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European Journal of Endocrinology -19-0184 are beneficialtoskeletalhealthsincetheyenhance factor (IGF-I)( elevated circulating levelsofGHandinsulin-likegrowth adenoma resultingin (GH) generallycausedbyapituitary characterized byexcessivesecretionofgrowthhormone Acromegaly is a chronic and disabling disease Introduction pathophysiological andclinicalinformation. associated withacromegalyandprovidesaperspectiveofpossibletherapeuticapproachesbasedonemerging of acromegalyandtheeffectivenessbone-activedrugsisunknown.Thisreviewanupdateonbonedisorders complication islow,thepredictionoffractureriskdifficulttoascertain,fracturesremainsaftercontrol and IGF-Iexcess.Themanagementofskeletalfragilityinacromegalyisachallenge,sincetheawarenessthis causes skeletalfragility,andvertebralfracturesarereportedinaremarkablenumberofsubjectsexposedtoGH enhanced leadingtodeteriorationofbonemicrostructureandimpairmentstrength.Indeed,acromegaly the maintenanceofskeletalarchitectureinadults.WhenGHandIGF-Iaresecretedexcess,boneremodeling is life, bystimulatinglongitudinalbonegrowthinchildren,theacquisitionofmassduringadolescenceand Growth hormone(GH)andinsulin-likegrowthfactor-I(IGF-I)exertphysiologicalactionsontheskeletonthroughout Abstract The UConnMusculoskeletalInstitute,Health,Farmington,Connecticut,USA Clinical andResearchCenter,IRCCS,Rozzano,Milan,Italy, 1 Gherardo Mazziotti mechanisms andtreatment Bone disordersassociatedwithacromegaly: MANAGEMENT OFENDOCRINEDISEASE Department ofBiomedicalSciences,HumanitasUniversity, https://doi.org/ https://eje.bioscientifica.com Review growth hormoneinbonemetabolism. hormones,particularly has madeseveralcontributions totheunderstandingofrolepituitary main field of interest is the neuroendocrinology of bone and during the last 15 years, Dr Mazziotti TumorPituitary CenterofExcellence of HumanitasResearch Center ofRozzano(MI),Italy. His of Milan,HeadMetabolicBoneDiseasesandOsteoporosis Sectionandbonespecialistinthe Gherardo Mazziotti Invited Author’s profile Under physiological conditions, GHandIGF-I 10.1530/EJE 1 ). -19-0184 1 , 2 , Andrea G A Lania , MD,PhDisanAssociateProfessorofEndocrinologyatHumanitas University 2 © 2019EuropeanSociety ofEndocrinology G Mazziottiandothers Printed inGreatBritain 1 , 2 and 2 Endocrine, DiabetesandAndrologyUnit,Humanitas 3 Departments ofOrthopaedicSurgeryandMedicine, Ernesto Canalis because offindingsdemonstratingthatGHandIGF-I in fractures ( overlooked asariskfactorforskeletalfragilityand characteristically enlargedbones,acromegalyhasbeen effects andthefactthatsubjectswithacromegalyhave and remodeling( longitudinal bonegrowth,aswellmodeling Bone andacromegaly Published byBioscientifica Ltd. 3 3 , 4 ). Recently, thisparadigmwasrevisited 2 ). Basedonthesephysiological Downloaded fromBioscientifica.com at09/26/202110:40:08AM (2019) Endocrinology European Journalof hunimed.eu gherardo.mazziotti@ Email to GMazziotti should be addressed Correspondence 181 181 :2 , R45–R56

R45 –R56 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com multinucleated cellsarisingfrommononuclearprecursors osteoclasts and osteoblasts ( basic multicellularunits(BMUs)bytheactivityof micro-damaged bonethroughoutlife. maintain calcium homeostasis and to remove potentially to of coupledboneresorptionandformation,necessary GH andIGF-Ialsostimulateboneremodeling,aprocess development or after growth and throughout life ( osteoclasts. Bonemodelingoccurseitherduringskeletal independent and uncoupledaction of osteoblastsand a processwherebybonesareshapedorreshapedbythe the actionsofGHandIGF-Ionbonemodeling( These effectsontheepiphysealplateareparalleledby stimulating chondrocyteproliferationanddifferentiation. a centralroleinendochondralboneformationby During the first two decades oflife, GH andIGF-I play the skeleton Physiology oftheGH-IGF-Iaxisin pathophysiological andclinicalinformation. of possibletherapeuticapproachesbasedonemerging associated withacromegalyandprovidesaperspective drugs inacromegalyareunknown( disease ( in subjectsfollowingthesuccessfultreatmentof bone mineraldensity(BMD)( is challengingsinceVFsarenotpredictedbychangesin increased riskofvertebralfractures(VFs)( bone architecture leadingtodecreasedbonestrengthand excess maycauseabnormalitiesintrabecularandcortical GH/IGF-I Review This reviewisanupdateonbonedisorders The managementofskeletalfragilityinacromegaly Bone remodelingiscarriedoutinmicroscopic 7 , 8 ) andtheefficacysafetyofbone-active OC OB CD OPG/RANKL Boneresorption