重组人甲状旁腺激素基因工程研究进展

甲状旁腺激素（parathyroid hormone,PTH）是由甲状旁腺主细胞分泌的碱性单链多肽类激素。它主要调节脊椎动物体内钙和磷的代谢。目前,PTH及其类似物已成为治疗骨质疏松症的首选药物。随着PTH基因序列的阐明,通过基因工程手段获得高效、低毒、稳定的重组PTH,已成为研究热点。本文对PTH的结构功能、基因工程研究及临床应用问题进行综述。     

甲状旁腺激素治疗骨质疏松症的研究进展

甲状旁腺激素(PTH)在骨代谢中具有促进骨骼重建、增加骨密度的作用,因此有效的应用新型的骨形成促进剂PTH,将为骨质疏松症等代谢性骨病提供新的药物选择。     

甲状旁腺激素构效关系的研究进展

甲状旁腺激素(PTH)是生物体内调节钙、磷代谢最为重要的肽类激素之一,其氨基端1-34片段具有全分子PTH与受体结合的能力及生物活性,被广泛用于研究PTH的结构与功能。PTH二级结构中富含α-螺旋,该螺旋结构在PTH与受体相互作用中起重要作用,其中羧基端负责与受体结合,氨基端负责生理活性。现从甲状旁腺激素的结构、与受体的相互作用和构效关系等角度出发,综述了甲状旁腺激素近年来的研究状况,为开发新型骨质疏松症治疗药物提供理论依据。     

治疗骨质疏松的微电子贴剂结果肯定

以色列的透皮药物输送公司Trans-pharma Medical报告了其输送人甲状旁腺激素hPTH（1—34）的透皮贴剂治疗骨质疏松症的肯定结果。hPTH（1-34）是负责调节人体内钙和磷代谢的PTH肽片段，具有与天然存在的内源激素hPTH（1-84）相同的生物活性。     

甲状旁腺激素激动剂特立帕肽

骨质疏松症是一种以低骨量和骨组织退化为特征的最常见的代谢性骨病。这种疾病将导致大量骨质丢失，骨骼脆性增加，容易发生骨折。常见骨折部位是髋骨、脊椎骨和腕骨。市场上多数治疗骨质疏松症的药物，如雌激素、双磷酸盐类和降血钙素均属骨吸收抑制剂。而其他一些药物如氟化物、甲状旁腺激素(PTH)是骨形成促进剂。     

01020 中外／第一鼻腔给药的PTH治疗骨质疏松症的新资料

中外／第一和三得利制药公司提前公布他们鼻腔给药的重组甲状旁腺激素(PTH)CHS-13340(SUN-E3001)(Ⅰ)的资料，在此之前，在日本进行的新的初步Ⅱ期临床试验的资料表明该产品能增加骨质疏松症病人的骨质。     

甲状旁腺激素测定对肾性骨病的临床指导意义及分析

目的：探讨甲状旁腺激素测定对慢性肾功能不全肾性骨病患者的临床指导意义。方法：选自血液净化中心2007-2008年血液透析患者84例，检测透析前甲状旁腺激素（PTH）指标，根据胛H测定结果调整骨化三醇用量，比较治疗前及治疗后4周PTH的变化值。结果：84例患者治疗前血清PTH为（502．58±288．35）ng／dl，治疗后4周血清PTH为（342．19±206．31）ng／dl。结论：对临床肾功不全患者定期进行PTH监测，为指导临床医生用药提供标准，减少肾功能不全患者继发甲状旁腺功能亢进发生，降低临床肾性骨病发生率。     

甲状旁腺激素的成骨小片段：治疗骨质疏松症的新制剂

患骨质疏松症的绝经后妇女易骨折骨细胞对小梁骨的过度吸收而失代偿的结果。目前使用破骨细胞抑制剂降钙素，二膦酸盐或雌激素治疗该症，它们可阻止骨质吸收无而刺激新骨生成的作用，本文综述了甲状腺激素中激活腺苷酸环化酶的片段是一种提高骨质疏松症疗效的制剂，它效地刺激成骨细胞形成强健的骨质。     

甲状旁腺激素相关肽与骨质疏松

甲状旁腺激素相关肽（PTHrP,1-36)是体内一种真实的分泌形式,它与甲状旁腺激素（PTH,1－34）具有很高的同源性,不仅一级序列同源,三级结构相似,而且能与共同的受体PTH／PTHrP受体相结合,在实验动物和人体上均有效地促进骨骼合成。本文从理论上解释了PTHrP(1-36)作为骨质疏松潜在药物的可能性。     

