Translation: Dr. Andrea Gasparik Ildiko

 

 

Aportul crescut si continuu de calciu, pe tot parcursul vietii, creste riscul de fracturi la varsta a III-a



Thijs R. Klompmaker Wai@WaiSays.com 

Amsterdam

Medical Hypotheses 2005; 65(3): p552-558

(pdf)

sumar in Medline

 

 

 

SUMAR

 

Restrictia calorica prelungeste durata vietii. Restrictia calcica poate mentine sanatatea oaselor.
In osteoporoza, DMO a scazut semnificativ datorita lipsei formarii osteoblastilor din os. Preventia traditionala a osteopporozei se focuseaza pe maximizarea DMO, dar nu s-au facut inca studii privind efectele mentinerii constante a DMO la valori crescute asupra sanatatii osoase la atingerea varstei a III-a. Surprinzator, in tarile cu o medie crescuta a DMO, rata fracturilor in randul varstnicilor este semnificativ mai crescuta, decat in tari cu o medie DMO scazuta. Studiile indica faptul ca acest lucru nu are la baza diferente genetice. De asemenea, in hiperparatiroidismul primar, la hotar cu osteoporoza, valorile DMO pot fi semnificativ crescute fata de normal.
S-ar spune ca DMO nu oglindeste sanatatea osoasa pe termen lung, ci doar rezistenta osoasa de moment. De asemenea, este posibil ca pastrarea unui DMO crescut sa duca, de fapt la deteriorarea sanatatii osoase.
Din moment ce osteoporoza apare cu precadere la varstnici si pentru ca numarul osteoblastilor in osul poros este mai scazut, la baza ar putea fi imbatranirea osteoblastilor.
La subiectii sanatosi, celulele osoase osteoblaste raspund la influxul de calciu prin formarea unei matrice la nivelul careia are loc precipitarea calciului. In procesul de creare a matricei, mor 50-70% din numarul 
osteoblastilor implicati. Cu cat e mai mare influxul de calciu, cu atat mai mare e activitatea osteoblastilor, respectiv rata apoptozica a acestora. O apoptoza osteoblastica crescuta duce la o scadere a capacitatii de inmultire a osteoblastilor specifici varstei (ARORC, age-related osteoblast replicative capacity).
Spre deosebire de osul sanatos, in cel osteoporotic scaderea capacitatii de multiplicare a osteoblastilor este mai accentuata. Datorita posibilei lipse a activitatii osteoblastilor, microfracturile nu pot fi reparate. Mentinerea sustinuta a unui DMO crescut are drept consecinta o rata continua si crescuta de modelare osoasa, care, in anumite zone, uzeaza capacitatea de multiplicare a osteoblastilor specifici varstei, iar aceasta duce intr-un final la microfracturi irreparabile.
In ceea ce priveste influenta asupra sanatatii osoase pe o perioada lunga, s-a dovedit ca un nivel adecvat de estrogeni are rol protectiv impotriva osteoporozei.
In general, acest lucru se atribuie caracteristicii de inhibitie pe care estrogenii o au asupra activitatii osteoclastilor.
De fapt, efectul de retea pe care o au asupra metabolismului osteoblastilor poate fi cheia prevenirii osteoporozei. Cantitati adecvate de estrogeni inhiba activitatea osteoblastilor, apozitia calcica si rata apoptozica a osteoblastilor, protejand astfel capacitatea de multiplicare a osteoblastilor specifici varstei.

Concluzie:

In ceea ce priveste osteoporoza, mai mult capacitatea de multiplicare a osteoblastilor specifici varstei, decat DMO reflecta sanatatea osoasa.
In ceea ce priveste capacitatea de multiplicare a osteoblastilor specifici varstei, cantitati adecvate de estrogeni au rol protectiv, in contrast cu efectele hiperparatiroidismului si ale unui aport crescut de calciu.
E nevoie de teste de laborator (pe soareci) pentru a stabili efectele pe viata ale consumului crescut versus scazut de calciu, in caz de accentuare a incidentei de fracturi osoase.


INTRODUCERE


Osteoporoza este o problema majora de sanatate publica. Eforturile de prevenire nu au dat roade, dovada fiind incidenta crescuta a fracturilor osteoporotice de varsta. Timp de decenii, prevenirea osteoporozei s-a axat pe cresterea masei osoase optimale, dar in tari cu media DMO crescuta, incidenta osteoporozei este de asemenea crescuta.

