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age,cone-shapedepiphyses, thickskin,and heartdisease. WMS is transmitted eitherby an
autosomaldominantoranautosomalrecessive,GDbyanautosomalrecessive,andADbyan
autosomaldominantmodeofinheritance.
37
TheskeletalfeaturesofWMSaretheoppositeofthosefoundinMarfansyndrome.Patients
(OMIM #608328) display short stature, brachydactyly (short and stubby hands and feet),
hypermuscularity,andjointstiffness.However,ectopialentisistypicalofbothsyndromes.
38,39
SyndromesofPTHResistance:Pseudohypoparathyroidism
Brachydactyly of feetand ectopic subcutaneousossificationsare well-described features of
pseudohypoparathyroidism(PHP).
In patients with PHP, failure of target tissues to respond appropriately to the biologic
actions of parathyroid hormone (PTH), which is elevated, leads to functional
hypoparathyroidism.
The signs and symptoms are principally manifestations of a reduced concentration of
ionizedextracellularcalcium.Hypocalcemiacausestetany,whichisincreasedneuromuscular
irritabilitymanifestedasparesthesiasinthedistalextremitiesandface,musclecramps,and,if
severe,laryngospasm,seizures,orreversible heartfailure.Otherclinicalfeatures ofchronic
hypocalcemia include increased intracranial pressure, dry and rough skin,
spondyloarthropathy, cataracts, and calcification of the basal ganglia that may rarely cause
extrapyramidalneurologicdysfunction.HypocalcemiacancauseQTprolongationonanEKG.
Patientscanadaptto chronic hypocalcemia, andoccasionallyasymptomaticpatientswill be
diagnosedonlyafteralowserumcalciumisdetectedafterroutinebloodscreening.
40
PseudohypoparathyroidismType1
ThebluntednephrogenouscAMPresponsetoPTHinsubjectswithPHPtype1iscausedbya
deficiencyofGsα,thesignalingproteinthatcouplesPTH1Rtostimulationofadenylylcyclase.
TherearetwoformsofPHPtype1:generalizeddeficiencyofGsα,becauseofmutationsofthe
GNAS gene, are classified as PHP type 1a (PHP 1a; OMIM #103580), whereas more
restricted deficiency of Gsα, because of mutations that affect imprinting of GNAS, are
classifiedasPHPtype1b(PHP1b;OMIM#603233).PHPtype1cislikelyavariantofPHP
1a.
Pseudohypoparathyroidism1a
PHP1aisthemostcommonvariantandreadilyrecognizedduetoaconstellationofclinical
features termed Albright hereditaryosteodystrophy (AHO) thatincludes shortstature,round
facies, brachydactyly of hands and/or feet, and/or mental retardation, ectopic subcutaneous
ossifications,andobesity.
41,42
PHP1aresultsfromheterozygousmutationsonthematernalalleleoftheimprintedGNAS
genethatreduceexpressionorfunctionoftheGsαprotein.Thesepatientsalsohaveresistance
to other hormones (e.g., thyroid-stimulating hormone [TSH], gonadotropins, calcitonin, and
GH-releasing hormone). Primary hypothyroidism without goiter and GH deficiency are
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common.
43–46
Patients with paternally inherited GNAS mutations have phenotypic features of AHO
withouthormonalresistance,aconditiontermedpseudopseudohypoparathyroidism(PPHP).
47
Pseudohypoparathyroidism1b
PatientswithPHP1blacktypicalfeaturesofAHObutmaystillhavemildbrachydactyly.PTH
resistanceistheprincipalmanifestationbutsomepatientshavemildTSHresistance.
48,49
HYPOPARATHYROIDISM-RETARDATIONDYSMORPHISMSYNDROME
The hypoparathyroidism-retardation-dysmorphism syndrome (HRD, MIM #241410), also
known as the Sanjad–Sakati syndrome, is a rare form of autosomal recessive
hypoparathyroidism due tomutationsintheTBCEgeneencoding aproteinrequired for the
foldingoftubulin.Inadditiontoparathyroiddysgenesis,affectedpatientshaveseveregrowth
and mental retardation, microcephaly, microphthalmia, small hands and feet, and abnormal
teeth.ThisdisorderisfoundalmostexclusivelyinindividualsofArabdescent.
