ARTICOLE DE ORIENTARE

OSTEOPOROZA N SPONDILITA
ANCHILOZANT: II ETIOPATOGENEZ
Osteoporosis in ankylosing spondylitis: II Etiopathogenesis
Dr. Laura Muntean
Clinica Reumatologic, Universitatea de Medicin i Farmacie Iuliu Haieganu, Cluj-Napoca

Rezumat
Leziunile structurale din spondilita anchilozant (SA) se caracterizeaz printr-un proces de neoformare osoas
cu apariia sindesmofitelor, care reprezint trstura distinctiv a acestei boli. n paralel cu osteoproliferarea
excesiv, n SA are loc o pierdere de mas osoas ce determin osteoporoz (OP) i creterea riscului fracturar.
Efectele negative ale SA asupra osului au fost demonstrate de studii dedicate evalurii densitii minerale osoase
(DMO), markerilor metabolismului osos i incidenei fracturilor. n literatura recent exist mai multe studii care
au demonstrat c pacienii cu SA au DMO sczut la nivelul coloanei lombare i oldului, cu unele diferene n
funcie de stadiul bolii. Pierderea de mas osoas are loc precoce n cursul bolii, iar monitorizarea acesteia se
face cel mai bine prin evaluarea DXA la nivelul colului femural. n stadiile tardive ale bolii, prezena sindesmofitelor
determin o fals cretere a DMO lombare. Puine studii au analizat markerii turnover-ului osos la pacienii cu SA
i au furnizat rezultate contradictorii. Fracturile vertebrale pe fond de OP sunt complicaii frecvente, dar adesea
nerecunoscute ale SA, care pot contribui la patogeneza durerii i deformrii spinale. Patogeneza OP din SA
nu este nc elucidat, dar activitatea inflamatorie a bolii pare s aib un rol major. Acest articol sintetizeaz
principalele date din literatur despre evaluarea i etiopatogeneza OP din SA.
Cuvinte cheie: osteoporoz, spondilit anchilozant, densitate mineral osoas, markeri osoi, fracturi
vertebrale

Summary
Structural damage in ankylosing spondylitis (AS) is characterized by osteoproliferation leading to development of
syndesmophytes, regarded as the hallmark of the disease. Besides excessive bone formation, AS is characterized by
bone loss leading to osteoporosis (OP) and increased risk of vertebral fractures. The negative effects of AS on bone
have been illustrated by studies focusing on bone mineral density (BMD), markers of bone metabolism and fracture
incidence. Several studies in the recent literature have documented low bone mass in the spine and hips of AS patients,
with differences according to the stage of the disease. Bone loss occurs early in the disease and its progression is better
assessed by using DXA at the femoral neck. In late AS, the presence of syndesmophytes could falsely elevate the spine
BMD values. There are only few studies that have analyzed bone turnover markers in patients with AS and yielded
conflicting results. Vertebral fractures due to OP are a common, but frequently unrecognized complication, that contribute
to spinal pain and deformity in patients with AS. Pathogenesis of OP in AS is not yet elucidated, but it seems that disease
activity plays a major role. This article reviews data from literature about evaluation and etiopathogenesis of OP in AS.
Key words: osteoporosis, ankylosing spondylitis, bone mineral density, bone turnover, vertebral fracture

ETIOPATOGENEZ
Cunoaterea etiopatogenezei OP asociate SA este
de mare interes pentru prevenirea complicaiilor i
mbuntirea prognosticului bolii. S-a sugerat c
urmtorii factori ar putea fi implicai n pierderea de
mas osoas din SA: activitatea fizic redus, factori
hormonali, factori genetici, tratamentul medicamentos i activitatea inflamatorie a bolii.

Imobilitatea este un factor de risc bine cunoscut

pentru OP i ar putea fi un factor etiologic n SA,
ntruct modificrile axiale caracteristice bolii pot
determina o reducere a mobilitii. Pe de alt parte,
DMO a fost redus chiar i la pacienii cu durat
scurt a bolii, care aveau mobilitatea pstrat i un
nivel al activitii fizice similar cu al martorilor sau
care urmau un program de kinetoterapie (20,24,73).
De asemenea, nu s-a gasit nici o relaie ntre pierderea

Adres de coresponden:
Dr. Laura Muntean, Universitatea de Medicin i Farmacie Iuliu Haieganu, Str. Louis Pasteur, Nr. 6, Cluj-Napoca