低钙血症慢性肾功能衰竭患者继发性甲状旁腺功能亢进的治疗效果

目的具有低钙血症的血液透析患者PTH对于骨化三醇治疗的敏感性和治疗效果。方法22例有低钙血症及SHPT的血液透析患者,每日均服用骨化三醇0.75g,3次/周透析,透析液钙浓度为3.5mEq/L。骨化三醇治疗30周前后监测PTH及钙值。结果治疗前PTH及钙值分别为（907±127）pg/ml及（3.89±0.12）mg/dl。在骨化三醇治疗期间,除2例无反应外,余20例PTH由（846±129）pg/ml降至（72±12）pg/ml（P〈0.001）,PTH下降超过85%,治疗前PTH与血钙及磷有关。结论有低钙血症的血液透析患者,骨化三醇对于严重地SHPT有较好的疗效,治疗前PTH与血钙及磷的变化有关。     

甲状旁腺素研究进展

甲状旁腺素是治疗骨质疏松症的重要药物,具有刺激骨骼生长,加强骨组织微结构,降低骨脆性的作用。但是,甲状旁腺素属于肽类药物需注射给药且价格昂贵,发展新型非肽类骨质疏松症治疗药物成为当前研究热点。文章综述了甲状旁腺素的生物学活性、结构特征及其构效关系,并对甲状旁腺素与受体的结合机制进行了总结,为开发新型非肽类抗骨质疏松症药物提供了理论依据。     

降钙素及甲状旁腺激素在骨质疏松中的诊断价值探讨

目的：探讨降钙素和甲状旁腺激素在骨质疏松中的诊断价值。方法：选择96例骨质疏松患者为观察组,另选85例非骨质疏松患者为对照组,检测血液中的降钙素和甲状旁腺激素浓度,并与前臂远端、第四腰椎、股骨大转子的骨密度水平比较分析,探讨降钙素和甲状旁腺激素在骨质疏松中的诊断价值。结果：观察组血液中降钙素和甲状旁腺激素浓度分别为（13.71±1.49）pmol/mL、（22.63±6.172）pg/mL,前臂远端骨、第四腰椎、股骨大转子的骨密度水平分别为（0.53±0.65）g/cm2、（0.76±0.19）g/cm2、（0.73±0.18）g/cm2,与对照组比较,降钙素浓度水平低于对照组（P<0.05）,甲状旁腺激素浓度水平则明显高于对照组（P<0.01）。结论：老年骨质疏松症患者血液中的降钙素和甲状旁腺激素浓度变化比较明显,在骨质疏松的诊断中有较大的意义。     

甲状旁腺激素生理作用和构效关系研究

对甲状旁腺激素的生理作用及机制、分子结构、受体结合和构效关系等方面的研究作一综述，以期为开发新型骨质疏松症治疗药物提供理论依据。甲状旁腺激素是一种生理活性多肽，体内独特的成骨作用使其作为治疗骨质疏松症药物的研究日益深入。     

降钙素、睾酮及甲状旁腺激素与骨质疏松患者骨密度的关系

目的：探讨降钙素、睾酮及甲状旁腺激素与骨质疏松患者骨密度的关系。方法选择确诊老年骨质疏松症患者40例为观察组,选取正常体检者40例为对照组,测定两组不同部位骨密度,并分析降钙素、睾酮及甲状旁腺激素水平的变化。结果观察组第四腰椎、股骨大转子及前臂远端骨密度均显著低于对照组（P＜0.05）。观察组降钙素、睾酮水平均低于对照组（P＜0.05）,甲状旁腺激素水平高于对照组（P＜0.05）。结论老年骨质疏松症患者降钙素、睾酮水平降低,甲状旁腺激素升高,可作为临床诊断的指标之一。     

Full length parathyroid hormone,PTH(1-84), for the treatment of severe osteoporosis in postmenopausal women

ABSTRACT

Objective: To review and analyse the evidence supporting the use of full length parathyroid hormone, PTH(1-84), in the treatment of osteoporosis based on a search of several literature sources; articles selected for review were published between 1990 and 2008.

Background: PTH(1-84) is approved for the treatment of osteoporosis in postmenopausal women at high risk of fracture in Europe. It was well tolerated in clinical trials and demonstrated bone building properties and fracture prevention particularly for the lumbar spine in the treatment of postmenopausal women.

Results: The TOP clinical trial showed that PTH(1-84) treatment for 18 months resulted in a 61% reduction (p = 0.001) in new vertebral fracture incidence when compared with placebo and reduced the risk of a first vertebral fracture by 68% (p = 0.006) in women without a prevalent fracture at baseline. PTH(1-84) increased bone mineral density (BMD) at vertebral and non-vertebral sites the lumbar spine BMD increasing regardless of T-score, age, prior osteoporosis therapy or number of years post-menopause. The PaTH study showed that treatment with PTH(1-84) for 12 months increased BMD at the trabecular spine and hip. Lumbar spine BMD gains were largest with sequential administration of PTH(1-84) followed by alendronate but were smaller with concurrent administration involving anabolic and antiresorptive agents. Lumbar spine BMD increases were also seen in trials involving PTH with raloxifene and PTH in combination with hormone replacement therapy.