Chondrogenesis Bone modeling/ Boneformation Endochond Ph r emodeling y 6 siolog 11 ), thefractureriskpersists G Mazziottiandothers , ra y l 5 12 ). ). Osteoclasts are 5 Conncectivecellfunction Chondrocytefunction ). impair Gr and peri Bone lossand o Ac Boneformation Boneresorption wth ofcart stru ed bonequality r omegaly ct ar ur Fig. 1 ticular es 9 ilag , 10 e ). ), and resorption In vitro ligand (RANKL)( are asignificantsource ofreceptoractivatorNFkappaB responsible for skeletal responses to mechanical load and and structuralstrengthofbone( that playsaroleinmaintainingthematerialproperties bone environmenttoformacommunicatingnetwork connect themamongthemselvesortoothercellsinthe ( into liningcellsorosteocytescandiebyapoptosis in thebonemarrowandtheycandifferentiatefurther Osteoblasts derivefrommesenchymalcellsthatreside months. with newmatrix,inaprocessthattakes3–5 the resorbedsurfaceattractsosteoblaststhatfillBMU weeks.Thereafter, resorption, aprocessthattakes3–5 of thehematopoieticlineageandareresponsibleforbone of IGF-I,synthesizedintheliverunderGHcontrol( and bone formation are mediated by the systemic form the osteoblastlineage,mostofeffectsinosteoblasts osteoblastic function( carboxylation ofosteocalcin,whichisamarker osteoblastogenesis ( proteins, whichalongwithWntplayaroleinenhancing also stimulatestheexpressionofbonemorphogenetic like-1, knowntosuppressfatandbonemass( expression offetalantigen1,thesolubleformdelta- indirectly ( ( control of IGF-I ( osteoblasts ( The GHreceptorisexpressedbychondrocytesand Bone andacromegaly 13 23 ? , , Although GHmayhavedirecteffectsoncellsof ARTHROPATHY OSTEOPATHY 14 24 , ). GHstimulates osteoblastogenesis directly or effectsofGHandIGF-Ionboneformation 15 ). Osteocyteshavecytoplasmicprocessesthat 25 18 , , 26 19 22 17 , , factor kappa- RANKL, Receptoractivatorofnuclear OC, osteoclast;OPG,osteoprotegerin; disease. CD,chondrocyte;OB, osteoblast; cells andcartilageinphysiology and insulin-like growthfactor-I(IGF-I)onbone Effects ofgrowthhormone(GH)and Figure 1 ) and of IGF-binding proteins (IGFBPs) ). 27 20 28 ). Forexample,GHsuppressesthe , 31 21 , Downloaded fromBioscientifica.com at09/26/202110:40:08AM ). ) and its expression is under the 29 , Β 30 ligand. ). GHstimulatesthe 16 181 ). Osteocytesare :2 27 ). GH R46 32 via freeaccess ).

European Journal of Endocrinology following ovariectomyandskeletal unloadinginrats( formation andprotectsagainst thebonelossobserved Interestingly, recombinant IGFBP-2 stimulates bone circulating IGF-I concentrations in femalemice ( reflecting theprotective effectsofpersistentlyhigh inmale but notinfemalemice,possibly are observed in mineralizingsurface/bone surface ( abnormalities in trabecularbonestructure and reduction ( effectsof IGFBP-2 onosteoblastogenesis direct stimulatory volume ( causes adecreaseinboneformationandtrabecular deletion oftheIGF1receptor( periosteal boneformation( toareductionin decrease incorticalvolume,secondary display amodestskeletalphenotype,characterizedby 46 by theGH-independentlocalproductionofIGF-I( but normaltrabecularboneandthismaybeaccountedfor mouse) or theGH receptor exhibit reduced cortical bone, mutations intheGH-releasinghormonereceptor(lit/lit the maintenanceofcancellousbone( skeletal IGF-Iappearstoplayamoresignificantrolein tomaintaincorticalbonestructure,whereas necessary Pre-clinical studieshaveindicatedthatsystemicIGF-Iis and resorption In vivo increase ofIGF-IbioavailabilityinducedbyIGFBP-4. 44 cells andthefunctionsofosteoblastsosteoclasts( whereas IGFBP-4inhibitsthedifferentiationofprogenitor and -4.IGFBP-2stimulatesosteoblastogenesis( of bonemarrowmacrophages( enhances theformationofosteoclast-likecellsincultures preosteoclasts andmatureosteoclasts( osteoclastogenesis ( the expressionofRANKLand,asaconsequence, levels ofbonematrixandmass.IGF-1stimulates protease ( of matrixmetalloproteinase13,acollagen-degrading type I collagen transcription and decreases the synthesis the functionofmatureosteoblasts( modest effectsonosteoblastdifferentiationandenhances control ofparathyroidhormone(PTH)( osteoblasts is not enhanced by GH and is under the It is important to note that the synthesis of IGF-I in 41 Review ). The latter effects may be counteracted by a concomitant ). Thelattereffectsmaybecounteractedbyaconcomitant ). Similarly, aliver-specific micecarrying , Consistent withthe The effects of IGF-I on bone are modulated by IGFBP-2 The effectsofIGF-IonbonearemodulatedbyIGFBP-2 42 effectsofGHandIGF-Ionboneformation ), 48 36 Igfbp2 ). ), ensuring the maintenance