156

REVISTA ROMN DE REUMATOLOGIE VOL. XIX NR. 3, An 2010

REVISTA ROMN DE REUMATOLOGIE VOL. XIX NR. 3, AN 2010

de os i mobilitatea vertebral, impotena funcional

(evaluat prin Health Assessment Questionare, HAQS) sau activitatea fizic zilnic a pacienilor cu SA
(85,86). Faptul c mai muli pacieni cu sindesmofite
aveau DMO redus n comparaie cu cei fr
sindesmofite, sugereaz c imobilitatea nu joac un
rol predominant n patogeneza OP din SA (33).
Implicarea factorilor hormonali este controversat. Unii autori au raportat niveluri sczute ale hormonilor gonadali la pacienii cu SA, care nu au fost
ulterior confirmate (17). n plus, Mitra i colab. nu
au gsit nici o corelaie ntre hormonii sexuali, DMO
i fracturile vertebrale la brbaii cu SA precoce (88).
Din rezultatele disponibile n prezent nu pare s
existe o alterare semnificativ a secreiei hormonilor
gonadali, suprarenali i pituitari n SA (89). Pe de
alt parte, ntr-un studiu recent, pe o cohort mare i
bine caracterizat de pacieni cu SA, Franck i colab.
au demonstrat o corelaie pozitiv ntre DMO femural
i nivelurile serice de testosteron liber la pacienii de
sex masculin i nivelurile de estradiol seric la femeile
cu SA. Dei aceste modificri au fost subtile, ar putea
indica implicarea unor mecanisme endocrine n
patogeneza pierderii de os din SA (53).
Factorii genetici au probabil o contribuie minor
la reducerea masei osoase n SA. Se tie c att
metabolismul osos, ct i procesele inflamatorii sunt
influenate de receptorul vitaminei D (vitamin D
receptor, VDR). n OP primar s-a demonstrat o
corelaie modest ntre polimorfismul genei VDR i
DMO (90). ntr-un studiu recent, la brbaii cu SA
s-a raportat o asociere semnificativ ntre polimorfismul codonului de iniiere a VDR (Fok I) i DMO
vertebral, precum i cu parametrii de activitate ai
bolii. Autorii studiului sugereaz o posibil interaciune ntre sistemul vitaminei D, citokine i os, care
ar putea avea implicaii diagnostice i terapeutice n
SA (91).
Se tie c AINS inhib sinteza prostaglandinelor
care au efect anabolizant asupra osului. S-a crezut c
utilizarea ndelungat a AINS n tratamentul SA ar
putea avea un efect nefavorabil asupra masei osoase.
n studiile pe animale, tratamentul de durat cu AINS
a determinat scderea masei osoase i a rezistenei
osului. Pe de alt parte, la femeile n postmenopauz
diclofenacul inhib resorbia osoas evaluat prin
telopeptidele colagenului. Tratamentul cu AINS nu
afecteaz excreia urinar a piridinolinelor, ceea ce
sugereaz c n doze terapeutice nu influeneaz
semnificativ metabolismul osos (56). Nu s-au raportat
diferene semnificative ntre DMO lombar i

