Asacalciotropichormone,PTHisapotentregulatorofboneresorptioninadults.ThePTH/PTHrPreceptorisexpressedonosteoblastsbutnotonosteoclasts.ThereforePTHactsonosteoblaststoincreaseexpressionofosteoblastparacrinefactors(i.e.,M-CSF,RANKL)thatupregulateosteoclastdifferentiationandboneresorption.1,25-DihydroxyvitaminDalsostimulatesboneresorptionbyupregulatingRANKLexpressioninosteoblasts.
ItisimportanttorecognizethatPTH(alongwith1,25-dihydroxyvitaminD)willpromoteboneresorptionwhenPTHlevelsarehigh(i.e.,duringahypocalcemicchallenge).WhenPTHlevelsarenormal,however,boneremodelingisalocallycontrolledprocessbywhicholddamagedboneisreplaced.Interestinglyithasbeenshownthatintermittentadministrationoflow-dosePTHpromotesosteoblastsurvivalandboneanabolicfunctions,increasesbonedensity,andreducestheriskoffractureinhumans.
DiscoveryoftheRANK/RANKL/OPGsystemhaspresentednewtherapeuticopportunitiesfortreatingosteoporosis.AbiologicalantiresorptivedrugbasedonahumanizedantibodydirectedagainstRANKLisnowavailablefortreatmentofpostmenopausalosteoporosis.Thishasproventobeaneffectivetreatmentthatimprovesbonedensityandreducestheriskoffracture.
Fig.40.10C )producesahypocalcemicchallengebydecreasinggastrointestinalabsorptionofCa++ andPi.Adropinserum[Ca++]increasescompensatoryPTH geneexpression,PTHsecretion,parathyroidcellproliferation,andPTH-mediatedupregulationofrenal1-hydroxylase.Intheabsenceofsufficient25-hydroxyvitaminDprecursor,however,1,25-dihydroxyvitaminDlevelsfall.ThesecondaryelevationofPTHmobilizesCa++ fromboneandkidneybutpromotesrenalexcretionofPi,causinghypophosphatemia.BecausetheCa++ × Piproductinserumislow,bonemineralizationisimpaired.Inchildrenthisleadstorickets, inwhichthegrowthoflongbonesisabnormalandimpaired.Theribcage,wrists,andanklesshowcharacteristicbonedeformities,andtheimpairedmineralizationcausesbowingofthelegs.Inadults,vitaminDdeficiencyleadstoosteomalacia, whichischaracterizedbypoormineralizationofnewlyformedosteoid,visibleonradiographsaspseudofractures.Inseverecases,osteomalaciaresultsinweakness,bonepain,andincreasedriskoffracture.
°PTH °1,25(OH)2D3 ˜1,25(OH)2D3
Regulation of Serum Phosphate by FGF23