of appropriate -null micehavelowosteocalcinlevels, 37 ). TheIGF-Ireceptorispresentin in vitro 47 ). Incontrast,theconditional Igf1r 40 / G Mazziottiandothers ex vivo ). ) inmurineosteoblasts 35 ). IGF-Iupregulates 38 49 studiesreporting 2 33 ). Mice carrying ). Micecarrying , ). Theseeffects , 39 34 Igf1 ), andIGF-I ). IGF-Ihas deletion 41 , 2 , 51 50 42 45 43 ). ). ), ), , , diagnosis rangesbetween40 and50 yearsofage( sex ratioiscloseto1and the meanageattimeof implications oftheseeffectsremainunclear( pulsatility, butthephysiologicalandpathophysiological and IGF-Imayinfluencecircadian PTHsecretionand in the proximal renal tubule by IGF-1 ( an effectmediatedbythestimulationof1 IGFBP-4, like that of IGFBP-5, is an inhibition of osteoblast IGFBP-4, likethatofIGFBP-5,isaninhibitionosteoblast it seems thattheprevalenteffectof these observations, IGFBP-4 protease-dependentmechanism( possibly becauseofincreasedIGFbioavailabilityviaan recombinant IGFBP-4exhibitedenhancedboneformation and osteoblastnumber( significant reductioninosteoidvolume,surface rate andmineralappositionrate,associatedwitha expressing osteoblastscausedadecreaseinboneformation ( effectsofIGFBP-4onosteoblastogenesis direct inhibitory reasons ofthesesex-relatedfindingsareunclear( mice haveadecreaseintrabecularbonevolume.The increased trabecularbone,whereasfemale recombinant IGFBP-4( overexpression of evaluated inmicefollowingtheinactivation( approximately 3–4cases/100,000 inhabitants( prevalence of30–60cases/100,000 andanincidenceof Acromegaly isachronic disease withanestimated clinical aspects Acromegaly: epidemiologyand rate andisindependentoftheactionsPTH( increase inthemaximaltubularphosphatereabsorption ( renal calciumreabsorptioninthedistaltubule( to an increase in intestinal calcium absorption ( of vitaminDleadstoapositivecalciumbalancesecondary production inexperimentalanimals( of vitaminDbyGHandIGF-I.stimulatescalcitriol ( GH andIGF-1regulatecalciumphosphatemetabolism metabolism Effects ofGHandIGF-Ioncalcium–phosphate function andboneformation( Bone andacromegaly 43 55 55 , ). Theanti-phosphaturiceffectofGHisduetoan ). Theseeffectsaremainlymediatedbytheactivation GH hasphosphate-retainingactionsinthekidney Consistent withthe The effectsofIGFBP-4ontheskeleton 44 ), thetransgenicoverexpressionof Igfbp4 44 52 Downloaded fromBioscientifica.com at09/26/202110:40:08AM , aswelltheadministrationof in vitro ). In contrast, mice administered ). Incontrast,miceadministered ). Igfbp4- 53 https://eje.bioscientifica.com , / ex vivo 54 null malemicehave ). 181 56 58 :2 findings of the findingsofthe ) andmen( ). The activation Igfbp4 α -hydroxylase 52 62 in vivo Igfbp4 ). Despite ). Despite 43 ). 60 in 63 43 61 64 59 ) orthe ). ). The ). Bglap

). GH R47 were , ) and -null 65 57 via freeaccess ). ), - European Journal of Endocrinology https://eje.bioscientifica.com concominant osteoarthritis and osteoporosis( mechanisms ( and arthropathysharecommon pathophsyiological ( one occurringduringnormalendochondralossification and osteoclastfunctiondirectlyinawaysimilartothe growth induced by GH excess may influence osteoblast osteoblasts ( toward cartilageoradipocytesinsteadofmature excess mayinducemesenchymalstemcellcommitment subjects withacromegaly, Belaya gene expression in sphenoid bone tissue samples of to enhancedosteoclastogenesis( to theactionsofIGF-IoninductionRANKLleading and IGF-I( turnover isdirectlyrelatedtothelevelsofcirculating GH markers ofboneturnover( were reportedinseveralstudiesevaluatingbiochemical The predominanteffects of GH excesson bone resorption increase in bone resorption than in bone formation ( In acromegaly, boneturnoverisenhancedwithagreater and resorption Effects ofGHexcessonboneformation Bone disordersinuntreatedacromegaly with elevatedorequivocalserumIGF1levels( acromegaly andthistestshouldbeperformedinsubjects an oralglucosetolerancetestconfirmsthediagnosisof acromegaly ( < sample documentingthecoexistenceofaserumGHlevel GH secretionispulsatile;however, arandomserum not recommended in the diagnosisof acromegaly because levels ofIGF1( upon the identification of persistently elevated serum considered acomplicationofacromegaly. frank diabetesmellitus( hypertension, sleepapnea,impairedglucosetoleranceor atthetimeofdiagnosisarearterial frequently observed disease at the time of diagnosis ( of affectedindividualspresentwithcomplicationsthe followingtheonsetofdisease,majority 10 years the diagnosisofacromegalyisoftenmadeapproximately tumormasseffects.Because excess andtolocalizedpituitary