双膦酸盐氨基双膦酸钠和依膦缓解原发性骨质疏松症疼痛及药物副作用的观察.pdf

药物研究 作者单位:100730北京医院内分泌科双膦酸盐氨基双膦酸钠和依膦缓解原发性骨质疏松症疼痛及药物副作用的观察金世鑫李葆玲汪耀摘要目的观察双膦酸盐氨基双膦酸钠(alendronate,商品名fosamax)和依膦(etidronate)缓解原发性骨质疏松症患者的疼痛的疗效及副作用。方法依据BMD减少量,结合脊柱X线片诊断骨质疏松,女 65岁、男 70岁,且排除继发性骨质疏松来诊断原发性骨质疏松症,伴疼痛者入选作药物观察。结果20例疼痛患者服药后17例获疼痛缓解,其中4例获明显缓解。A lendronate与etidronate的疼痛缓解率近似,但后者必须间断用药,停药期疼痛常复发。药物副反应仅见到烧心与消化不良。结论双膦酸盐alendronate和etidronate可以缓解原发性骨质疏松症的疼痛,副反应轻。关键词氨基双膦酸钠依膦原发性骨质疏松症疼痛Alendronate and etidronate in relieving pain due to pri maryosteoporosis and their side effects:report of 20 casesJin Shixin,L iBaoling,W ang YaoDepartment of Endocrinology,Beijing Hospital,Beijing100730,ChinaAbstractObjectiveTo observe the therapeutic effect of alendronate and etidronate in relievingosteoporotic pain and their side effects.M ethodD iagnosis of pri mary osteoporosiswas based on BMDdecrease by DEXA?L unar assays combined w ith spinal X2ray film s,on old ages of men 70 years andwomen 65 years,and on excluding secondary osteoporosis.Twenty patients w ith osteoporotic painwere enrolled,of whom 7were treated w ith alendronate and 13w ith 10 etidronate.ResultsAmong 17of 20 patientswho had relief from the symptom,4 hadmarked i mprovement.A lendronate and etidronateshowed si m ilar i mprovement ratesw ithout statistical significance,but pain often recurred during suspen2sion of etidronate.Only heartburn and abnormal digestion were seen as side effects of the drugs.Con-clusionBisphosphonates alendronate and etidronate can relieve osteoporotic pain and havem ild side ef2fects.Key wordsA lendronateEtidronatePri mary osteoporosisPain近年来已有报道双膦酸盐alendronate(fosamax)能降低绝经后骨质疏松性骨折的发病率1和降低椎体骨折妇女再发生骨折的危险性2,骨折所相应的疼痛也获缓解。双膦酸盐etidronate的长期、间歇应用对绝经后骨质疏松也显示疗效3。本文观察这两种双膦酸盐改善骨质疏松症疼痛的临床疗效和药物副作用,并复习双膦酸盐的临床药理。44CH I NESE JOURNAL OF OSTEOPOROSIS Vol.5 No.3 19991方法111原发性骨质疏松症的诊断依据:用DEX2A?L unar骨密度仪所测得的BMD,妇女小于青年女性峰值减215SD,男性小于310SD;本组女性绝经15年以上,男性 70岁;排除多发性骨髓瘤、原发性甲状旁腺功能亢进、肾小管酸中毒和肾小球功能不全。脊柱X线片用于协助诊断骨质疏松。112有以下骨质疏松性疼痛者入选本组观察:疼痛一个加号(+)是指无自发出现的疼痛,在行走一长段路以后或白天日常活动到下午或晚上发生疼痛;并非每天疼痛,但隔几天就痛;常常不需用药。疼痛两个加号(+)是指比(+)疼痛更严重的疼痛,常于行走短路程或短时间后发生,或自发出现疼痛,常需贴膏药或服药以缓解疼痛。经治疗后,(+)疼痛明显缓解,或疼痛消失一段时间者,记录为(-)。113 用 药 方 法:Fosamax 10 mg Q.D,etidronate 012 bid共15天,休息85天后再服药。2结果211Fosamax和etidronate缓解疼痛的效果逐例列于表1。服用fosamax的7例中有6例出现疼痛缓解,服用etidronate患者13例中的11例疼痛缓解,但因该药不能连续服用,于停药后可复发疼痛。表1二膦酸盐的疼痛减轻效应病例性别年龄药物?月症状的变化和所需时间(治疗前?治疗后)背痛腰痛骶痛髋痛膝痛腿痛月1男78ALN2+?-+?+-12女69ALN4-+?-+?-23女67ALN5-+?-24女66ALN2-+?-25女82ALN2-+?-16男80ALN2-+?+-+?+-7男79ALN3-+?-+?-18女86ETN12-+?-19女65ETN9+?-+?-110女63ETN6-+?-+?-111女78ETN9+?-+?