PHP or PPHP may be suspectedin patients whopresent with somatic features ofAHO.
However, several aspects of AHO, such as obesity, round face, brachydactyly, and mental
retardation, also occur in other congenital disorders (e.g., Prader–Willi syndrome,
acrodysostosis,Ullrich–Turnersyndrome).
HYPERPHOSPHATEMIA/TUMORALCALCINOSIS
Soft tissue calcifications mayalso be a consequences of chronic hyperphosphatemia. In the
settingofchronickidneydisease(CKD),hyperphosphatemiapromotesmineral depositionin
softtissuesbecauseitstimulatesvascularcellstoundergoosteogenicdifferentiation.Medial
calcification of peripheral arteries associated with hyperphosphatemia may lead to
calciphylaxis,adisorderwithhighmortalityandmorbidity.
HyperphosphatemicFamilialTumoralCalcinosis
Hyperphosphatemicfamilialtumoralcalcinosis(MIM#211900)isarareautosomalrecessive
metabolic disorder notable for progressive deposition of calcium phosphate crystals in
periarticular spaces and soft tissues. The biochemical hallmark of this condition is
hyperphosphatemiaduetoincreasedrenal tubularreabsorptionofphosphate;however,there
arenormophosphatemicforms(MIM#610455).MutationsarefoundinGALNT3,FGF23,and
KLOTHO.Themutationsleadtolossoffunction,resultingininadequateFGF23proteinlevels
orFGF23action.
50–52
Themajorityofpatientshavethosemanifestationspresentbyage20.
Patientswithfamilialtumoralcalcinosishaveheterotopiccalcificationsthataretypically
painless and slow growing, butmay reachthe size of an orange;however,the masses can
becomepainful iftheyinfiltrateinto adjacentstructures. Largecalcified tophus-likenodules
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maybenotedaround the jointsofthetoes andthemalleolus.However,themost frequently
affectedjointsarehips,elbows,shoulders,andscapulae.
53
The clinical complications are related to the infiltration of skin, marrow, teeth, blood
vessels,andnerves.Rangeofmotionisgenerallynotaffectedunlessthemassesbecomelarge.
Avariablypresentfeatureofthediseaseisanabnormalityindentition.Biochemically,thereis
also increased 1,25(OH)2D3with normal calcium andalkalinephosphatase levels. Urinary
phosphateexcretionisfrequentlylow.Radiographsshowlargeaggregatesofirregularlydense
calcifiedlobuleslocatedinregionsknowntobeoccupiedbybursae.
Morefrequently,heterotypiccalcificationisassociatedwithCKD–mineralbonedisorder
(MBD).ThepandemicofCKDandend-stagerenaldiseaseandtheroleoftheCKD–MBDin
the associated mortality make the syndrome a major public health issue. The skeletal
remodeling disorders caused by CKD contribute directly to the heterotopic mineralization,
especially vascular calcification, and the disordered mineral metabolism that accompany
CKD.
54,55
Most softtissue calcificationsare attributedtotheincreased calcium phosphate product
due to renal osteodystrophy and excess bone resorption. The syndrome of calciphylaxis is
characterizedbyvascularcalcificationsinthetunicamediaofperipheralarteriesthatinduce
painful violaceous skin lesions, which progress to ischemic necrosis. This syndrome is
associatedwithseriouscomplicationsandhighmortality.
Tumoral calcinosis is a form of soft tissue calcification that involves the periarticular
tissues. Calcium deposits may grow to enormous size and interfere with the function of
adjacentjointsandorgans.
Othercommonskeletalsymptomsthesepatientsreportisslowlyprogressivebonepainthat
maybe diffuse orlocalizedwithtenderness to local pressureand is aggravated byweightbearing.Occasionally,itmaymimicarthritis.