symptoms andsignsattributabletobothGHIGF-1 74 0.4 Review ). Onemayspeculatethat acromegalicosteopathy The biochemical diagnosis of acromegaly is based The biochemicaldiagnosisofacromegalyisbased Acromegaly ischaracterizedbythepresenceof μ g/L and a normal IGF1 level excludes the diagnosis of g/L andanormalIGF1levelexcludesthediagnosisof 40 68 74 ). Theincreasedboneremodelingislikelydue i. 1 Fig. ). The lack of serum GH suppression during ). The lack of serum GH suppression during 67 ). Itwashypothesizedthatthecartilage ). The random sampling of serum GH is ). TherandomsamplingofserumGHis ), asproposedinindividuals with 66 69 ). Skeletalfragilityisoftennot , 70 , G Mazziottiandothers 64 et al 71 40 ). Comorbidities most ). Theincreasedbone , . suggestedthatGH 72 , 73 ). Analyzing 67 75 ). , 76 ). 6 ). trabecular thicknessandincreasedseparation et al structural changes inacromegaly( understanding ofthetrabecularandcorticalbone and histomorphometricanalysishasallowedabetter ( activity ofosteoclastsandosteoblastsatthetissuelevel an increaseintrabecularandcorticalbonemasshigh human studiesusinghistomorphometricanalysisrevealed are foundinsubjectswithacromegaly. Indeed,seminal competence ( trabecular andcorticalbonearchitecture andmechanical exhibit markedly increased bone resorption and impaired element a metallothionein1transcriptionalregulatory mouse modelsoverexpressingGHunderthecontrolof bone lossandabnormalitiesinstructure.Transgenic The increaseinboneturnoveracromegalymayleadto and architecture Effects ofGHexcessonbonehistomorphometry which isaffectedinadistinct mannerbyGH,possibly is mainlyrelatedtothe properties ofcorticalbone, bones ( but donotseemtobeacause offragilityfracturesinlong with acromegalyexplaintheincreasedincidenceofVFs The structuralabnormalitiesincancellousboneofsubjects Effects ofGHexcessonfracturerisk decreased corticaldensity( increased corticalporosity/porevolume( compartment isaffected,andGHexcessassociatedwith to these changes in cancellous bone, the cortical bone gonadal functionwasnormal( strength inactiveacromegalicpatientsevenwhen abnormalities intrabecularbonemicrostructureand studied ( closely correlatedwiththegonadalfunctionofsubjects subjects withacromegaly. Thesestructuralalterations and trabecularnumber in thedistaltibiaand radius of trabecular density, trabecularbonevolume/tissuevolume tomography (HR-pQCT),Madeira high-resolution-peripheral quantitativecomputerized with active acromegaly ( and alteredbiomechanicalcompetenceinsubjects with previousdatareportingabnormalbonearchitecture without acromegaly( in subjectswithacromegalyandVFscomparedto thickness was increased, but the cortical bone was porous demonstrating decreasedcancellousbone;cortical Bone andacromegaly 79 ). However, recentworkusingmicroarchitectural . recentlydescribedreducedtrabecularbonevolume, 3 , 83 4 , ). However, subsequent work demonstrated 66 77 ). Thefragilityoftheperipheral skeleton , 78 ). Abnormalitiesinbonestructurealso 81 Downloaded fromBioscientifica.com at09/26/202110:40:08AM ). Theseresultswereconsistent 85 82 ). ). Using the less invasive 84 et al , 80 85 181 . reporteddecreased ). DalleCarbonare , :2 86 81 ). Inaddition , 84 , 87 R48 ) and via freeaccess European Journal of Endocrinology publication ofX-rays. 40%, respectively( on aheightratiodecreaseof20–25%, 25–40%andmorethan approach, VFsweredefined mild, moderateandseverebased shape andheight.Accordingto aquantitativemorphometric the vertebralbodywithsixpointstodescribe fractures (arrows).Vertebralwereidentifiedmarking Vertebral X-raysoftwosubjectswithacromegalyandvertebral Figure 2 risk offractureswascorrelatedwiththedurationactive of theskeletalexposuretoGHandIGF-Iexcess,since provided suggestiveevidencethatVFsareaconsequence slightly greaterinmenthanwomen( control subjects( risk whichisthree-toeight-foldgreatercompared prevalence ofVFsinacromegalyisabout40%,afracture with acromegaly( of VFsinpre-menopausalwomenandmalesubjects consistently anddemonstratedanincreasedincidence In addition,cross-sectionalstudiesconfirmedthisfinding of VFs in post-menopausal women with acromegaly ( described forthefirsttimeanincreaseinprevalence morphometric approach ( mainly incancellousbone.Applyingaradiologicaland to highboneremodeling,anactivitythattakesplace stress risers on trabeculae. These effects are closely related fragility, whichisrelatedtofocalareasoferosioncreating model ofacromegaly( of inertia the femoral bone is high in an experimental lead toaporouscorticalbone.Interestingly, themoment potential