及成骨能力,提示PTH可作为一种药物来改善β肾上腺素能骨诱导能力[16]。Hang󰀁Li等人研究表明

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70World Latest Medicine Information (Electronic Version) 2018 Vo1.18 No.51

PTH和维生素K2联用与PTH或MK单独比较明显提高血

清骨钙素水平(一种骨形成特异的标记物)。该研究结果表明,所有治疗组增加了新的植入物表面的骨形成。此研究结果证实了,PTH󰀁1-34与维生素K2联合治疗可能比PTH或维生素K2单独治疗对骨质疏松大鼠骨愈合有积极的影响[17]。

3 甲状旁腺激素治疗骨质疏松症的临床应用

甲状旁腺激素治疗骨质疏松症涉及的人群主要有绝经后患有骨质疏松症的妇女和糖皮质激素引起的骨质疏松症患者。甲状旁腺激素与钙、磷浓度有相互的作用,骨质疏松时,钙离子浓度发生下降,则会刺激人体甲状旁腺激素分泌量增加。甲状旁腺激素的增加也可引起肾小管对磷的重吸收减少。rhPTH1-34是唯一的合成肽,刺激骨形成的药物激活成骨细胞和抑制破骨细胞。目前,每天皮下注射是唯一可用的手段。连续rhPTH1-34释放治疗导致骨组织代谢降解;只有间歇性治疗是治疗骨质疏松症的有效方法。

最近,Nakazawa󰀁T等人成功的临床研究报道在rhPTH-34载通过无线控制间歇释放药物的微芯片。然而,这个系统需要侵入性手术植入,如需广泛的临床应用这是一个巨大的障碍。在这项研究中,研究者开发了一个简单的阴离子聚电解质微球的制备方法利用微流控光聚合技术,展示了它在脉冲传输重组人甲状旁腺激素1-34中的潜力。一种阴离子聚电解质微球积极吸收高达23.4±0.9µG的阳离子rhPTH1-34和释放一个脉冲的方式反应的Ca2+离子。脉动释放刺激骨形成标志物和矿物质的表达成骨细胞,该实验数据支持聚电解质微球可以作为重组人甲状旁腺激素1-34载体治疗骨质疏松症[18]。

陈迪等通过对96例骨质疏松症患者的降钙素和甲状旁腺激素水平的分析,探讨其在骨质疏松症治疗过程中的诊断意义,在研究周期内96例质疏松症患者为观察组,85例同期的健康体检人群为对照组,研究结果显示,观察组甲状旁腺

激素水平远高于对照组[19]

。甲状旁腺激也可用于双磷酸盐治疗后的辅助治疗,Cosman.F和同事随机分配以前服用阿仑膦酸钠的妇女或每日hPTH(1–34)联合阿仑膦酸钠治疗,受

试对象腰椎显著增加骨密度分别为6.1%和5.4%[20]

。Lane󰀁NE等人通过51例绝经后妇女服用甲状旁腺激素联合激素替代疗法可使腰椎骨密度增加12.6%[21]。COSMAN.F等人通过对52例已接受激素替代疗法2年的女性患者研究发现持续的HRT维持几乎所有的PTH诱导骨量。停用甲状旁腺激素后1年增加。此外,甲状旁腺激素联合激素治疗是一种有效的增加骨量的方法,尤其是增加椎骨的骨量,骨折的发生率仅为HRT的75~100%。该研究还显示,一些已接收激素替代疗法的骨质疏松症患者,通过引用甲状旁腺激素可进一步获益,减少或消除脊椎骨折等[22]。Hegde󰀁V等人表明每日注射甲状旁腺激素(PTH1-34),或全长蛋白PTH(1-84)可增加骨量,减少绝经后妇女、老年男性和女性糖皮质激素性

骨质疏松症患者骨折发生率[23]

4 展望

骨质疏松症是一种全身性的骨代谢疾病,在影响全身骨量的同时,对口腔健康也有极大的影响,目前关于甲状旁腺激素的实验研究较多,但其作用机制仍不明确,需更多的实验证据支持。同时,每日皮下注射甲状旁腺激素对患者造成诸多不便,动物实验中副作用相对较大,特立帕肽价格相对于其他抗骨质疏松药物较昂贵,虽效果显著但广泛应用于临床尚需一定时间。今后的研究,一方面深入探讨甲状旁腺激素促进骨重建的作用机制,另一方面,需要更多的新药研发,为骨质疏松症患者提供更多疗效好副作用小的新型抗骨质疏松症药物。

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