FIBRODYSPLASIAOSSIFICANSPROGRESSIVA
Fibrodysplasia ossificansprogressiva (FOP:MIM #135100) is a rare heritable disorder of
connectivetissuecharacterizedbycongenitalmalformationsofthegreattoesandprogressive
heterotopicendochondralossification(HEO)incharacteristicanatomicpatterns.
56,57
FOP,firstdescribedin1692,hasmorethan800casesreportedandisamongtherarestof
humanafflictions,withanestimatedincidenceof1per2,000,000individuals.Allracesare
affected.Autosomaldominanttransmissionwithvariableexpressionandcompletepenetrance
isestablished58;however,reproductivefitnessislowandmostcasesaresporadic. Gonadal
mosaicismhasalsobeendescribed.
59
Malformationsofthegreattoesarepresentatbirthinallclassicallyaffectedindividuals.
Typically,episodesofsofttissue swelling (flare-ups)leadingtoHEObeginduring thefirst
decadeoflife.
60,61
Thesepatientsbecomeimmobilizedbythethirddecadeoftheirlife.
PAGETDISEASEOFTHEBONE
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ThesecondmostcommonbonediseaseafterosteoporosisisPagetdiseaseofthebonewhere
thefeetareonlyrarelyaffected;however,anklearthritismaydevelopadjacenttopareticbone.
This is a localizeddisorder ofbone remodeling due toincreased osteoclast-mediated bone
resorptionandsubsequentcompensatoryincreasedbornformation,resultinginadisorganized
mosaicofwovenandlamellarboneataffectedskeletalsites.Theaffectedboneisexpandedin
size, vascular and susceptible to deformity and fractures.62 Although most patients are
asymptomatic,someexperiencebonepain,arthritis,deformities,andfractures.
Thepathophysiologyisnotfullyelucidatedbutappearstobebecauseofacombinationof
genetic and environmental factors. Paget disease occurs commonly in families and can be
transmitted vertically in an autosomal dominant pattern. Fifteen percent to 30% of Paget
disease patients have positive family histories of the disorder,
63–65
and the risk of a first-
degreerelative developing theconditionisseventimes greaterthan forsomeonewithout an
affectedrelative.66MultiplegeneticlocihavebeenlinkedtofamilialPagetdisease,andthree
genes have been identified. Mutations in SQSTM1 occur in 30% of patients with familial
disease.
67
ThereisarestrictedgeographicdistributionfortheoccurrenceofPagetdisease:Itismost
common inEurope,NorthAmerica, Australia,andNew ZealandinpersonsofAnglo-Saxon
descent and is extremely uncommon in Asia, Africa, and Scandinavia. Both genders are
affected,withaslightmalepredominance,andpresentsafterage40andmostcommonlyafter
age50.
Patients have elevated serum total alkalinephosphatase as well as other bone turnover
markers (serum C-terminal telopeptide of collagen [CTX], urine N-terminal telopeptide of
collagen [NTX], serum procollagen type 1 N-terminal propeptide [P1NP], serum bone-
specificalkalinephosphatase).
68
Pagetdiseasemaybemonostoticorpolyostoticandoftenasymmetric.Thehandsandfeet
are rarelyaffected. Themostcommon sites ofinvolvement includethepelvis, femur,spine,
skull,andtibiaandlesscommonlythehumerus,clavicle,scapula,ribs,andfacialbones.Most
patients are asymptomatic, and the diagnosis often follows an incidentally noted elevated
serum alkaline phosphatase (SAP) or when a radiograph taken for an unrelated problem
reveals typical skeletal changes. Symptoms include bone pain from a site of pagetic
involvement, either at rest or with motion, an unpleasant sensation of warmth, a bowing
deformityofthefemurortibiawithgaitabnormalitiesthat canleadtoabnormalmechanical
stresses,andseveresecondaryarthritisatjointsadjacenttopageticbone(e.g.,thehip,knee,or
ankle). Patients may also complainof backpainfrom enlargedpagetic vertebrae, vertebral
compressionfractures or spinal stenosis, andkyphosis. Skull-relatedmanifestations include
increase inhead size with or without frontal bossing or deformity, headache,hearing loss,
facial deformity, and dental problems. Fractures and malignant transformation may occur;
however,theyarenotafeatureofthefootlesions.