negative effects of high bone remodeling that in corticalbonemass,whichmaypartcounteractthe periosteal boneformationwithaconsequentincrease trabecular bone.Moreover, GHhypersecretioninduces because boneremodelingislessactiveincorticalthan Review 89 6 91 ). Interestingly, theprevalenceofVFsis ). Thetwosubjectsconsentedto the , 92 88 , 93 ). GHexcesscausesvertebral 89 , ) ( 94 i. 2 Fig. , G Mazziottiandothers 95 ). Theoverallmedian ), Bonadonna 5 ). Arecentstudy t al et 90 ). . and thecontrolofclinical manifestationsofthe of thehormonalexcess, the removaloftumor The therapeuticgoalsinacromegaly arethenormalization Bone disordersintreated acromegaly effects areunclear. mass ( with prolongation of pulse duration and increase in pulse protein ( because of an increase in serum levels of vitamin D-binding peripheral bioavailabilityofvitaminDinacromegaly consistently ( hypovitaminosis Disfoundinpatientswithacromegaly have backpain,impairedqualityoflifeandapossible VFs ( individuals withfractureshaveeithermultipleorsevere with acromegaly( ( thoracic spineandtheyareoftenanteriorwedgefractures radius ( peripheral HR-QCTofthebonestructureatdistal (DXA)oftheproximalfemurand absorptiometry histomorphometry, tridimensionaldual-energyX-ray of bonesamplesfromindividualswithacromegalyby bone microstructurewasfoundfollowingtheanalysis an associationbetweenfracturesandabnormalitiesin should beconsideredamarkerofskeletalfragility, since receptor thathasincreasedaffinityforGH( found inindividualsharboringanexon-3deficientGH disease ( and IGF-IonvitaminDactivationbythekidney( bone turnoverinducedbyGHexcess( part, amarkerofskeletalfragilityreflectingtheincreased IGF-I ( in thegutandtodirectantiphosphaturicactionof calcitriol-stimulated phosphateandcalciumabsorption and hypercalciuria ( hyperphosphatemia andatendencytowardhypercalcemia Active acromegalyisassociatedwithmild phosphate metabolism Effects ofGHexcessoncalciumand acromegaly ( complicationsin worse outcomeofcardiopulmonary Bone andacromegaly 91 ), possiblycontributingtothekyphosisofsubjects Noteworthy, VFsdevelopmorefrequentlyinthe VFs arenota simple radiological finding butthey Notwithstanding the stimulatory effectsofGH Notwithstanding thestimulatory 95 55 104 81 7 ), maypredisposesubjectswithfracturesto 102 ). Hypercalciuria maybe considered,atleastin ). Moreover, ahigher incidence of fractures was , ); however, the skeletal implications of these 85 , 98 100 , 103 87 , 99 , ). ). GHexcessinfluencesPTHpulsatility 101 97 ). 55 ). Thefactthatmorethan50%of ). Thereisevidencesuggestinglower , Downloaded fromBioscientifica.com at09/26/202110:40:08AM 72 ), closely related to increased https://eje.bioscientifica.com 181 55 :2 ). 96 ). R49 55 via freeaccess ), European Journal of Endocrinology https://eje.bioscientifica.com bone remodeling. alterations inbonestructure orpersistentlyincreased ( microindentation in individuals with treated acromegaly level propertiesofcorticalboneasmeasuredbyimpact trabecular bonescore(TBS)( microstructure as assessedby DXA measurementof control ofacromegalyaretheimpairmenttrabecular skeletal fragilitypersistsnotwithstandingbiochemical VFs ( uncertain sinceallsubjectsincludedinthestudyhad these histomorphometricfindingsonfracturerisk was compared tothosewithactivedisease,buttheimpact of bone samples from patients with controlled acromegaly number and function and reduced osteocyte number in Dalle Carbonare function isalteredintheseindividuals( do not offer a direct proof that osteoblast number or in subjectswithcontrolledacromegaly, butthestudies hypothesized thatosteoblastogenesismaybeimpaired structure, and a reduction in fracture risk. Recent studies turnover isaccompaniedbyanimprovementinbone ( turnover followingthebiochemicalcontrolofacromegaly a decreaseinserumlevelsofbiochemicalmarkersbone Cross-sectional and prospective studies have demonstrated phosphate metabolism bone structureandcalcium- Effects ofacromegalytherapyonboneturnover, in thosewhoarenotsurgicalcandidates( therapy in subjects with inoperable or residual disease or maybeusedasadjuvantoralternative radiosurgery any significant effect ontumor mass ( the GRApegvisomantnormalizesIGF-Ilevelswithout in controllingGHsecretionandtumorsize,whereas and second-generation(pasireotide)SSAsareeffective generation (i.e.octreotideLARandlanreotideautogel) selected casesasafirstlineoftreatment( or in in patientswith persistent disease after surgery receptor antagonists(GRAs).Theseareusuallyprescribed of eitherlong-actingsomatostatinanalogs(SSAs)orGH visual impairment( tumors orthosewithneurologicalcomplications,suchas treatment, especiallyinsubjectsharboringfullyresectable Transsphenoidal isconsideredthefirstlineof surgery disease. Altogether, theseleadtoadecreaseinmortality. 