In Europa, DMO la femeile adulte din Polonia este mai scazut decat a celor din Franta, Italia si Spania (1); la fel, mai scazuta este incidenta de fractura de sold (legat de varsta) (2). In Suedia, media DMO este mai crescuta (3), la fel fiind si incidenta de fractura de sold (2).
Subiectii japonezi au o masa osoasa maxima mai scazuta decat confratii lor europeni, la fel fiind si in cazul incidentei fracturii de sold (mai scazuta in Japonia decat in Vest) (4). Acest lucru nu se datoreaza diferentelor genetice. Japonezele-americane, nascute in Statele Unite au valori DMO echivalente femeilor albe (5).
Femeile din China au un DMO mai scazut si risc de fracturi de sold si mai scazut decat femeile in Europa si America de Nord (6). Aceasta nu se datoreaza diferentei genetice. Femei premenopauzale de origine chineza care au imigrat in Danemarca de mai mult de 12 ani, au valori DMO identice cu cele ale danezelor in premenopauza (7).
In Gambia, aportul de calciu, media DMO si incidenta osteoporozei sunt foarte scazute (8). Din nou, nu exista cauze genetice. Nu exista diferente semnificative de DMO intre adultii de origine gambiana si caucaziana care traiesc in Marea Britanie (9).
Mentinerea unui DMO scazut ar putea pastra sanatatea osoasa pe termen lung ?
Poate DMO nu reprezinta sanatatea osoasa pe termen lung, ci doar rezistenta osoasa de moment. Si poate ca mentinand un DMO la valori inalte ar putea duce la uzura sanatatii osoase, rezultand intr-un final in slabirea rezistentei osoase; intocmai ca accelerarea constanta a masinii duce mai rapid la stricarea ei. 


HIPOTEZA: FRACURILE OSTEOPOROTICE SUNT REZULTATE ALE UNEI CAPACITATI REPLICATIVE OSTEOBLASTICE -UZATE (ARORC)


Restrictia calorica prelungeste durata vietii (10-13) prin intarzierea schimbarilor fiziologice si biologice specifice varstei (14-16). Restrictia calcica poate pastra sanatatea osoasa prin intarzierea scaderii capacitatii osteoblastilor specifici varstei de a forma osul nou.


Efectele de scurta durata ale aportului crescut de calciu au fost deja stabilite. In oasele noastre, osteoblastii creaza matricea la baza careia are loc precipitarea calcica. Aportul crescut de calciu duce la o activitate crescuta a osteoblastilor si rate crescute de formare osoasa, care, in functie de ratele de resorbtie poate creste valoarea DMO si astfel sa creeze oase mai puternice.
In mentinerea unui DMO mai crescut, atat formarea, cat si resorbtia osoasa sunt crescute. Din nefericire, in compunerea unei noi matrici, 50-70% dintre osteoblastii implicati in proces mor (17), ei avand o capacitate proliferativa limitata (18-20).
Activitatea osteoblastica crescuta si diferentierea celulelor, coincide unei rate apoptozice crescute a osteoblastilor (21,22), specifica zonei proliferative (21,23,24). Rate apoptozice crescute de osteoblasti accelereaza descresterea capacitatii replicative a osteoblastilor specifici varstei.
Osteoblastii din osul poros au o capacitate replicativa redusa (25,26).
Astfel, in osul osteoporotic, numarul osteoblastilor disponibili este mai scazut (27-29) si/sau activitatea osteoblastilor este afectata (28-32), la fel ca in oasele "exagerat de imbatranite" (25,33). Datorita lipsei acestei activitati osteoblastice, matricea pre-calcifiata disponibila este mai redusa (34) si microfracturile nu pot fi reparate (35).
La pacientii osteoporotici, nu exista imbatranire prematura generalizata a celulelor (36). In schimb, reducerea activitatii osteoblastilor este regionala (27,28), indicand factori externi, cum ar fi suprasolicitarea regionala a osteoblastilor. 


ASEMENI DIETEI CRESCUTE IN CALCIU, VALORI INADECVATE DE ESTROGENI STIMULEAZA ACTIVITATEA OSTEOBLASTICA SI CRESTE APOPTOZA EI