157

femural la pacienii cu SA care urmau tratament cu

AINS n comparaie cu cei fr tratament (53,85,86).
n prezent, nu exist date care s susin implicarea
AINS n patogeneza OP din SA. Corticosteroizii
sunt rar folosii n SA i de asemenea nu par s influeneze semnificativ masa osoas (17,23).
Activitatea inflamatorie a bolii pare s aib un rol
major n patogeneza OP din SA. Date recente sugereaz c inflamaia sistemic, chiar i infraclinic,
precipit pierderea de mas osoas i crete riscul
fracturar. Aceast relaie strns ntre inflamaie i os
este subliniat de observaia c toate bolile inflamatorii cronice, i n special cele reumatismale, se
asociaz cu o prevalen crescut a OP i a fracturilor
de fragilitate (92).
Se tie c procesul patologic n SA ncepe la
nivelul entezelor, unde se produce o inflamaie
local, care este la originea eliberrii unor citokine i
a unor factori de cretere, ce determin leziuni osoase
(16). Aceste fenomene locale sunt dificil de investigat
din cauza accesibilitii reduse la nivelul entezelor.
S-a artat c o serie de citokine proinflamatorii, n
principal TNF, IL-1 i interleukina 17 (IL-17) sunt
activatori poteni ai osteoclastelor, fie prin stimularea
direct a acestor celule, fie indirect prin inducerea
expresiei ligandului receptorului activator al factorului nuclear kappa B (receptor activator of nuclear
factor kB ligand, RANKL). n plus, IL-1 i TNF
induc apoptoza osteoblastelor, contribuind la pierderea de mas osoas i prin alterarea formrii osoase
(93). RANKL, un membru al superfamiliei de citokine
TNF, este exprimat la suprafaa osteoblastelor i precursorilor acestora i reprezint factorul cheie al
osteoclastogenezei. Pe lng forma transmembranar
de RANKL, exist i o form solubil (sRANKL)
secretat de limfocitele T activate. Ambele forme de
RANKL i exercit efectele prin legarea de receptorul
activator al factorului nuclear kappa B (receptor
activator of nuclear factor kB, RANK), care este
exprimat de ctre precursorii osteoclastelor, osteoclastele mature i celulele dendritice. n urma acestei
interaciuni, RANKL stimuleaz diferenierea i
activarea osteoclastelor, precum i prelungirea supravieuirii acestora prin inhibarea apoptozei. Efectele
RANKL sunt blocate de un antagonist endogen,
osteoprotegerina (OPG), care funcioneaz ca un
receptor solubil capcan (antagonist) pentru
RANKL, mpiedicnd competitiv legarea acestuia de
RANK pe precursorii osteoclastelor. Producia i activitatea RANKL i OPG sunt influenate de numeroase
citokine, mediatori ai inflamaiei i hormoni

158

calciotropi. Remodelarea osoas i pierderea de

mas osoas este controlat de echilibrul dintre
RANKL/RANK i OPG. Prin urmare, sistemul
RANKL/RANK/OPG constituie o punte molecular
ntre homeostazia osoas i imunitate, fiind considerat
un factor major implicat n afectarea scheletal din
reumatismele cronice inflamatorii (94). n SA, creterea resorbiei osoase indus de excesul local de
citokine proinflamatorii determin o pierdere de os
trabecular adjacent sediilor de inflamaie a entezelor,
ceea ce explic apariia OP vertebrale la pacienii cu
boal activ. Aceast prim faz resorbtiv acioneaz ca un factor de stres i este urmat de un proces
de formare osoas extensiv care conduce la apariia
sindesmofitelor (16,95). n stadiile avansate de boal,
suportul mecanic conferit de neoformarea de os extraspinal ar putea determina o reducere a forelor gravitaionale i a stresului compresiv de la nivelul trabeculelor vertebrale, ceea ce determin o reducere a
densitii trabeculelor i agraveaz OP (34). Pe de
alt parte, pierderea de mas osoas a fost observat
i la nivelul sediilor neafectate clinic, n principal la
nivelul femurului, sugernd implicarea unor factori
sistemici n etiopatogenia OP din SA (16).
La pacienii cu SA, nivelurile serice ale IL-6, IL1 i TNF au fost crescute n comparaie cu martorii
i s-au corelat cu activitatea i severitatea bolii
(60,85,96,97). De asemenea, IL-17 a fost crescut i
s-a corelat cu fosfataza acid tartrat rezistent (un
marker de resorbie), dar nu cu parametrii de inflamaie sau DMO (98,99).
Franck i colab. au gsit niveluri serice ale OPG
semnificativ sczute la pacienii cu SA n comparaie
cu martorii, care nu s-au corelat cu valorile proteinei
C-reactive, DMO i ale markerilor de resorbie
osoas. n plus, au observat c la aceti pacieni nu
exist o cretere compensatorie a OPG cu vrsta, n
contrast cu subiecii sntoi i cu OP primar, ceea
ce sugereaz o alterare semnificativ a acestui antagonist al resorbiei osoase n SA (53). n contrast, n
alte dou studii care au cuprins un numr mic de
pacieni, OPG seric a fost crescut (100,101).
ntr-un studiu recent, Kim i colab. nu au gsit
diferene semnificative ntre nivelul circulant al OPG
la spondilitici i lotul de control. n schimb, nivelul
seric al sRANKL, precum i raportul sRANKL/OPG
au fost semnificativ crescute i s-au corelat cu DMO
femural i manifestrile radiologice de inflamaie
activ. Aproximativ dou treimi dintre pacieni au
avut DMO femural redus i aceast modificare a
reflectat activitatea bolii. Aceste rezultate sugereaz

