Asacalciotropichormone, PTH, is a potent regulator of bone resorption in adults. The PTH/PTHrP receptor is expressed on osteoblasts but not on osteoclasts. Therefore, PTH acts on osteoblasts to increase the expression of osteoblast paracrine factors (i.e., M-CSF, RANKL) that upregulate osteoclast differentiation and bone resorption. 1,25-Dihydroxyvitamin D also stimulates bone resorption by upregulating RANKL expression in osteoblasts.

It is important to recognize that PTH (along with 1,25-dihydroxyvitamin D) will promote bone resorption when PTH levels are high (i.e., during a hypocalcemic challenge). When PTH levels are normal, however, bone remodeling is a locally controlled process by which old damaged bone is replaced. Interestingly, it has been shown that intermittent administration of low-dose PTH promotes osteoblast survival and bone anabolic functions, increases bone density, and reduces the risk of fracture in humans.

The discovery of the RANK/RANKL/OPG system has presented new therapeutic opportunities for treating osteoporosis. A biological antiresorptive drug based on a humanized antibody directed against RANKL is now available for the treatment of postmenopausal osteoporosis. This has proven to be an effective treatment that improves bone density and reduces the risk of fracture.

Figure 40.10C produces a hypocalcemic challenge by decreasing gastrointestinal absorption of Ca++ and Pi. A drop in serum [Ca++] increases compensatory PTH gene expression, PTH secretion, parathyroid cell proliferation, and PTH-mediated upregulation of renal 1-hydroxylase. In the absence of sufficient 25-hydroxyvitamin D precursor, however, 1,25-dihydroxyvitamin D levels fall. The secondary elevation of PTH mobilizes Ca++ from bone and kidney but promotes renal excretion of Pi, causing hypophosphatemia. Because the Ca++ × Pi product in serum is low, bone mineralization is impaired. In children, this leads to rickets, in which the growth of long bones is abnormal and impaired. The rib cage, wrists, and ankles show characteristic bone deformities, and the impaired mineralization causes bowing of the legs. In adults, vitamin D deficiency leads to osteomalacia, which is characterized by poor mineralization of newly formed osteoid, visible on radiographs as pseudofractures. In severe cases, osteomalacia results in weakness, bone pain, and increased risk of fracture.

PTH
1,25(OH)2D3
1,25(OH)2D3
Regulation of Serum Phosphate by FGF23
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