REFERATE GENERALE

ACTUALITI N GENETICA OSTEOPOROZEI

New insights in the genetics of osteoporosis
Nicoleta Baculescu1, Ctlina Poian1, 2 1 Universitatea de Medicin i Farmacie Carol Davila, Bucureti 2 Institutul Naional de Endocrinologie C.I. Parhon, Bucureti

Rezumat
Osteoporoza primar este o boal comun legat de vrst, caracterizat prin afectarea homeostaziei osoase i risc crescut de fractur. Studiile familiale au artat c variaia densitii minerale osoase (BMD) este condiionat genetic, fractura osteoporotic avnd, de asemenea, o component genetic. Rezultatele studiilor GWAS (genomewide association studies) i meta-analizele acestora publicate n ultimii ani au evideniat o serie de locusuri asociate semnicativ cu BMD, aparinnd cilor RANK-RANKL-OPG i WNT, dar i sistemelor de difereniere a celulelor stem mezenchimale sau de osicare encondral. O parte a locusurilor asociate BMD s-a asociat semnicativ i cu riscul de fractur, ca de exemplu 17q21.31 (SOST), 11q13.2 (LRP5), 10q21.1 (DKK1), 1p36.12 (WNT4) i 7q31.31 (WNT16), spre deosebire de SNP-urile genelor sistemului RANK-RANKL-OPG (TNFRSF11A, TNFSF11, TNFRSF11B), ce au prezentat asocieri doar cu BMD. Aceste date contribuie la o nelegere mai bun a mecanismelor ziopatologice din osteoporoz i la descoperirea unor noi metode terapeutice. Cuvinte cheie: osteoporoz, BMD, riscul de fractur, gene, SNP-uri

Abstract
Primary osteoporosis is a common age-related disease characterized by an imbalance in bone homeostasis, increasing the risk of fractures. Twin and family studies have shown that bone mineral density (BMD) variance is in part genetically determined and osteoporotic fractures have also a heritable component. Over the last years, a series of genome-wide association studies (GWAS) and meta-analysises evidenced several loci associated with BMD at genome-wide signicance, clustering within the RANK-RANKL-OPG and WNT signaling pathways but also in the mesenchymal stem cell differentiation or endochondral ossication systems. Some of these BMDassociated loci were also signicantly associated with risk of fracture, including 17q21.31 (SOST), 11q13.2 (LRP5), 10q21.1 (DKK1), 1p36.12 (WNT4) and 7q31.31 (WNT16), whereas SNPs in genes of the RANK-RANKLOPG pathway (TNFRSF11A, TNFSF11, TNFRSF11B) were associated with BMD only. These data provide key insights into the pathophysiological mechanisms of the disease and may contribute to the identication of new drug targets for the treatment of osteoporosis, beyond previously available therapy. Key words: osteoporosis, BMD, risk of fracture, genes, SNPs

INTRODUCERE
Osteoporoza primar se caracterizeaz prin scderea masei osoase i deteriorarea microarhitecturii osului, ambele prezente n general la persoane vrstnice i specic la femeile post-menopauz, avnd drept consecin creterea riscului de fractur (1). Cercetrile iniiale n domeniul osteoporozei, centrate pe studiul sistemului RANK-RANKL-OPG, factori cu rol cheie n activarea resorbiei osoase, au condus la descoperirea unor noi formule terapeutice

antiresorbtive bazate pe blocarea cii RANK ligand (Receptor Activator of NF-kB), implicat n promovarea osteoclastogenezei i apariia osteoclatelor mature (1,2). Prin contrast, studiul formrii osoase, mecanism cel puin la fel de important ca i resorbia osoas, a fost mult timp neglijat, ns n ultimii ani au fost publicate tot mai multe date legate de impactul reducerii activitii osteoblastelor i creterii apoptozei acestora, ambele componente n ziopatologia osteoporozei (3-5).

