Bisphosphonate the first 40 years.

ReviewBisphosphonates:Thefirst40yearsR.GrahamG.Russell⁎NuffieldDepartmentofOrthopaedics,Rheumatology&MusculoskeletalSciences,andtheOxfordNIHRBiomedicalResearchUnit,TheOxfordUniversityInstituteofMusculoskeletalSciences,TheBotnarResearchCentre,NuffieldOrthopaedicCentre,Headington,OxfordOX37LD,UKTheMellanbyCentreforBoneResearch,UniversityofSheffield,Sheffield,UKabstractarticleinfoArticlehistory:Received29April2011Revised29April2011Availableonline1May2011Keywords:BisphosphonatesOsteoclastsBoneresorptionBonemetastasesOsteoporosisHydroxyapatiteThefirstfullpublicationsonthebiologicaleffectsofthediphosphonates,laterrenamedbisphosphonates,appearedin1969,soitistimelyafter40yearstoreviewthehistoryoftheirdevelopmentandtheirimpactonclinicalmedicine.ThisspecialissueofBONEcontainsaseriesofreviewarticlescoveringthebasicscienceandclinicalaspectsofthesedrugs,writtenbysomeofmanyscientistswhohaveparticipatedintheadvancesmadeinthisfield.Thediscoveryanddevelopmentofthebisphosphonates(BPs)asamajorclassofdrugsforthetreatmentofbonediseaseshasbeenafascinatingstory,andisaparadigmofasuccessfuljourneyfrom‘benchtobedside’.Bisphosphonatesarechemicallystableanaloguesofinorganicpyrophosphate(PPi),anditwasstudiesontheroleofPPiasthebody'snatural‘watersoftener’inthecontrolofsofttissueandskeletalmineralisationthatledtotheneedtofindinhibitorsofcalcificationthatwouldresisthydrolysisbyalkalinephosphatase.TheobservationthatPPiandBPscouldnotonlyretardthegrowthbutalsothedissolutionofhydroxyapatitecrystalspromptedstudiesontheirabilitytoinhibitboneresorption.AlthoughPPiwasunabletodothis,BPsturnedouttoberemarkablyeffectiveinhibitorsofboneresorption,bothinvitroandinvivoexperimentalsystems,andeventuallyinhumans.AsevermorepotentBPsweresynthesisedandstudied,itbecameapparentthatphysico-chemicaleffectswereinsufficienttoexplaintheirbiologicaleffects,andthatcellularactionsmustbeinvolved.Despitemanyattempts,itwasnotuntilthe1990sthattheirbiochemicalactionswereelucidated.Itisnowclearthatbisphosphonatesinhibitboneresorptionbybeingselectivelytakenupandadsorbedtomineralsurfacesinbone,wheretheyinterferewiththeactionofthebone-resorbingosteoclasts.Bisphosphonatesareinternalisedbyosteoclastsandinterferewithspecificbiochemicalprocesses.Bispho-sphonatescanbeclassifiedintoatleasttwogroupswithdifferentmolecularmodesofaction.Thesimplernon-nitrogencontainingbisphosphonates(suchasetidronateandclodronate)canbemetabolicallyincorporatedintonon-hydrolysableanaloguesofATP,whichinterferewithATP-dependentintracellularpathways.Themorepotent,nitrogen-containingbisphosphonates(includingpamidronate,alendronate,risedronate,ibandronateandzoledronate)arenotmetabolisedinthiswaybutinhibitkeyenzymesofthemevalonate/cholesterolbiosyntheticpathway.Themajorenzymetargetforbisphosphonatesisfarnesylpyrophosphatesynthase(FPPS),andthecrystalstructureelucidatedforthisenzymerevealshowBPsbindtoandinhibitattheactivesiteviatheircriticalNatoms.InhibitionofFPPSpreventsthebiosynthesisofisoprenoidcompounds(notablyfarnesolandgeranylgeraniol)thatarerequiredforthepost-translationalprenylationofsmallGTP-bindingproteins(whicharealsoGTPases)suchasrab,rhoandrac,whichareessentialforintracellularsignallingeventswithinosteoclasts.Theaccumulationoftheupstreammetabolite,isopentenylpyrophosphate(IPP),asaresultofinhibitionofFPPSmayberesponsibleforimmunomodulatoryeffectsongammadelta(γδ)Tcells,andcanalsoleadtoproductionofanotherATPmetabolitecalledApppI,whichhasintracellularactions.Effectsonothercellulartargets,suchasosteocytes,mayalsobeimportant.OvertheyearsmanyhundredsofBPshavebeenmade,andmorethanadozenhavebeenstudiedinman.Asreviewedelsewhereinthisissue,bisphosphonatesareestablishedasthetreatmentsofchoiceforvariousdiseasesofexcessiveboneresorption,includingPaget'sdiseaseofbone,theskeletalcomplicationsofmalignancy,andosteoporosis.SeveraloftheleadingBPshaveachieved‘block-buster’statuswithannualsalesinexcessofabilliondollars.Asaclass,BPssharepropertiesincommon.However,aswithotherclassesofdrugs,thereareobviouschemical,biochemical,andpharmacologicaldifferencesamongthevariousBPs.EachBPhasauniqueprofileBone49(2011)2–19⁎TheBotnarResearchCentre,NuffieldDepartmentofOrthopaedics,Rheumatology&MusculoskeletalSciencesUniversityofOxford,NuffieldOrthopaedicCentre,Headington,Oxford,OX37LD,UK.E-mailaddress:[e-mail]..8756-3282/$–seefrontmatter©2011ElsevierInc.Allrightsreserved.doi:10.1016/j.bone.2011.04.022ContentslistsavailableatScienceDirectBonejournalhomepage:‘designer’BPscontinuetobemade,andthereareseveralinterestingpotentialapplicationsinotherareasofmedicine,withunmetmedicalneedsstilltobefulfilled.TheadventurethatbeganinDavosmorethan40yearsagoisnotyetover.ThisarticleispartofaSpecia