REVISTA ROMN DE REUMATOLOGIE VOL. XIX NR. 3, AN 2010

c mai degrab dezechilibrul ntre RANKL i OPG,

dect nivelul seric individual al acestora, ar putea fi
implicat n patogeneza OP din SA (99).
Mai muli cercettori au raportat existena unei
corelaii ntre DMO i reactanii de faz acut (VSH
i proteina C-reactiv), care sunt markerii biologici
cel mai frecvent utilizai pentru cuantificarea inflamaiei n SA. ntr-un studiu longitudinal cu durata de
urmrire de 19 luni, Gratacos i colab. au demonstrat
clar c exist o relaie ntre pierderea de mas osoas
i activitatea bolii. Astfel, DMO a fost evaluat la 34
de pacieni cu SA precoce i a sczut semnificativ
numai la pacienii cu boal activ persistent. n
plus, acetia au avut valori serice ale IL-6 semnificativ
crescute n comparaie cu pacienii cu boal inactiv.
Rata de pierdere osoas la pacienii cu SA activ a
fost de 5% la nivel lombar i respectiv 3% la nivelul
colului femural, valori similare cu cele raportate
pentru poliartrita reumatoid i OP postmenopauz
(85). Aceste rezultate au fost confirmate i de ali
cercettori (53,86,87). n studiul lui Kim i colab.
DMO femural s-a corelat semnificativ cu multipli
indici obiectivi [VSH, proteina C-reactiv, BASMI
(Bath Ankylosing Spondylitis Metrology Index)] i
subiectivi [BASDAI (Bath Ankylosing Spondylitis
Disease Activity Index), BASFI (Bath Ankylosing
Spondylitis Functional Index), BAS-G (Bath
Ankylosing Spondylitis Patient Global Score)] de
activitate a bolii. Autorii au sugerat c prezena unei
DMO reduse la pacienii cu SA reflect indirect
activitatea bolii (99). Exist ns i studii n care
aceast corelaie nu a fost observat, fapt explicat
prin caracteristicile variabilelor studiate: parametrii
inflamaiei sunt evaluai n momentul studiului, n
timp ce DMO este o variabil, longitudinal (40, 47,
85). n sprijinul ipotezei etiopatogeniei inflamatorii
a OP din SA vin i studiile care au evideniat o
corelaie ntre markerii de resorbie osoas i parametrii inflamatori (17).

PERSPECTIVE TERAPEUTICE
La ora actual nu exist un tratament specific
pentru OP secundar din SA. n absena unor studii
controlate de evaluare a eficienei diverselor mijloace
terapeutice antiosteoporotice n aceast populaie,
tratamentul nu poate fi dect empiric (34). n practica
clinic, tratamentul OP din SA este similar cu cel
utilizat n OP primar, cu excepia rolului limitat pe
care l are terapia de substituie hormonal, avnd n
vedere faptul c cei mai muli pacieni sunt brbai
tineri (34,102). Tratamentul se bazeaz n principal

REVISTA ROMN DE REUMATOLOGIE VOL. XIX NR. 3, AN 2010

pe utilizarea bisfosfonailor care sunt medicamente

antiresorbtive potente ce i-au demonstrat eficacitatea
n toate formele de OP. n plus, aminobisfosfonaii
au i proprieti antiinflamatorii, dependente de doz,
motiv pentru s-a ncercat utilizarea lor n terapia SA
refractare la AINS (103). n mai multe studii,
Maksymowych i colab. au demonstrat c pamidronatul administrat intravenos determin o ameliorare
semnificativ a activitii bolii (104). S-a sugerat c
pe lng efectul de cretere a masei osoase n SA,
bisfosfonaii ar putea avea i un efect de reducere a
formrii sindesmofitelor (71). Sunt ns necesare
studii controlate i randomizate de evaluare a eficacitii bisfosfonailor n prezervarea masei osoase i
reducerea riscului fracturar la pacienii cu SA.
Antagonitii TNF utilizai n tratamentul SA au
demonstrat o eficacitate remarcabil n reducerea
activitii inflamatorii a bolii (105). Recent, s-a
demonstrat c ameliorarea inflamaiei n spondilartropatiile seronegative sub tratamentul cu infliximab
i etanercept a determinat o cretere rapid (n
primele 6 luni) a DMO lombare i femurale. Aceste
studii, n care inhibiia TNF a determinat scderea
inflamaiei sistemice i creterea masei osoase

159

adaug noi dovezi n favoarea ipotezei inflamatorii a

OP din SA (68,69,106). n plus, s-a observat o
cretere a greutii corporale i a masei slabe, la pacienii cu spondiloartropatii seronegative tratai cu
infliximab (69).