Adres de coresponden: Dr. Ctlina Poian, Institutul Naional de Endocrinologie C.I. Parhon, B-dul. Aviatorilor Nr. 34-36, Bucureti e-mail: endoparhon@gmail.com

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Au fost descrise trei ci majore ce condiioneaz regenerarea osoas, reprezentate de: a) calea BMP (bone morphogenetic protein), b) calea WNT i c) calea mediat de activarea PTH1R (parathyroid hormone receptor). Acestea sunt caracterizate de conexiuni semnicative la nivel intracelular, iar studii recente au evideniat semnicaia blocrii lor pentru normalizarea masei osoase, sugernd noi inte terapeutice n osteoporoz (6). Proteinele BMP aparin superfamiliei factorilor de cretere TGF-, activarea receptorilor BMP avnd drept consecin iniierea procesului de transcriere la nivel nuclear, e prin intermediul semnalului intracelular MAP-kinazic, e prin fosforilarea proteinelor SMAD1/5/8 (6;7) (Fig.1). Calea WNT este format din semnalele canonic i respectiv non-canonic, n funcie de tipul coreceptorilor. Semnalul canonic este indus de liganzi WNT la nivelul proteinelor transmembranare Frizzled (FZD family proteins) i la nivelul coreceptorilor membranari LRP5/6, cu activarea transcrierii genelor WNT-dependente prin translocarea la nivel nuclear a -Cateninei. Semnalul non-canonic WNT este mediat de proteinele FZD i coreceptorii ROR2/RYK, avnd drept rezultat activarea proteinelor G i a cascadei intracelulare Ca2+ dependente (8). La nivelul celulelor stem mezenchimale (MSC), celule de origine ale osteoblatelor (dar i ale altor tipuri de celule mezodermale precum adipocitele, condrocitele sau broblatii) (9), semnalul canonic mediat de WNT2, WNT3 sau WNT3a induce proliferare i meninerea ntr-un status nedifereniat, n timp ce semnalul noncanonic, mediat de WNT5a, WNT5b sau WNT11, induce osteogeneza (6;10-12) (Fig. 1). PTH (parathyroid hormone) activeaz cea de-a treia cale major a regenerrii osoase. Astfel, administrarea intermitent de PTH stimuleaz formarea osoas att la nivel periostal, ct i trabecular (13) (Fig. 1), reprezentnd o metod terapeutic alternativ n osteoporoz. Pe de alt parte, activarea continu a receptorilor PTH are un efect nociv la nivelul homeostaziei osoase prin amplicarea expresiei RANKL de ctre osteoblastele n maturare, ulterior cu stimulare a formrii osteoclatelor i resorbie osoas (6;14). Studiile efectuate pe numere limitate de pacieni dar i cele ample, GWAS (genome-wide association studies), au evideniat c polimorsmele unor gene ce codeaz diferii factori implicai att n formarea, ct i n resorbia osoas se asociaz semnicativ cu osteoporoza primar, susinnd natura poligenic a bolii (15-18).

FIGURA 1. Rolul cilor BMP, WNT i PTH intermitent n formarea osoas. Semnalul BMP, mediat de fosforilarea proteinelor SMAD1/5/8. Semnalul WNT canonic, mediat de -catenin. Semnalul WNT noncanonic, mediat de c-jun NH2-terminal kinase (JNK), dar i de hidroliza fosfatidilinozitol 4,5-bifosfatului (PIP2) via fosfolipaze C (PLC) specice, cu activarea unor izoforme particulare ale protein kinazei C (PKC) i a cascadei intracelulare Ca2+ dependente. PTH intermitent, via semnal APMc/PKA are efect antiapoptotic i/sau prodifereniere la nivelul preosteoblatelor (pre-Ob) post-mitotice n osul periostal i efect antiapoptotic la nivelul Ob mature n osul trabecular, rezultnd creterea numrului de Ob i creterea formrii osoase.

SNP-uri (single-nucleotide polymorphisms) asociate semnicativ cu osteoporoza primar i fractura osteoporotic ESR1 Receptorii estrogenici de tip 1 au reprezentat un candidat semnicativ pentru studiul reglrii genetice a masei osoase, iar rezultatele studiilor GWAS au conrmat asocieri semnicative ale unor SNP-uri ESR1 precum rs9479055, rs4870044, rs1038304 i rs692913 cu BMD, att la nivel lombar, ct i la nivelul colului femural (19-22). Mecanismele moleculare prin care polimorsmele ESR1 inueneaz masa osoas nu sunt foarte clare, dar sunt evidene pentru stimularea transcrierii genice (22). TNFRSF11A Gena TNFRSF11A (18q21), codeaz RANK, membru al superfamiliei receptorilor TNF. RANK este exprimat la nivelul osteoclastelor i precursorilor acestora, avnd rol critic n reglarea diferenierii i funciei acestui tip de celule. Unele studii au conrmat asocierea RANK-BMD (23,24), rs3018362 aparinnd genei RANK ind primul SNP raportat ca asociindu-se semnicativ cu BMD (19,20). Studiile GWAS efectuate att n populaii europene, ct i asiatice au conrmat asocierea dintre rs3018362 si BMD (21,22).