109 5 ). However, itisunclearwhetherthedecreaseinbone Review Medical treatmentisbasedupontheadministration ). Thesemaybetheresultof permanent orirreversible 81 ). Furtherfindingstosupporttheconceptthat t al et 67 ). . reporteddecreasedosteoblast 108 G Mazziottiandothers ) andalteredtissue- 105 67 74 ). Stereotactic ). , 106 67 ). First- , 107 ). pre-existing (i.e.,prevalent)VFsareidentified( present ( acromegaly ( why fractureriskpersistsinsomepatientswithcured The persistentabnormalitiesinbonestructureexplain Effects ofacromegalytherapyonfracturerisk phosphate metabolismonskeletalfunctionisunknown. D excretion andinhibitsrenalsynthesisofdihydroxyvitamin a phosphaturicfactorthatpromotesrenalphosphate risk ( for the diagnosis of osteoporosis and prediction of fracture spine, totalhipandfemoralneckbyDXAisthemainstay In clinicalpractice,measurementofBMDatthelumbar Diagnosis ofosteopathyinacromegaly acromegaly-induced skeletalfragility Proposed approachtosubjectswith underlying disease. effects ofthedrugsfromthoseonactivity since thedesigndidnotallowtodiscriminateskeletal However, the results of these studies were inconclusive pegvisomant onfractureriskinacromegaly( some studiesinvestigatedthepossibleeffectsofSSAsand to changesinserumfibroblastgrowthfactor-23( the biochemicalcontrolofacromegalywasnotrelated ( of hypercalciuria increaseinserumPTH andsecondary serum calciumandphosphoruswiththenormalization accompanied by a significant and rapid decrease in of subjectsexposed to GHexcess have decreased BMD, excess ( be influencedbythebone enlargementcausedbyGH measured atthelumbarspine ( hypertrophy mayleadtoanoverestimationofBMD characterized byosteophyteformationandfacet-joint are notcapturedbyBMD.Degenerativejointalterations, microarchitecture associatedwithGHhypersecretion validated inacromegaly, whereabnormalities of bone the biochemical control of the disease ( have directeffectsonperipheraltargetsindependent of on thehypothesisthatdrugsusedinacromegalymay marker ofskeletalfragilityinacromegaly( latter findingisconsistentwiththeconceptthatVFsarea Bone andacromegaly 72 3 ( , The biochemicalcontrolofacromegalyisusually 113 110 122 123 ). Theimpactofthealterationsincalciumand , 7 ). Unfortunatly, thisapproachhasnotbeen , 111 114 ). Becauseofthesereasons, a limitednumber 7 ). Thedecreaseinserumphosphateafter , ), diabetesmellituscoexists( 8 ), particularly, whenhypogonadismis Downloaded fromBioscientifica.com at09/26/202110:40:08AM 5 ). Moreover, BMDcould 181 :2 116 118 115 , , 117 119 114 ) orwhen 7 , ). Based 8 , , ). The R50 121 120 112 via freeaccess ). ), ), European Journal of Endocrinology describing theshapeand heights ofvertebralbodies. ( applied toimagesofthespine acquiredeitherbyDXA ( isperformedonspinalX-rayimages morphometry depending on the risk profile at baseline. Quantitative months) 18 and duringtheirfollow-up(i.e.,every all subjectswithacromegalyatthetimeofdiagnosis the presenceofVFsbyamorphometricapproach in are all compelling reasons for a direct evaluation for diabetes mellitus( hypersecretion ( with acromegalicosteopathy. valuable intheassessmentandmanagementofindividuals non-invasive 3D-SHAPERandTBSassessmentscouldbe with acromegaly and VFs ( to fractures( low TBSvalueindicatesimpairedstructurethatisproned value reflectsbettertrabecularbonestructure,whereasa pixel gray-levelvariationsintheDXAimage.AhighTBS lumbar spineDXAimage.TBScapturesthemeanrateof level texturalmetricthatcanbeextractedfromthe2D using DXAimagesisthemeasurementofTBS,agray- simple andfeasibleapproachtoassessbonestructure VFs comparedtothosewithoutfractures( BMD at the proximal femur in acromegalic subjects with approach demonstratedadecreaseincorticalvolumetric proximal femur( layer independentofthetrabecularmacrostructureat 3D-SHAPER wasdevelopedtoanalyzethecorticalbone bone structureassessmentusingDXAimagestermed skeletal fragilityandpredisposedtoVFs.Anon-invasive the clinicianinidentification ofacromegalicswith are morefeasiblediagnostictechniquesthatmayassist dose limit their use in clinical practice. However, there HR-QCT ( with GHhypersecretionandVFsmaybeprovidedby evaluation ofbonemicrostructuralalterationsassociated identifying individuals withosteoporosis. A moreaccurate part duetoalackofspecificandstandardizedcut-offsfor value