Conclusions: PTH(1-84) has demonstrated effective bone building qualities and extends the therapeutic options available to osteoporotic women. The use of PTH(1-84) followed by sequential administration of an antiresorptive has proved effective at increasing trabecular BMD and points towards new treatment regimens offering improvements in BMD and fracture prevention.     

The effects of teriparatide on the incidence of back pain in postmenopausal women with osteoporosis

ABSTRACT

Objectives: Back pain is a major cause of suffering, disability, and cost. The risk of developing back pain was assessed following treatment with teriparatide [rh(PTH 1–34)] in postmenopausal women with osteoporosis.

Research design and methods: A secondary analysis of back pain findings from the global, multi-site Fracture Prevention Trial was conducted where postmenopausal women with prevalent vertebral fractures were administered teriparatide 20?µg (?n = 541) or placebo (?n = 544) for a median of 19 months. Treatment-emergent back pain data were collected during adverse event monitoring, and spine radiographs were obtained at baseline and study endpoint.

Main outcome measures: The risk of back pain stratified by severity of new or worsening back pain and the risk of back pain associated with both number and severity of new vertebral fractures.

Results: Women randomized to teriparatide 20?µg had a 31% reduced relative risk of moderate or severe back pain (16.5% vs. 11.5%, P = 0.016) and a 57% reduced risk of severe back pain (5.2% vs. 2.2%, P = 0.011). Compared with placebo, teriparatide-treated patients experienced reduced relative risk of developing back pain associated with findings of: one or more new vertebral fractures by 83% (6.5% vs. 1.1%, P < 0.001), two or more new vertebral fractures by 91% (2.5% vs. 0.20%, P = 0.004), and one or more new moderate or severe vertebral fractures by 100% (5.1% vs. 0.0%, P < 0.001).

Conclusions: Teriparatide-treated women had reduced risk for moderate or severe back pain, severe back pain, and back pain associated with vertebral fractures. The mechanism of the back pain reduction likely includes the reduction both in severity and number of new vertebral fractures.     

长期血透患者甲状旁腺素测定的临床意义

目的　探讨检测长期血透患者甲状旁腺素对继发性甲状旁腺功能亢进的早期诊断、预防和治疗的临床意义。方法　选择 84例长期血液透析患者 ,分为服钙剂组与不服钙剂组 ,另选择 30例非肾功能减退患者为正常对照组 ,分别检测患者血清甲状旁腺素、钙、磷、尿素氮、肌酐等。结果　服钙剂组患者血清甲状旁腺素、磷明显低于不服钙剂组 ,两者之间有显著性差异 (P<0 .0 5) ;而两组患者间的血清钙没有显著性差异 (P>0 .0 5) ;长期血透患者的血清甲状旁腺素明显大于正常对照组 ,与尿素氮、肌酐和磷呈正相关。结论　甲状旁腺素检测对长期血透患者继发甲状旁腺功能亢进的早期诊断、预防和治疗有重要指导意义 ;服用钙剂能预防和治疗继发性甲状旁腺功能亢进 ,减少继发性甲状旁腺功能亢进的发生率     

血液灌流联合血液透析对维持性血液透析患者甲状旁腺激素的清除及血小板的影响

目的观察维持性血液透析患者使用血液灌流串联血液透析方法对甲状旁腺激素清除和血小板的影响。方法将60例稳定维持性血液透析患者完全随机分为2组各60例：血液灌流联合血液透析（HP＋HD）组,单纯血液透析组（HD）,HP＋HD组行血液灌流2h后继续透析至4h,HD组行规律透析,每次4h。观察2组甲状旁腺激素及血小板变化。结果（HP＋HD）组PTH治疗后由（986．7±531．2）ng／L降至（768．7±495．9）ng／L,治疗前后差异有统计学意义（P〈0．05）;而治疗前后血小板无下降。HD组甲状旁腺激素及血小板均无显著性变化。结论血液灌流联合血液透析可以有效清除甲状旁腺激素,无血小板下降的倾向。     

Hydroxyapatite nanorods loaded with parathyroid hormone (PTH) synergistically enhance the net formative effect of PTH anabolic therapy

Parathyroid hormone (PTH) has been a major contributor to the anabolic therapy for osteoporosis, but its delivery to bone without losing activity and avoiding adverse local effects remain a challenge. Being the natural component of bone, use of hydroxyapatite for this purpose brings a major breakthrough in synergistic anabolism. This study focuses on synthesis, characterization and evaluation of in vitro and in vivo efficacy of PTH (1-34) adsorbed hydroxyapatite nanocarrier for synergistic enhancement in the anabolic activity of PTH for bone regeneration. The negative zeta potential of this nanocarrier facilitated its affinity to the Ca²⁺ rich bone tissue and solubilization at low pH enhanced specific delivery of PTH to the resorption pits in osteoporotic bone. In this process, PTH retained its anabolic effect and at the same time an increase in bone mineral content indicated enhancement of the net formative effect of the PTH anabolic therapy.     

葛根素防治骨质疏松症的作用机制研究进展

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