S-a stabilit ca nivelul optim de estrogeni are rol protectiv impotriva osteoporozei. Aceasta se atribuie in general efectelor sale predominant inhibitorii asupra resorbtiei osoase, dar influenta nivelului adecvat de estrogeni asupra metabolismului osteoblastilor poate fi una dintre cheile catre intelegerea etiologiei osteoporozei.
S-a sustinut deseori ca estrogenii stimuleaza activitatea osteoblastilor, dar aceste dovezi pot fi rezultatele metodelor inadecvate folosite anterior.
Dupa verificari si caracterizari ale rapoartelor privind efectele anabolice ale estrogenilor asupra formarii osoase la sobolanii in crestere, datele adunate au demonstrat ca estrogenii inhiba formarea osoasa (37).
Alte studii au indicat efecte anabolice in primele sase zile de administrare a estrogenilor sau atunci cand (38) s-au administrat intermitent (39).
Pe perioada indelungata, estrogenii nu stimuleaza, ci suprima osteoblastogeneza (40), atenuand rata nasterii osteoblastilor (41,42), inhiba proliferarea, diferentierea si activitatea osteoblastilor umani (43-45), formarea osoasa (47-49) si previne moartea celulelor osteoblaste (42,50,51), crescand astfel durata de viata a osteoblastilor (40,42,52). Dintr-un punct de vedere, estrogenii pot inhiba activitatea osteoblastica prin modificarea efectelor parathormonului (PTH) (53).
Mai presus, deoarece osteoporoza afecteaza cu prevalenta femeile postmenopauzale, deficienta estrogenica este responsabila de cresterea osteoblastogenezei (54), creste numarul (55), activitatea osteobalstica (56), accelerand formarea osoasa (49,54,75-61) (cu precadere resorbtia osoasa), crescand rata apoptozei osteoblastice (62) si scurtand durata lor de viata (63,64).
In ceea ce priveste intelegerea etiologiei osteoporozei, efectele de retea ale estrogenilor asupra DMO nu prezinta probleme, pentru ca DMO indica oar rezistenta osoasa de moment. In schimb, efectele de retea ale unor niveluri adecvate si inadecvate de estrogeni asupra activitatii osteoblastice, a ratei apoptozice si ARORC sunt esentiale, explicand posibilele efectele detrimentiale asupra sanatatii osoase finale a unei diete crescute in calciu.


EFECTELE HIPERPARATIROIDISMULUI ASUPRA ARORC SUNT SIMILARE EFECTELOR SUPLINIRII DE CALCIU IN CANTITATI CRESCUTE

 

Opus si inhibat de un nivel adecvat de estrogeni, hiperparatiroidismul prelungit este o binecunoscuta cauza a osteoporozei, ceea ce este adesea atribuit efectelor stimulative pe care le are asupra resorbtiei osoase. Cu toate acestea, osteoblastele sunt cele mai importante celule tinta pentru parathormoni (PTH) (65). Efectele asupra numarului de osteoblaste si activitatea de formare osoasa sunt similare atat in cazul unui PTH intermitent, cat si al unuia continuu (66). PTH stimuleaza proliferarea osteoblastilor (67-71), creste diferentierea osteoblastilor (70,72,73), creste numarul si rata de apoptoza a osteoblastilor (74,75), stimuland formarea osoasa (76-78). Suplimentarea de PTH poate avea efectele (23,79-82) unei diete crescute in calciu.
In hiperparatiroidism, rata de formare osoasa (si resorbtia) este vizibil elevat (83) si cresterile in markerii de formare si resorbtie par sa fie de marimi echivalente (84). De aceea, in hiperparatiroidism, valorile DMO difera mult (85), depinzand de echilibrele regionale dintre numarul crescut de osteoblasti si activitatea osteoclastilor. Unele valori DMO pot fi semnificativ mai crescute decat in cadrul studiilor (86). Totusi, valorile DMO rezultate nu sunt o garantie, pentru ca ele reflecta doar rezistenta osoasa de moment. Ea ar putea fi data de sanatatea osoasa pe termen lung, care e compromisa de rate apoptozice crescute ale osteoblastilor. Apoptoza osteoblastica parathormon indusa este specifica zonei proliferative (23,24), indicand faptul ca efectele PTH asupra apoptozei pot fi explicate doar pe baza efectului anabolic asupra proliferarii osteoblastilor, similar dietei crescute in calciu.
Intr-un final, hiperparatiroidismul duce la extenuarea ARORC, cauzand osteoporoza. Hiperparatiroidismul creste riscul de fractura (87-89).
Facand abstractie de efectele de retea asupra DMO, estrogenii inhiba, iar aportul crescut de calciu si hiperparatiroidismul cresc turnoverul osos. In ceea ce priveste ARORC, estrogenii asadar au rol protector, fiind opusul efectelor hiperparatiroidismului si ale dietei crescute in calciu.


CALCITRIOLUL POATE AVEA ROL PROTECTOR IN OSTEOPOROZA DATORITA EFECTELOR SALE INHIBITORII ASUPRA PTH


Efectele protectoare sau de opunere ale 1.25 dihidroxicolecalciferolului (Calcitriol) asupra ARORC depind de coexistenta nivelurilor PTH. Asemeni PTH, dar cu o mai mica extindere, Calcitriolul stimuleaza direct activitatea si diferentierea osteoblastilor (22), crescand apopotoza osteoblastica, accelerand descresterea ARORC. Totusi, in mod indirect, Calcitriolul poate avea un rol protector datorita efectelor sale inhibitorii asupra nivelurilor PTH, creand o scadere atat in cadrul activitatii osteoclastilor, cat si a osteoblastilor (90), ceea ce atenueaza descresterea ARORC. 