ofthisfindinginpredictingVFriskisunknown, reported tobedecreasedinacromegaly( by changesinthesizeofbones.Volumetric BMDwas independent fromthecorticalboneandisnotinfluenced determine thebonedensityoftrabecularcompartment VFs eveninthepresenceofnormalBMD( in acromegaly( and bone densityisnot a reliable predictor of fracture risk 130 129 Review The highincidenceoffracturesrelatedtoGH Volumetric BMDmeasuredbyQCTisusedto ) orbychestX-rays( ), althoughaquantitative approachmayalsobe 83 , 87 128 6 ), butthehighcostandincreasedradiation ). Subjectswithacromegalymaydevelop ). LowTBSvaluesarefoundinsubjects 126 6 ), untreatedhypogonadism( 115 ) andlumbarvertebrae( ) andpre-existingVFs( 99 85 , ). Based on this knowledge, 131 G Mazziottiandothers ). VFsareidentifiedby 124 90 , 85 125 , 91 ). Another 127 ), butthe , 95 ). This 7 ). , 7 8 ), ), ) However, somerecommendationsbasedontheexperience of acromegalic osteopathy cannotbeevidencebased. specific guidelineshavebeendeveloped.Thetreatment safety ofbone-activedrugsinacromegaly;therefore, no No studieshavebeenperformedontheeffectivenessand Treatment ofosteopathyinacromegaly bearing joints( of acromegaly, affectingbothweight-andnon-weight- of the most prevalent and invalidating complications bodies causedbyarthropathy( the presenceofosteophytesanddeformitiesvertebral when theyinvolvetheupperthoracicvertebrae,dueto mild VFsinacromegalymaybechallengingparticularly 40%, respectively( a height ratio decrease of 20–25%, 25–40% and over VFs aredefinedasmild,moderateandseverebasedon According toaquantitativemorphometricapproach, by summing the score of each individual fracture ( is ancompositemeasureofthegradeVFscalculated subjects withahigherspinedeformityindex( acromegaly with two ormore prevalent VFs ( inindividualswithcontrolled/cured has beenobserved of theunderlyingacromegaly. Infact,progressionofVFs or moderate-severepre-existingVFs,regardlessofthestate therapy may be considered in subjects with either multiple a few longitudinal studies on VFs ( subsequent therapeuticapproach.Basedontheresultsof of individuals with VFs may offer guidance on the treatment with bone-active drugs? The earlyidentification studies canbeconsidered. of onetheco-authors(GM)andresultsrecentclinical longitudinal studies ( skeletal exposuretoGHexcess. Basedontheresultsfrom tothe continued an effort to preventfractures secondary without VFsbutwithpersistently activeacromegalyin targeted therapy may also be considered in individuals hypogonadism ( coexistent riskfactorsforfractures,suchasuntreated therapeutic decision making, particularly in males with with skeletalfragility( in theidentificationofvertebraldeformitiesassociated tools, suchasTBSor3D-SHAPERDXAmayassistclinicians the analysis of bone structure by non-invasive diagnostic fractures in thepresence of arthropathy. Inthese cases, value andthepotentialpitfallsindiagnosisofthese VFs ismoreuncertain,becauseoftheirlowerpredictive The managementofacromegalicsubjectswithsinglemild Bone andacromegaly The fundamental question is who may benefit from a 132 7 ) anddiabetesmellitus( ). 89 7 , 85 ). Noteworthy, thediagnosisof 121 Downloaded fromBioscientifica.com at09/26/202110:40:08AM ). This could serve asaguidefor ). Thiscouldserve ), it may be reasonable to start Fig. 2 https://eje.bioscientifica.com 7 , ). Arthropathyisone 181 8 ), anti-osteoporotic :2 8 ) and in those 115 7 ). Bone- ), which R51 133 via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com The authorthanksMaryYurczakfor secretarialassistance. Acknowledgements the public,commercialornot-for-profit sector. This research did not receive any specific grant from any funding agency in Funding nothing todeclare. has C E Pharma; Novartis and Pfizer SPA, Ipsen from honoraria speaker speaker honorariafromEliLilly;AGLreceivedresearchgrantsand G M received consultant fees from Ipsen SPA and Novartis Farmaand Declaration ofinterest bone-active drugsinthisclinicalsetting. acromegaly andtoevaluatetheeffectivenesssafety of determinants ofskeletalfragilityinactiveandcontrolled risk of mortality. Studies are needed to identify the functionaswellanincreased life andcardio-respiratory due tothepotentialnegativeimpactofVFsonquality awareness ofthiscomplicationacromegalyisnecessary subjects withcontrolled/curedacromegaly. Clinical architecture andtherisk ofVFspersistseveninselected of acromegalyimprovesbutdoesnotrestoreskeletal toward hypercalcemia and hypercalciuria. Treatment accompanied bymildhyperphosphatemiaandatendency risk ofVFs.Theseskeletalabnormalitiesareusually abnormalities