Bone scans are the most sensitive means of identifying possible pagetic sites, but are
nonspecific,and alsocanbepositiveinnonpageticareas thathavedegenerative changesor,
more ominously, metastatic disease. Plainradiographsof bonesnotedtobe positive on the
bone scanprovide themost specific information, because radiographic findingsare usually
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characteristictothepointofbeingpathognomonic.Enlargementorexpansionofbone,cortical
thickening,coarseningoftrabecularmarkings,andtypicallyticandscleroticchangesmaybe
found.Radiographsalsoshowtheconditionofthejointsadjacenttoinvolved sites,identify
fissure fractures, indicate the degree to which lytic or sclerotic lesions predominate, and
demonstratethepresenceorabsenceofdeformityorfracture.
HYPOPHOSPHATASIA
HPP is the rare heritable rickets or osteomalacia (OMIM #146300, #241500, #241510)
69
characterized biochemically by subnormal activity of the tissue-nonspecific isoenzyme of
alkalinephosphatase(TNSALP).
70,71
AlthoughTNSALPisnormallypresentinalltissues,HPP
disturbspredominantlytheskeletonandteeth.Muscleweaknessisoftenanimportantfinding.
Approximately350cases havebeen reported,showingaremarkable range ofseverity with
fouroverlapping clinical forms described according to patientagewhen skeletal disease is
discovered: perinatal, infantile, childhood, and adult. Odonto-HPP features dental
manifestationsonly.Generally,theearliertheskeletalproblems,themoreseveretheclinical
course.PerinatalandinfantileHPPare verysevere forms with highmortalityifthey remain
untreated.
Interestingly,theadultformofHPPmaypresentwithrecurrent footfractures. AdultHPP
usually presents during middle age, often with poorly healing, recurrent, metatarsal stress
fractures.72 Fractures can mend spontaneously, but healing may be delayed, including after
osteotomy. Patients may recall rickets and/or premature loss of deciduous teeth during
childhood. Chondrocalcinosis, pseudogout, and pyrophosphate arthropathy from calcium
pyrophosphate dihydrate crystal deposition mayoccur.70 Radiographscan show osteopenia,
metatarsalstressfractures,chondrocalcinosis,andsubtrochantericfemoralpseudofractures.
HPP rickets/osteomalacia isremarkablebecauseserumlevels ofcalciumandPi are not
reduced,andALPactivityislow,nothigh.71InchildhoodandadultHPP,approximately50%
of patients are hyperphosphatemic because of enhanced renal reclamation of Pi (increased
TmP/GFR[theratioofthemaximumrateoftubularphosphatereabsorptiontotheglomerular
filtrationrate]).
70,71
Three phosphocompounds accumulate endogenously in HPP: phosphoethanolamine,
inorganic pyrophosphate (PPi), and pyridoxal 5′-phosphate (PLP). PPi assay is a research
technique. If vitamin B6 is not supplemented, elevated plasma PLP is an especially good
markerforHPP.Theworsethehypophosphatasemia(lowserumALPactivity),thegreaterthe
plasmaPLP,andthemoreseveretheclinicalmanifestations.
70,71
Mutation analysis ofTNSALP is available commercially. Approximately280 mutations
(approximately80%missense)havebeenidentified.
