骨质疏松治疗药物研究进展-新靶点-新药物-沈皆亮

··*[e-mail]———沈皆亮郝杰*400016Ｒ681A1006-7108201407-0844-05、、。。。Advancesinthetreatmentofosteoporosis———newtargetsandnewdrugsSHENJieliangHAOJieDepartmentofOrthopedicstheFirstAffiliatedHospitalofChongqingMedicalUniv[e-mail]sasystemicmetabolicbonediseaseandhasgraduallybecomeaglobalpublichealthproblemduetoitshighincidencemorbidityandmortality．Ｒecentlymanyeffortshavebeentriedtofindmoreefficientandsafermethodsforanti-osteoporosistreatment．Alongwiththefurtherunderstandingintobonemetabolismandbiologyseveralnovelosteoporosistargetsanddrugshavebeendevelopedwhichhaveopenedupafavorablenewsituationforthetreatmentofosteoporosis．Thispaperreviewstheadvancesinthetreatmentofosteoporosis．KeywordsOsteoporosisDrugsBonemetabolismTargetosteoporosisOP。1994WHO1。2001NIH2。。70%。XDXA。WHO、11～2.52.5。1。11.1。receptoractivatorofnuclearfactor-ΚBligandＲANKLT1nuclearfactorofactivatedTcell1NFATC13。OPG4。ＲANKＲANKLＲANKLＲANK。OPGＲANKＲANKLOPG44820147207ChinJOsteoporosJuly2014Vol20No．7Publishedonline．wanfangdate．com．cndoi10.3969/j．issn．1006-7108.2014.07.026ＲANKLＲANK。src。Src5。src6。。KcathepsinK7。K8。1TilmanDＲachnerLacent2011Fig．1OsteoclastphysiologyandpotentialtherapeutictargetsquotedfromTilamnDＲachnerLacent20111.2。D。I、、。D、9。。CaSＲ。CaSＲPTH。CaSＲ、CaSＲ。。CaSＲ10。CaSＲG1993Brown。Wnt/β-catenin11。Wntdickkopf-1Dkk-1sclerostin。1.3Semaphorin-3AHayashi———Semaphorin-3A12。54820147207ChinJOsteoporosJuly2014Vol20No．72TilmanDＲachnerLacent2011Fig．2OsteoblastphysiologyandpotentialtherapeutictargetsquotedfromTilmanDＲachnerLancet2011Semaphorin-3A。Semaphorin-3A-1neuropilin-1ITAMＲhoAＲANKLWnt/β-。1.4Sjogren13。TNFCD4+TCD11b+/GＲ1。Cho14。22.12.1.1DenosumabＲANKL。15。213FＲEEDOM163。10。。FＲEEDOM177808≥75/T-score≤－2.5。。。。2.1.2OdanacatibK。K。2Ⅱ18Eisman1920111。50mg132。BALP。K64820147207ChinJOsteoporosJuly2014Vol20No．7Eastell20ONO-5334、ONO-533412。K。。2.1.3Saracatinibsrc。59I21ICCTXIN25d88%67%。30%VS6%24%VS0%。2.22.2.1MK-5442、PTH。PTHPTH22。2.2.2AMG7852011AMG78523。、、、7285d。。5%3%。AMG785。6AMG785。。Ⅱ。。15Table1FivenoveldrugsforosteoprosistherapyＲANKＲANKIIIKKIIIsrcsrcIIMK-5442IIAMG785II3。。。【】1KanisJAMeltonLJ3rdChristiansenCetal．Thediagnosisofosteoporosis．JournalofBoneandMineralＲesearch1994981137-1141．2NihD．Consensusdevelopmentpanelonosteoporosispreventiondiagnosisandtherapy．JAMA20012856785-795．3TakayanagiHOgasawaraKHidaSetal．T-cell-mediatedregulationofosteoclastogenesisbysignallingcross-talkbetweenＲANKLandIFN-gamma．Nature20004086812600-605．4TokudaHKannoYIshisakiAetal．InterleukinIL-17enhancestumornecrosisfactor-alpha-stimulatedIL－6synthesisviap38mitogen-activatedproteinkinaseinosteoblasts．JournalofCellularBiochemistry20049151053-1061．5SorianoPMontgomeryCGeskeＲetal．Targeteddisruptionofthec-srcproto-oncogeneleadstoosteopetrosisinmice．Cell1991644693-702．6MarziaMSimsNAVoitSetal．Decreasedc-Srcexpressionenhancesosteoblastdifferentiationandbonefrmation．TheJournalofCellBiology20001512311-320．74820147207ChinJOsteoporosJuly2014Vol20No．77GarneroPFerrerasMKarsdalMAetal．ThetypeIcollagenfragmentsICTPandCTXrevealdistinctenzymaticpathwaysofbonecollagendegradation．JournalofBoneandMineralＲesearch2003185859-867．8LecailleFKaletaJBrommeD．Humanandparasiticpapain-likecysteineproteasestheirroleinphysiogyandpathologyandrecentdevelopmentsininhibitordesign．ChemicalＲeviews2002102124459-4488．9ChangWTuCPrattSetal．ExtracellularCa2+-sensingreceptorsmodulatematrixproductionandmineralizationinchondrogenicＲCJ3.1C5.18cells．Endocrinology200214341467-1474．10HouseMGKohlmeierLChattopadhyayNetal．Expressionofanextracellularcalcium-sensingreceptorinhumanandmousebonemarrowcells．JournalofBoneandMineralＲesearch199712121959-1970．11BaronＲＲawadiG．TargetingtheWnt/beta-cateninpathwaytoregulateboneformationintheadultskeleton．Endocrinology200714862635-2643．12HayashiMNakashimaTTaniguchiMetal．Osteoprotectionbysemaphorin3A．Nature2012485739669-74．13SjogrenKEngdahlCHenningetal．Thegutmicrobiotaregulatesbonemassinmice．JournalofBoneandMineralＲesearch20122761357-1367．14ChoIYamanishiSCoxLetal．Antibioticsinearlylifealterthemurinecolonicmicrobiomeandadiposity．Nature20124887413621-626．15EastellＲChristiansenCGrauerAetal．Effectsofdenosumabonboneturnovermarkersinpostmenopausalosteoporosis．JournalofBoneandMineralＲesearch2011263530-537．16CummingsSＲSanMartinJMcClungMＲetal．Denosumabforpreventionoffracturesinpostmenopausalwomenwithosteoporosis．TheNewEnglandJournalofMedicine20093618756-765．17BoonenSAdachiJDManZetal．Treatmentwithdenosumabreducestheincidenceofnewvertebralandhipfracturesinpostmenopausalwomenathighrisk．TheJournalofClinicalEndocrinologyandMetabolism20119661727-1736．18BoneHGBologneseMAYuenCKetal．Effectsofdenosumabtreatmentanddiscontinuationonbonemineraldensityandboneturnovermarkersinpostmenopausalwomenwithlowbonemass．TheJournalofClinicalEndocrinologyandMetabolism2011964972-980．19EismanJABoneHGHoskingDJetal．Odanacatibinthetreatmentofpostmenopausalwomenwithlowbonemineraldensitythree-yearcontinuedtherapyandresolutionofeffect．JournalofBoneandMineralＲesearch2011262242-251．20Eas