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TNFRSF11B Gena TNFRSF11B (8q24) codeaz osteoprotegerina (OPG) sintetizat de osteoblaste. Aceasta blocheaz competitiv receptorii RANK, conducnd la inhibarea proliferrii i diferenierii osteoclastelor, cu blocare consecutiv a resorbiei osoase. Astfel, OPG are un rol critic n metabolismul osos, ind gen candidat n numeroasele studii de asociere genetic n osteoporoza. Variantele A163-G, T245-G i G1181-C se numr printre cele mai importante dintre primele polimorsme ale OPG descrise ca asociate cu osteoporoza (24;25). Au fost raportate i SNP-uri noi n populaia european: rs4355801, rs6993813, respectiv rs6469804 (19;20;26), toate asociate cu BMD att la nivel lombar, ct i la nivelul colului femural. Mai mult, asocierile rs6469804 i rs6993813 cu BMD lombar i/sau femural, s-au replicat i n alte grupuri etnice (21). TNFSF11 Gena TNFSF11 (13q14) codeaz RANKL, membru al superfamiliei factorilor de cretere TNF, cu rol n stimularea resorbiei osoase prin activarea receptorilor RANK. Gena TNFSF11 a fost studiat ca gen candidat n reglarea BMD i susceptibilitatea la osteoproroz. Cu toate c exist date contradictorii, de-CODE GWAS a conrmat c RANKL este o gen de susceptibilitate pentru osteoporoz, evideniind mai multe polimorsme TNFSF11 asociate cu BMD lombar (19;20). Aceste asocieri au fost ulterior conrmate i n metaanaliza GEFOS (18). Rezultatele provenite din populaiile europene nu s-au replicat ns i n alte grupuri etnice (21). O metaanaliz recent, publicat n 2012 (27), a descris noi SNP-uri asociate semnicativ cu BMD, aparinnd cii de difereniere a celulelor stem mezenchimale, precum RUNX2 (runt-related transcription factor 2), SP7 sau SOX9, sistemului de osicare encondral format din procese eseniale pentru dezvoltarea scheletic n etapa fetal precum SPP1 (osteopontina), MEF2C (myocite-specic enhancer factor 2C), RUNX2, SOX6, PTHLH (PTHrP), SP7 i SOX9, dar i sistemului WNT - LRP5, CTNNB1 (-catenina), SFRP4 (secreted frizzled-related protein 4), WNT3, WNT4, WNT5B, WNT16, DKK1 (Dickkopf-1) i AXIN1 (axin-1). Spre deosebire de ESR1 i de sistemul RANKRANKL-OPG, asociate doar cu BMD, o parte a SNP-urilor menionate mai sus s-au asociat semnicativ i cu riscul de fractur vertebral sau non-vertebral. Printre acestea amintim SNP-uri ale sistemului WNT, format din LRP5 (11q13.2), WNT4