+-212女66ETN6-+?-+?-213女72ETN9+?-+?-114女70ETN6-+?-115女68ETN3-+?-+?-116女67ETN6-+?-117女70ETN6-+?-118女66ETN6-+?+?+-19女73ETN6-+?+-20女70ETN6-+?-+?-1注:ALN:A lendronate 10 mg Q.D.;ETN:Etidronate 012g每天二次共15天,停药85天212Fosamax和etidronate的副反应见表2。未发现吞咽痛、胸骨后痛、腹泻、皮疼、肝功能损害、大便潜血阳性、尿蛋白阳性等副作用。所见烧 心3例 中,1例 为 服fosamax,2例 为 服etidronate。所 见 消 化 不 良2例 中,均 为 服etidronate。1例长期患支气管哮喘者,服fos2amax未见任何副反应。54中国骨质疏松杂志1999年8月第5卷第3期表2二膦酸盐alendronate和etidronate的副作用症状A lendronate(7例)Etidronae(13例)吞咽痛无无胸骨后痛无无烧心1?72?13消化不良无2?13腹泻无无肝功能损害无无阳性粪潜血无无尿蛋白阳性无无3讨论A lendronate每天10 mg对原发性老年骨质疏松症安全有效1,2。类似的结果见于间歇性周期口服etidronate每100天服药15天,每天014 g3。本组病例观察结果为,缓解骨质疏松症疼痛alendronate 86%(6?7),etidronate达84%(11?13)。服药12个月出现疼痛缓解。etidronate停药期间可出现疼痛复发。A lendronate(fosamax)用于老年骨质疏松症的最佳剂量,对升高脊椎骨骨密度的疗效每日10 mg和5 mg二者近似。但在髋部骨密度则每日10 mg明显优于每日5 mg。老年人骨质疏松症患者对双膦酸盐的有效性和耐受性,均未发现比非老年人敏感性增高的情况。A len2dronate在3年前被美国FDA批准应用,它对绝经后骨质疏松症是新的有效药。老年人群和青壮年人群相比,alendronate的疗效似无明显区别4。各种双膦酸盐均特异地作用于骨,以骨为靶组织,并不渗入其他细胞,也不跨过细胞膜而进入细胞内。用放射物标记的alendronate研究显示,约50%被骨组织摄取,其余50%以原来结构被肾迅速排出。中度肾功能不全的患者,对alendronate的疗效反应和可耐受性,无任何改变4。双膦酸盐进入骨组织后选择性积聚于破骨细胞下方的骨吸收表面,与骨吸收期局部暴露出来的羟基磷酸钙结晶结合,从而不仅抑制破骨细胞活性(破骨细胞附于骨吸收表面上的皱折缘减少,细胞内骨架发生变异,酶活性降低,酸排泌减少),而且促进细胞凋亡使破骨细胞数量减少5。这种破骨细胞只能在骨表面挖掘一个浅浅的骨吸收凹陷(浅挖洞),而不能如同在无双膦酸盐的骨表面上那样挖掘出深深的骨吸收凹陷(深挖洞)。这种破骨细胞还能游移到其他无alendronate吸附的骨表面,发挥它的正常的“深挖洞”溶骨作用。A lendronate对成骨细胞没有直接作用,骨形成过程仍正常。但etidronate连续用药、每天600800 mg时出现骨矿化障碍,即抑制羟基磷酸钙结晶本身或其前体的形成和生长。该药改为200mg bid共15天、再停药85天的方法后,已克服上述缺点。骨内双膦酸盐迅速被新生的骨组织覆盖,此后暂时无药理活性。仅仅是存在于或暴露于骨再塑表面上的双膦酸盐才有机会遇到破骨细胞、从而发挥抑制破骨细胞皱折缘形成等溶骨作用(即骨吸收作用)。埋藏于新骨内的双膦酸盐半寿期很长,比如alendronate半寿期超过10年。但因埋于骨内而不在骨吸收表面上,所以无药物活性4。一旦骨吸收过程又将双膦酸盐暴露于骨吸收表面上,药物可能恢复活性。长期被双膦酸盐覆盖、骨组织更新甚少的骨可发生脆性增加。依赖正常骨更新而修复的微骨裂(m i2crocracks)若得不到修复也增加骨折危险性。这是大剂量长期应用双膦酸盐的副作用5。骨吸收抑制的证据来自于45Ca动力学研究,也来自骨吸收生化指标6。这种效用在2448小时内发生,比降钙素显效慢。若应用很大剂量的双膦酸盐,可长期且严重抑制骨吸收,能导致骨形成抑制,且不能修复微骨裂,最终引起骨脆性增加,易引起骨折5。参考文献1L iberman UA,W eiss SR,Broll J,et al.Effect of oral alen2dronate on bone m ineral density and the incidence of frac2(下转第32页)64CH I NESE JOURNAL OF OSTEOPOROSIS Vol.5 No.3 1999合成、释放多种细胞因子及生长因子而发挥间接的病生理作用9,10。正常情况下,A GEs是组织重建必不可少的,通过巨噬细胞释放TN F2和I L212、I L265等,同时分泌蛋白水解酶,以达到清除衰老和受损伤的物质,然后将其修复的目的。因此,A GEs在维持内环境稳定中起着重要作用。但随龄过量积累的A GEs作用于多种细胞,产生了过多的上述的细胞因子,而这些细胞因子如TN F、I L21、I L26等能够刺激破骨细胞的前体细胞向破骨细胞转变,同时增加破骨细胞的活性,从而导致骨吸收的增加11,12。由此可见,老年性骨质疏松的发病机制,可能为A GEs的随龄增加导致促成骨细胞增殖减弱,分化延迟,而破骨细胞的数量和活性相对增加导致骨丢失大于骨形成,最终引起骨质疏松。目前已发现数种能够抑制A GEs形成的药物,可望对老年性骨质疏松的防治起到重要作用。