73
FOOTFRACTURESINWOMENWITHOSTEOPOROSIS
Osteoporosis is a skeletal disease characterized by low bone mass and microarchitectural
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deteriorationofbonetissuewithaconsequentincreaseinbonefragilityandsusceptibilityto
fracture.74 Clinically, osteoporosis has been difficult to define: A focus on bone mineral
density(BMD)maynotencompassalltheriskfactorsforfracture,whereasafracture-based
definition will not enable identification of at-risk populations. In 1994, the World Health
Organization(WHO)75convenedtoresolvethisissue,definingosteoporosisintermsofBMD
andpreviousfracture.Thus,theWHOdefinitiondoesnottakeintoaccountmicroarchitectural
changesthatmayweakenboneindependentlyofanyeffectonBMD.Morerecently,therehas
beenamovetowardassessmentofindividualizedrisk,76withthedevelopmentoftheFRAX
algorithm,77 a Web-based tool that uses clinical risk factors and/or BMD to calculate an
individual’sabsoluteriskofmajorosteoporoticorhipfractureoverthenext10years.Thishas
theadvantageofincorporatingriskfactorsthatarepartlyindependentofBMD,suchasageand
previousfracture,andthusallows decisionsregardingcommencementoftherapytobemade
morereadily.Osteoporosis-relatedfractureshaveahugeimpacteconomically,inadditionto
theireffectonhealth:ThecosttotheU.S.economyisaround$17.9billionperannum,withthe
burdenintheU.K.being£1.7billion78mostlybecauseofhipfracturesthatcontributemostto
thesefigures.Thus,earlydiagnosisbasedonreasonablesuspicionleadingtodiagnostictesting
isparamount.
The 2004 report from the U.S. Surgeon General highlighted the enormous burden of
osteoporosis-relatedfractures.79Anestimated10millionAmericansover50yearsoldhave
osteoporosis,andthereareabout1.5millionfragilityfractureseachyear.Another34million
Americans are at risk of the disease. A study of British fracture occurrence indicates that
populationriskissimilarintheUK.80Thus,one intwo women aged50 yearswillhavean
osteoporosis-relatedfractureintheirremaininglifetime;thefigureformenisoneinfive.
Osteoporosis is a common disease especially amongpostmenopausal women and aging
men.Aftertheoccurrenceofthefirstfracture,osteoporosisisnolongera“silent”disease,and
thepatient’sriskforfuturefractureisincreasedseveralfold.
However,thereareconflictingdataconcerningwhether footfractures such as metatarsal
fracturesareassociatedwithlowBMDandthusmightbesentinelfractureevents.
TheMultipleOutcomesofRaloxifeneEvaluation(MORE)trial wasafractureoutcomes
study of postmenopausal women with osteoporosis. The location of first fractures among
womenwithosteoporosisandnopreviousfracturesatbaselinewasassessedafter3yearsof
follow-upintheplacebogroup.Patientswere atleast2yearspostmenopausalandupto80
years of age (95% Caucasian), without severe or long-term disabling conditions, and had
osteoporosisdefinedasfemoralneckorlumbarspineBMDT-scorebelow−2.5basedonthe
densitometer manufacturer’s databases. The assessment included fractures of the ankle,
calcaneus, tarsus, and metatarsus. Apart from the common and expected sites of fragility
fracturessuch as vertebral andradiusfractures,asmall number ofwomenexperienced foot
fracturesasinitialfractures,includingankle(0.6%)andmetatarsal(0.6%)fractures.Fractures
oftheankleandmetatarsaleachaccountedfor4%to6%ofallfractures.Nofracturesofthe
calcaneusortarsuswerereported.
81
Some studies have shownthat patientswith metatarsal fracture are at increased risk of
osteoporosisatthe spine,
82,83
whereas others haveconcludedthat footfractures are largely
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independentofspineBMD.
84
Retrospectivelyanalyzed data on68 postmenopausal womenconcluded thatlow trauma
metatarsal fracture is not a risk factor for low calcaneal (peripheral) BMD.85 This was in
agreement with a large longitudinal study,84 which did not show that foot fractures had a
statisticallysignificantassociationwithlumbarspineorcalcanealBMD,andhadonlyaweak
associationwithdistalradiusBMD.
A smaller cross-sectional study82 showed that the prevalence of spinal osteoporosis in
patients suffering from metatarsal fractures was similar tothatinpatientswhohad suffered
wristfracturesandgreaterthanthatoftheircontrolgroup.Thesedifferencesmaybeexplained
bydifferencesinpatientpopulation(e.g.,age,BMI),siteofbonedensityassessment(axialas
opposedtoperipheralmeasurement),orstudydesign(longitudinalvs.cross-sectional).