(1p36.12), WNT16 (7q31.31), SOST (17q21.31) i DKK1 (10q21.1) (27). LRP5 Studiile efectuate n sindromul osteoporoz pseudogliom (28) sau sindroamele de mas osoas crescut (29) au evideniat faptul c gena LRP5 (low-density lipoprotein receptorrelated protein 5) (11q13.4) are un rol cheie n reglarea masei osoase. Primele studii de asociere genetic efectuate n populaia general au evideniat c variantele comune LRP5 se asociaz cu variaii BMD (30-33). ntr-un studiu efectuat pe 45.000 de subieci ai consoriului GENOMOS, van Meurs et al. (34) au raportat c polimorsme de la nivelul exonilor 9 i 18 ai genei LRP5 se asociaz semnicativ cu BMD i riscul de fractur. Mai mult, LRP5 s-a evideniat drept determinant semnicativ al BMD att n unele studii GWAS (26), ct i n metaanalizele GEFOS (18) i cea publicat de Richards et al. (35). Studiile funcionale LRP5 au fost centrate n special pe mutaiile rare prezente la acest nivel. Analiza osoas efectuat la oareci cu inactivare intit LRP5 a artat c masa osoas redus a acestora este mai degrab consecina scderii formrii dect a creterii resorbiei (36). Pe de alt parte, exist evidene pentru faptul c anumite mutaii LRP5 asociate cu creterea masei osoase (G171V, G171R, A214T, A214V, A242T, T253I i D111Y) inhib interaciunea dintre LRP5 i DKK1 (Dickkopf-1), proteine inhibitorii ale semnalului WNT (37). Aceste date susin faptul c, n populaia general, mutaiile rare de la nivelul genei LRP5 au un impact major pe BMD, n timp ce polimorsmele au rol att n modularea densitii minerale osoase, ct i n determinarea riscului de fractur (22). Semnalul WNT are un rol crucial n ziopatologia osoas. Astfel, n absena liganzilor WNT, -catenina formeaz structuri complexe cu APC (adenomatous polyposis coli), Axina, GSK3 (glycogen synthase kinase 3) i CK1 (casein kinase I), acestea facilitnd fosforilarea i degradarea ulterioar a -cateninei la livelul proteozomilor. n prezena liganzilor WNT, complexele disociaz iar -catenina translocheaz la nivel nuclear, unde formeaz alt tip de complexe cu factorii de transcriere TCF/Lef1, iniiind procesele de transcriere genic. n acest context, diversele polimorsme descrise, WNT3, WNT4, WNT5B, WNT16, pot semnicative n modularea variaiilor BMD i/sau riscului de fractur. Sclerostina (gena SOST, 17q12-q21) aparine familei glicoproteinelor secretorii DAN, este sintetizat aproape exclusiv de osteocite (ce constituie

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peste 90 % din celulele osoase adulte) i are rol n inhibarea formrii osoase, reprezentnd, mpreun cu proteinele Dickkopf-1, principalii antagoniti ai semnalului canonic WNT la nivel extracelular prin legare competitiv la coreceptorii LRP5 i LRP6 (38-42). Asocierile mutaiilor inactivatoare SOST cu sindroamele de mas osoas crescut sclerosteoza i boala van Buchem susin gena SOST ca excelent candidat pentru studiul reglrii BMD. Iniial a fost evideniat asocierea semnicativ ntre polimorsmele SOST SRP-3 i SRP-9 (SOST promoter region) i BMD, att la femei, ct i la brbai, efect progresiv cu vrsta (43). Ulterior, studiul de-CODE GWAS a descris alte trei SNP-uri apropiate genei ca semnicativ asociate cu BMD la nivelul oldului (20). Gena SOST s-a asociat cu BMD i riscul de fractur i n metaanaliza publicat de Richards et al (35). Metaanaliza GEFOS a evideniat, de asemenea, asocierea cu BMD, dar aceasta nu a atins semnicaia statistic (18,22). Astfel, studiile de asociere genetic susin contribuia polimorsmului SOST la reglarea genetic a BMD, mecanismele ce stau la baza acestei asocieri ind n continu explorare. Studiile efectuate pe oareci KO pentru sclerostin au demonstrat efectul inhibitor al acesteia la nivelul semnalului BMP7 n osteocite, sugernd c sclerostina nu inhib formarea osoas doar prin blocare WNT la nivelul osteoblastelor i osteocitelor, ci i reglnd inhibitor semnalul BMP n osteocitele ce exprim sclerostina. Experimentele in vitro pe culturi celulare de osteocite au conrmat interaciunea sclerostinei cu pro-BMP7 i BMP7 la nivel intracelular, conducnd la degradarea proteozomal i blocarea secreiei BMP7 la nivelul acestor celule (44) (Fig. 2). Mai mult, studiile genetice i (pre)clinice, efectuate att pe modele animale, ct i la om, au demonstrat rolul cheie al sclerostinei n reglarea formrii osoase (45-47), aceasta ind sintetizat i secretat de osteocitele mature prin mecanisme sensibile la variaiile de ncrcare mecanic. Exist evidene ce susin c expresia sclerostinei este reglat negativ de stresul mecanic n cadrul sistemului mecanosenzorial format de osteocite, explicnd astfel creterea masei osoase simultan cu exerciiul zic i scderea acesteia n repaus (48). Pe lng stresul mecanic, au fost descrii i ali factori ce pot modica secreia sclerostinei, precum vrsta, estrogenii, prostaglandinele, PTH sau cortizolul, explicnd parial variaia BMD din postmenopauz, bolile inamatorii, administrarea de PTH sau sindromul Cushing (49).