intrabecularbonestructureandhigh characterized byincreasedboneturnover, profound Osteopathy isanemergingcomplicationofacromegaly, Conclusions additional fractures. restore the trabecular bone microstructure and prevent enhanced ( control ofacromegalyandwhenboneremodelingisnot However, whenVFsprogressdespitethebiochemical remodeling andonthesynthesisofIGF-Ibyskeleton. effects on bone not be effective, due to their stimulatory Anabolic therapywithteriparatideorabaloparatidemight the effects of GH and IGF-I excess on bone remodeling. such asdenosumabandbisphosphonates,maycounteract inhibitors of osteoclastogenesis and bone resorption, setting. Basedonpathophysiologicalconsiderations, performed totesttheirefficacyandsafetyinthisclinical is anotherchallenge,sincenostudieshavebeen multimodal therapyforoneyearorlonger. factures whenacromegalyispersistentlyactivedespite anti-osteoporotic drugsinpatientswithoutprevalent Review The choiceofbone-activedrugstouseinacromegaly 6 , 72 ), anabolictherapymaybeconsideredto G Mazziottiandothers

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Accepted 15May2019 Revised versionreceived1May2019 Received 13March2019 126 125 124 123 122 133 132 131 130 129 128 127 121 Bone andacromegaly Humbert L, Martelli Y, Fonolla R,Steghofer M,DiGregorio S, Valassi E, Crespo I,Malouf J,Vilades D, Leta R,Llauger J,Urgell E, Battista C, Chiodini I,Muscarella S,Guglielmi G,Mascia ML, Ueland T, Fougner SL,Godang K,Schreiner T&Bollerslev J.Serum Schousboe JT, Shepherd JA,Bilezikian JP&Baim S.Executive Crans GG, Genant HK&Krege JH.Prognosticutilityofa Claessen KM, Mazziotti G,Biermasz NR&Giustina A.Boneandjoint Torti C, Mazziotti G,Soldini PA, Foca E,Maroldi R,Gotti D,Carosi G Clark EM, Carter L,Gould VC,Morrison L&Tobias JH. Vertebral Mazziotti G, Maffezzoni F, Frara S&Giustina A.Acromegalic Ulivieri FM, Silva BC,Sardanelli F, Hans D,Bilezikian JP& Lopez Picazo M,MagallonBaro A,DelRioBarquero LM,Di Chiloiro S, Mazziotti G,Giampietro A,Bianchi A,Frara S, org/10.1007/s12020-016-0945-2) bone scoreinacromegaly. predictor ofspinevolumetricbonemineraldensityandtrabecular Aulinas A, Marin AM,Biagetti B 2265.2008.03322.x) Endocrinology mass inacromegalicpatients:alongitudinalstudy. Carnevale V &Scillitani A.Spinalvolumetrictrabecularbone 2006 more than70consecutivepatients. bone mineraldensityinactiveacromegaly:aprospectivestudyof GH andIGF-Iaresignificantdeterminantsofboneturnoverbutnot jocd.2013.08.004) Clinical Densitometry Position DevelopmentConferenceonbonedensitometry. ofthe2013InternationalSocietyforClinicalDensitometry summary 302–308. (https://doi.org/10.1016/j.bone.2005.04.003) semiquantitative spinaldeformityindex. doi.org/10.1159/000375450) disorders inacromegaly. org/10.1007/s12020-011-9586-7) in HIV-infected males. & Giustina A.Highprevalenceofradiologicalvertebralfractures org/10.1007/s00198-013-2567-3) screening. care orprimary effective whenusedaspartoffractureliaisonservices fracture assessment(VFA) bylateralDXAscanningmaybecost- s11102-016-0758-6) osteopathy. s12020-014-0280-4) osteoporosis. Caudarella R. Utilityofthetrabecularbonescore(TBS)insecondary TMI.2018.2845909) Medical Imaging assessment ofcorticalandtrabecularbone. the lumbarspineFromasingleanteroposteriorDXAimageincluding & Humbert L.3-Dsubject-specificshapeanddensityestimationof Gregorio S, Martelli Y, Romera J,Steghofer M,GonzalezBallester MA doi.org/10.1109/TMI.2016.2593346) images. shape, thetrabecularmacrostructureandcortexin3DfromDXA Malouf J, Romera J&Barquero LM.3D-DXA:assessingthefemoral vertebral fracturesinpatientswithacromegaly. pegvisomant andsomatostatinreceptorligandsonincidenceof Giustina A&DeMarinis L.Effectsof Mormando M, Pontecorvi A, 155 IEEE Transactions onMedicalImaging 709–715. (https://doi.org/10.1007/s11102-018-0873-7) Osteoporosis International Pituitary 2009 Endocrine 2018 70 (https://doi.org/10.1530/eje.1.02285) 2017 2013 37 378–382. 2014 Endocrine 2651–2662. Neuroendocrinology 20 16 Endocrine Downloaded fromBioscientifica.com at09/26/202110:40:08AM 47 63–69. 455–466. 435–448. 2012 et al. (https://doi.org/10.1111/j.1365- 2014 2016 European Journal ofEndocrinology European Journal (https://doi.org/10.1007/ Epicardialfatisanegative (https://doi.org/10.1109/ 41 (https://doi.org/10.1016/j. 512–517. 25 Bone 53 (https://doi.org/10.1007/ 2016 181 IEEE Transactions on 953–964. 2017 860–864. 2005 :2 Pituitary 103 36 (https://doi. Clinical 37 27–39. 86–95. (https://doi. (https://doi. 175–179. 2018 Journal of Journal (https:// (https:// 21 R56 via freeaccess