Tomczak et al. examined 21 patients (15 women and 6 men) who presented with
unexplainedmetatarsalfractures.Twentyofthe21hadbonedensitiessignificantlybelowthe
meanforcorrespondingage,gender, andrace. The averagebonedensity forthe 21 patients
was2.1standarddeviations(T−2.1)belowtheexpectedmeanforthecorresponding30-yearold referencepopulationand 1.7 standard deviations (z−1.7) below the mean for an age-,
gender-, weight-, and ethnicity-matched population. The authors conclude that there is a
previously unreported correlation between metatarsal insufficiency fractures and low bone
massinbothgenders,confirmedbytheabnormalBMDtesting.
FOOTSTRESSFRACTURES
Overuseinjuriesinathleteshaveaprevalenceof76%.86Thelowerlimbaccountsfor80%to
95%ofstressfractures.87Thereisincreasingparticipationinendurancesportsandmarathon
running,andtheincidenceofstressfracturesinrunnersis21%andhigherinarmyrecruitsat
31%.
88–91
Therefore,identifyingstressfracturesthatarepronetodelayedunionornonunion,suchas
whentheyareassociatedwithreducedBMD,isessential.
83,92
Postmenopausal women are particularly at risk of stress fractures. Also a worldwide
estimatesuggeststhat1billionpeoplearevitaminDdeficient,whichmaybeariskfactorfor
stress fracture occurrence.93 Therefore, it is essential to appropriately differentiate stress
fracturesthat resultfromreducedBMD or vitaminDdeficiencyandthosethatare proneto
nonunionduetotheanatomicalsite.
94
Thiswillguideavoidover-orundertreatingthiscondition.
With an aging population and an increase in exercising participants who are aged >50
years,
88,89
therewillbeanincreasedprevalenceofosteoporoticstressfracturesinthefoot.
83
The assessment of BMD in females is essential to avoid missing underlying causative
pathology. In a patient cohort,83 remarkably 95% of patients had underlying osteopenia or
osteoporosis.Bothprospectiveandretrospectivestudieshaveshownthatgenderisnotarisk
factor in musculoskeletal injuries, except for stress fractures, where female sex is a risk
factor.
95,96
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The increase in stress fracturesinfemales is multifactorial. The presenceof the female
athletetriadoranyofitscomponentsincreasestheathletes’riskofstressfracture.Research
hasfoundthatBMD,menstrualirregularityorabsenceofmenses,andinadequatenutritionand
thusdeficitsofenergyintake,knowntogetherasthefemaletriad,all increasestressfracture
risk.Inaddition,lowbodymassindexandincreasingageallraiseawomen’sriskofsuffering
astressfracture.
In a cohort-controlled study spanning premenopausal ages ranging from 18 to 45 years
matchedforage,sport,andweeklytrainingvolume,thestressfracturegrouphadsignificantly
lesstrabecularBMDandcorticalarea.97Severalotherstudieshavenotfoundalinkbetween
BMD and stress fractures in premenopausal women.
98–101
Postmenopausal women may be
morepronetostressfracturesasaresultofreducedBMD.
102
Tenfordeetal.
103
foundlatemenarchein748highschoolrunners(age>15years)tobean
independentriskfactorforstressfractures.Menstrualhistoryshouldbeobtainedinallwomen,
andhormonalandstructuralabnormalitiesthatmaycausesecondaryamenorrhea(absenceof
mensesfor>6months)shouldbefurtherinvestigated.
Inadequateintakeofcalcium and vitaminD, or inadequatecaloric intake, is associated
withreducedbonemass.
104
Decreasedbonemassincreasesthestrainontheremainingbone,
increasingthefatiguefracturerisk.
Duckham etal.
105
foundthatnutritionalpsychopathologyis associatedwith anincreased
risk of stress fractures in endurance athletes, which may be associated with menstrual
dysfunctionandcompulsiveexercise.