FIGURA 2. Efectul inhibitor al sclerostinei la nivelul cilor formrii osoase BMP i WNT. Sclerostina leag BMP7 la nivel intracelular, cu sechestrare i degradare proteozomal a BMP7. Blocarea cii WNT / betacatenin se produce la nivel extracelular, prin legarea sclerostinei secretate la coreceptorii WNT, LRP5/6 (adaptat dup Krause et al. Ref 44).

Astfel, o serie de studii efectuate la om au evideniat c valorile sclerostinei cresc progresiv cu vrsta, n paralel cu scderea masei osoase (50,51). Valorile serice ale sclerostinei au fost semnicativ mai mari la brbai fa de femei i semnicativ mai mari la femeile postmenopauz comparativ cu cele premenopauz (51). Creterea sclerostinei serice s-a corelat negativ cu BMD la nivelul colului femural i cu indexul de estradiol liber, n alt populaie postmenopauz (52). Alte studii au evideniat impactul terapiei cu estrogeni asupra nivelului sclerostinei serice, femeile postmenopauz substituite estrogenic pentru 4 sptmni nregistrnd o scdere semnicativ a valorilor sclerostinei serice, comparativ cu grupul control (49,53,54). Sclerostina este reglat i de mediatori ai inamaiei, acest mecanism putnd explica pierderea de mas osoas n context inamator. Prostaglandinele E2 au avut un efect de down-reglare pe expresia SOST i au activat calea WNT n celulele osteoblastice UMR106.01 (55), n timp ce expresia SOST a fost up-reglat n osteoblastele umane dup expunere la TNF- (49,56,57). Impactul analogului PTH, teriparatide PTH (1-34), i al activrii receptorilor PTH pe expresia sclerostinei a fost studiat att n culturi celulare i modele animale, ct i la om. Administrarea de PTH n culturi celulare i modele experimentale conduse la oarece s-a asociat cu scderea expresiei i secreiei sclerostinei (58). Mai mult, administrarea intermitent

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de PTH la femei postmenopauz, n cadrul unui studiu clinic prospectiv, a demonstrat o scdere semnicativ (12,7%) a valorilor serice ale sclerostinei (59). Pe de alt parte, ntr-un alt studiu clinic, administrarea de teriparatide pentru un interval mai mare de 6 luni nu s-a asociat cu modicarea valorilor sclerostinei serice (60). Alte evidene ale asocierii PTH sclerostin vin de la pacienii cu osteodistroe renal ce prezint att valori crescute ale PTH ct i valori reduse ale sclerostinei serice (49,61). Glucocorticoizii au impact pe metabolismul osos att prin creterea resorbiei, ct i prin scderea formrii osoase, conducnd la pierdere osoas trabecular, dar i cortical. RANKL s-a evideniat ca responsabil de creterea resorbiei osoase glucocorticoid-indus, n timp ce sclerostina este unul din factorii responsabili de scderea formrii post-expunere la glucocorticoizi. oarecii tratai cu prednisolon timp de 56 zile au prezentat o cretere semnicativ a expresiei sclerostinei i DKK1 la nivel osos, urmat de efectul negativ semnicativ pe osul trabecular. Interesant este faptul c dac tratamentul administrat acestor oareci a asociat i hPTH (1-34) (zilele 28-56), pierderea osoas indus de prednisolon a fost recuperat, iar expresia sclerostinei i DKK1 a fost semnicativ redus, comparativ cu monoterapia cortizonic sau cu placebo (62). La femeile postmenopauzale tratate cu glucocorticoizi, sclerostina seric a fost semnicativ mai mare comparativ cu cele fr terapie cortizonic, sugernd c, la om, glucocorticoizii au rol n modularea inhibitorilor serici ai cii WNT (49). Valori crescute ale sclerostinei serice au fost evideniate i la pacienii cu diagnostic de DZ tip 2, comparativ cu subiecii control (49;63). Astfel, sclerostina apare ca un modulator semnicativ n reglarea masei osoase, mai mult, un important studiu recent publicat, demonstrnd c la femeile vrstnice, valorile serice crescute de sclerostin s-au asociat cu un risc crescut de fractur de old, independent de BMD (64). Studiile preclinice efectuate pe modele animale au artat c administrarea de anticorpi monoclonali neutralizani ai sclerostinei a dus la creterea global a formrii osoase (la nivel trabecular, periostal, endocortical i intracortical), fr creterea resorbiei (similar cu terapia cu teriparatide sau PTH full length), n nal nregistrndu-se creterea grosimii trabeculare, a BMD i a rezistenei osoase (65,66). Administrarea subcutan n doz unic a AMG 785 (anticorp uman recombinant antisclerostin), la brbai sntoi sau femei post-menopauzale, a avut