参考文献1V lassara H,Bucala R,Striker L.Biology of disease:pathogenic effects of advanced glycosylation:biochem i2cal,biological and clinical i mplications for diabetes andaging.Lab Invest,1994,70(2):1382151.2V lassara H,BrownleeM,M anogub K,et al.CachectinTNF and I L21 induced by glucose2modified proteins:rolein normal tissues remodeling.Science,1988,240:154621548.3Paul RG,Bailey AJ.Glycosylation of collagen:the basisof its central role in the late complication of aging and di2abetes.Int J Biochem Cell Biol,1996,28(12):129721310.4M iyata T,M aeda K.New aspects in the pathogenesis ofdialysis2related amyloidosis:role of22m icroglobin modi2fied w ith advanced glycosylation end products in boneand joint destruction.NephrolDial Transplant,1996,11(suppl 2):1402143.5TakagiM,Kasayama S,Yamamoto T,et al.Advancedglycosylation end products sti mulate interleukin26 pro2duction by human bone2derived cells.J BoneM iner Res,1997,12(3):4392446.6司徒镇强,吴军正.细胞培养.北京:世界图书出版社,1996.1112115.7王玉甫,温孝恒,马健,等.糖尿病患者血清骨钙素水平及临床分析.中国骨质疏松杂志,1998,4(2):45246.8Fong Y,Edelstein D,W ang EA,et al.Inhibition of ma2trix2induced bone differentiation by advanced glycosyla2tion end2products in rats.Diabetologia,1993,36:8022807.9Kirstein M,A ston C,Hintz R,et al.Receptor2specificinduction of insulin2like grow th factor in human mono2cytes by advanced glycosylation end product2modifiedproteins.J Clin Invest,1992,90:4392446.10V lassara H.Recent progress in advanced glycosylationend2products and diabetic complication.Diabetes,1997,46(Suppl 2):s192s25.11KanataniM,Sugmoto T,FukaseM,et al.Role of inter2leukin26 and prostaglandins in the effect of monocyte2conditioned mediumon osteoclast formation.AmJPhysiol,1994,267:E8682E876.12Ki mble R,Vannice JL,Bloedow DC,et al.Interleukin21receptor antagonist decreases bone loss and bone resorp2tion in ovariectom ized rats.J Clin Invest,1994,93:195921969.(上接第46页)ture in postmenopausal osteoporosis.N Engl J M ed,333:143721443.2Black DM,Cumm ing SR,KarpsDB,et al.Random ized trialof the effect of alendronate on the risk of fracture in wom2en w ith existing vertebral fracture.Lancet,1996,438:153521541 1996.3Storm T,Steiniche T,Tham sborg G,et al.Changes in his2tomorphometry after long term treatmentw ith interm ittentcyclic etidronate for postmenopausal osteoporosis.J BoneM iner Res,1993:8,1992208.4 Proceeding of asatellitesymposiumof3rdEuropeanCongress of Gerontology.M erck&Co:U SA 1997,13215.5Fleisch H.Bisphosphonate:mechanism of action.EndocrineRev,1998,19(1):802100.6GasserAB,Morgan DB,Fleisch HA,et al.The influence oftwo diphosphonates on calcium metabolism in the rat.ClinSci,1972,43:31245.23CH I NESE JOURNAL OF OSTEOPOROSIS Vol.5 No.3 1999