Vitamin D is produced by sunlight in the skin and is then converted to theactive form
(1,25-dihydroxycholecalciferol) in the liver and the kidney. Vitamin D increases calcium
absorption in the gastrointestinal tract. A deficiency of vitamin D may lead to secondary
hyperparathyroidism,whichincreasesboneloss andpossiblestressfracture risk.VitaminD
deficiencyisnotuncommoninthegeneralpopulation.
106
Sonnevilleetal.
107
compared dietaryintakeofcalciumandvitaminDagainsttheriskof
stressfractures,andfoundthathighvitaminDintake(ratherthanahighcalciumintake)was
protectiveagainstthedevelopmentofstressfractures.Theauthorsfounda50%reductionin
the incidence ofstressfractures ingirls taking vitaminDwhoparticipatedina high-impact
activity.
Currently,theInstituteofMedicineguidelinessuggestthat600to800InternationalUnitsof
vitaminD is necessaryforadequatebone health inmost adults.Recently, McCabeetal.
108
recommenddosagesupto2,000InternationalUnits,becausevitaminDissafeandhasahigh
therapeutic index and improves training efficiency. Vitamin D status should be routinely
assessedsothatathletescanbecoachedtomaintainserum25(OH)vitaminDconcentrationof
>30ngpermL.
PERIPHERALDXAUSEINCLINICALPRACTICE
A variety of peripheral dual-energy X-ray absorptiometry (DXA [pDXA]) devices are
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1.
2.
3.
4.
available formeasuringthe forearm,heel, orhand.Inprinciple,theseareattractivebecause
they offer a quick, inexpensive, and convenient method of investigating skeletal status. In
practice,however,thesealternativetypesofmeasurementcorrelatepoorlywithcentralDXA,
withcorrelationcoefficientsintheranger=0.5to0.65.
109
Thelackofagreementwithcentral
DXA has proved abarrier to reaching a consensuson howtointerpret results from pDXA
devices
110
;thus,thesearenotrecommendedforuseintheclinicalsetting.
However,notalltypesoffracturesareequallywellpredictedbythestandardaxialBMD
measurements(spineandhip),whicharebestatpredictingfracturesatsitessuchasthehip,
spine,forearm, humerus,andpelvis, and are relativelyineffectiveforfractures ofthe face,
ankles,feet,andtoes.
111
OSTEONECROSIS
Regionalinterruptionofbloodflowtotheskeletoncancauseischemic(asepticoravascular)
necrosis. Ischemia, if sufficiently severe and prolonged, will kill osteoblasts and
chondrocytes.Clinicalproblemswillariseifsubsequentresorptionofnecrotictissueduring
skeletalrepaircompromisesthe bonestrength sufficiently tocause fracture,withsubsequent
deformity of bone and secondary damage to cartilage. It is estimated that there are
approximately15,000newcasesperyearintheUnitedStates.Thediseaseappearstooccur
morefrequentlyinmalesthaninfemales,withtheoverallmaletofemaleratiobeing8:1.The
ageofonsetisvariable,althoughinthemajorityofcases,thepatientislessthan50yearsof
age.Femalecasesareonaverage10yearsolderthanmalecases.
Osteonecrosisisoftenseeninassociationwithanumberofdifferentconditions.Trauma
with fracture, glucocorticoids, and alcoholism predispose to osteonecrosis. Accordingly,
disordersthatincreasethesizeand/ornumberofadipocyteswithincriticalareasofmedullary
space (e.g., alcohol abuse, Cushing syndrome) may ultimately compress sinusoids, thereby
leading to infarction of bone. Other factors potentially involved in the pathogenesis of
osteonecrosis include fat embolization, hemorrhage, and abnormalities in the quality of
susceptiblebonetissue.ThefactorVLeidenmutation(G1691A,Arg506Gln)isacommonrisk
factorforthrombophilia.
The femoral head is the most common location for the development of osteonecrosis,
althoughitmayalsooccuratothersitesincludingdistalfemur,humeralhead,wrist,andfoot.
Patientsmaydeveloppainthatcanpersistforweekstomonthsbeforeradiographsshowany
change,althoughpatientscanbeasymptomatic.
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