GLUCOCORTICOIZII CAUZEAZA OSTEOPOROZA DATORITA EFECTELOR PRO-APOPTICE DIRECTE

 

Terapia pe perioada lunga cu glucocorticoizi induce osteoporoza, a carei severitate depinde de doza si durata tratamentului (91).
Glucocorticoizii stimuleaza in mod direct o crestere in apoptoza osteoblastilor mature (92-94), spre deosebire de efectele indirecte ale hipertiroidismului si ale dietei crescute in calciu, care cresc apoptoza osteoblastilor prin stimularea proliferarii si activitatii osteoblastilor.
Glucocorticoizii scad DMO prin inhibarea activitatii osteoblastilor si accelereaza in acelasi timp scaderea ARORC prin inducerea apoptozei osteoblastilor. 


INFLUENTA LIMITATA A EXERCITIULUI INDICA EXTENUAREA CAPACITATII DE MULTIPLICARE A OSTEOBLASTILOR


Exercitiul este asociat in mod pozitiv cu DMO de sold, dar deseori pacientii osteoporotici nu-si pot creste valoarea DMO prin exercitiu (95). Posibilul castig de masa osoasa indusa prin exercitiu este mult mai scazut decat inducerea masei osoase nefolosite (96), ceea ce poate indica extenuarea ARORC.
Exercitiul este esential in mentinerea efectelor de absorbitie a socului de catre muschii mari (97). Pe perioada scurta, la adultii varstnici, exercitiul poate scadea partial riscul de fractura de sold (98), dar aceasta va accelera scaderea ARORC. La femeile in varsta, anterior diagnosticate cu fractura de sold, s-a gasit un efect protector al activitatii moderate de curand.
Totusi, la femei care au fost de curand foarte active, riscul de fractura de sold a fost usor ridicat (99), ceea ce poate indica o lipsa a capacitatii osteoblastilor de a repara microfracturile traumatice. Cu cat e mai tarziu in viata, cu atat efectele exercitiului sunt mai mici (100), datorita scaderii ARORC.
La varstnici cu media de varsta de 73 de ani, exercitiul nu are rol protector in fractura osteoporotica (101). La femei de aproximativ aceeasi varsta, cu fracturi postmenopauzale in antecedente, exercitiul nu le-a afectat valoarea DMO, nici ratele de fractura (102).
In ceea ce priveste riscul de fracturi osteoporotice, exercitiul poate avea efecte benefice de lunga durata prin focusarea lui asupra cresterii rezistentei musculare, mai degraba decat pe rezistenta osoasa.


CONCLUZIE


In ceea ce priveste osteoporoza, DMO reprezinta rezistenta osoasa de moment si ARORC reprezinta sanatatea osoasa pe termen lung. In ceea ce priveste ARORC, niveluri adecvate de estrogeni au rol protector, protejand viabilitatea osteoblastilor, opunand efectele pro-apoptotice asupra osteoblastilor ale terapiei glucocorticoide, hiperparatiroidismului si a dietei crescute in calciu. Mentinerea unui DMO crescut are efecte adverse asupra sanatatii osoase pe termen lung, explicand corelatia pozitiva dintre media DMO si incidenta de fractura de varsta pe tara.
Prevenirea osteoporozei poate fi un success prin incercarea reducerii mediei aportului de calciu la nivelul tarilor in care incidenta fracturilor osteoporotice este cea mai scazuta, aproximativ 300-500 mg/zi.
E nevoie de efectuarea unor teste de laborator pentru a stabili efectele pe viata ale unei diete foarte crescute in calciu (3%), crescute (1.5%), moderate (0.5%), scazute (0.2%) si foarte scazute (0.1%), respectiv (Ca/P = 1.5, Ca/Mg = 10, Mg >0.02%), in caz de accentuare a fracturilor osoase.
Efecte sporit benefice ale exercitiului pot fi obtinute prin tendinta de a creste rezistenta musculara, in loc de cea osoasa.
Daca aceasta teorie e corecta, milioane de oameni de pretutindeni au fost gresit tratati, iar preventia traditionala e posibil sa fi avut si va continua sa aiba efecte adverse puternice asupra sanatatii a sute de milioane de oameni. Chiar si cei mai conservatori estimeaza costuri astronomice.
 

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