drept rezultat o cretere dependent de doza a markerilor de formare osoas i o scdere dependent de doz a markerilor de resorbie (telopeptidul C, Ctx seric), sugernd prezena unei ferestre largi de tip anabolic. Evaluarea efectuat la 85 de zile postadministrare a evideniat creterea BMD att la nivel lombar, ct i la nivelul colului femural (67). n prezent sunt n derulare alte dou studii clinice de faz II, evalund vindecarea fracturilor post-administrare AMG 785 (la nivelul diazei tibiale, colului femural sau intertrohanterian). De asemenea, este n plin desfurare recrutarea femeilor post-menopauz pentru studiile clinice de faz III. Astfel, anticorpii antisclerostin reprezint o terapie promitoare n osteoporoz, nu numai prin creterea BMD, dar mai ales prin reducerea riscului de fractur. Toate aceste date genetice, experimentale i clinice, susin importana sclerostinei i a genei SOST n etiopatogenia osteoporozei i a fracturii osteoporotice. HTR1E Gena HTR1E (6 q14-q15) codeaz unul dintre receptorii 5-hidroxitriptaminei (serotonina), binecunoscut neurotransmitor cu proprieti promitogenice. Exist dovezi c serotonina intestinal acioneaz pe receptorii Htr1b prezeni la nivelul osteoblastelor, inhibnd proliferarea acestor celule (68), n timp ce serotonina sintetizat cerebral se leag la nivelul receptorilor Htr2c exprimai de neuronii nucleilor hipotalamici ventromediali, favoriznd acumularea de mas osoas via inhibare a activitii neuronilor simpatici (69). Recent, s-a demonstrat c rs9351097 i rs9362321, dou SNP-uri ale genei HTR1E aate n dezechilibru de legtur, se asociaz semnicativ cu un model integrat al parametrilor geometriei colului femural i, mai mult, un alt SNP al aceleiai gene, rs6919366, s-a asociat semnicativ cu riscul de fractur nonvertebral (70). Ca i n cazul sclerostinei, demonstrarea asocierii cu riscul de fractur este deosebit de important, determinarea precoce a factorilor de risc avnd rol n predicia fracturii osteoporotice n etapa vrstnic. AKAP6 O alt gen asociat semnicativ cu geometria integrat a colului femural este AKAP6, situat pe cromozomul 14, codnd protein kinase A (PRKA) anchor protein 6 (70). Aceast protein este exprimat n variate esuturi creier, cord, muchi scheletic att AKAP6, ct i 5-HT ind asociate cu semnalul intracelular AMPc (cyclic adenosine monophosphate).

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Deoarece 5-HT acioneaz intracelular prin semnalul AMPc (71) coordonat de AKAP6 (72), interaciunea AKAP6 HTR1E reprezint un alt mecanism al metabolismului osos, important de investigat pe viitor. Concluzionnd, genele evideniate ca semnicative n studiile de asociere genetic efectuate n

osteoporoz reect att natura poligenic a variaiei densitii minerale osoase, ct i complexitatea mecanismelor ziopatologice ale riscului de fractur, ecare dintre aceste gene reprezentnd i un posibil candidat pentru descoperirea unor noi formule terapeutice n osteoporoz.

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