CONCLUZII
OP este o manifestare extra-articular frecvent
la pacienii cu SA i poate fi observat nc din
stadiile precoce de boal. Pacienii cu SA au un risc
crescut de fracturi vertebrale osteoporotice, care
contribuie la patogeneza durerii i deformrii spinale.
Etiopatogeneza pierderii de mas osoas n SA este
mutifactorial i probabil implic mecanisme diferite
n funcie de stadiul bolii. Activitatea inflamatorie a
bolii joac un rol major n reducerea masei osoase,
pacienii cu SA activ avnd un risc crescut de OP.
Screening-ul OP se bazeaz pe investigarea pacienilor la risc i se face prin combinarea metodelor
osteodensitometrice cu determinarea markerilor biochimici ai turnover-ului osos. Tratamentul se bazeaz
pe modularea att a fenomenelor inflamatorii, ct i
a remodelrii osoase, prin utilizarea agenilor antiTNF i a bisfosfonailor.

BIBLIOGRAFIE
(Bibliografia este comun cu a notei I i ordinea citrilor o continu pe cea anterioar)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.

Braun J, Sieper J Therapy of ankylosing spondylitis and other

spondyloarthritides: established medical treatment, anti-TNF- therapy
and other novel approaches, Arthritis Res 2002, 4: 307-321
Sieper J, Braun J, Rudwaleit M et al Ankylosing spondylitis: an
overview, Ann Rheum Dis 2002, 61: 8 18
Khan MA Update on spondylarthropathies, Ann Intern Med 2002, 136:
896 907
Kim T, Uhm W, Inman R Pathogenensis of ankylosing spondylitis and
reactive arthritis, Curr Opin Rheumatol 2005, 17: 400-405
Boloiu H D Spondilita Anchilozant, Editura Dacia, Cluj Napoca,
1989
Van Der Linden S, Valkenburg HA, Cats A Evaluation of diagnostic
criteria for ankylosing spondylitis. A proposal for modification of the New
York criteria, Arthritis Rheum 1984, 27: 361368
O Shea F, Salonen D, Inman R The challenge of early diagnosis in
ankylosing spondylitis J Rheumatol 2007, 34: 5-8
Rudwaleit M, van der Heidje D, Khan MA et al How to diagnose axial
spondyloarthritis early? Ann Rheum Dis 2004, 63: 535 -543
Sieper J, Rudwaleit M Early referral recommendations for ankylosing
spondylitis (including pre- radiographic and radiographic forms) in primary
care, Ann Rheum Dis 2005, 64: 659-663
Braun J, Pincus T Mortality, course and prognosis of patients with
ankylosing spondylitis, Clin Exp Rheumatol 2002, 20 (Suppl 28): S16-S22
Anandarajah A, Ritchlin T Treatment update on spondyloarthropathy,
Curr Opin Rheumatol 2005, 17: 247-256
Calin A, Dijkmans B, Emery P et al Outcome of a multicentre
randomised clinical trial of etanercept to treat ankylosing spondylitis, Ann
Rheum Dis 2004, 63: 1594-1600
Van der Hejde D, Dijkmans B, Geusens P etc Efficacy and safety
of infliximab in patients with ankylosing spondylitis: results of 23-week
randomized, placebo-controlled trial (ASSERT), Ann Rheum Dis 2005,
52: 582-591

14. Baraliakos X, Listing J, Brandt J etal Radiographic progression in

patients with ankylosing spondylitis after 4 yrs of treatment with the antiTNF- antibody infliximab, Rheumatol 2007, 46: 1450-1453
15. Mazzantini M, Lane N Rheumatic diseases, glucocorticoid treatment
and bone mass. Recent developments, Clin Exp Rheumatol 2000, 18
(Suppl 21): S2-S4
16. Wendling D Bone loss in ankylosing spondylitis: Can we put the puzzle
together ? J Rheumatol 2005, 32: 1184-1186
17. Toussirot E, Wendling D Bone mass in ankylosing spondylitis, Clin
Exp Rheumatol 2000, 18 (Suppl 21):S16-S20
18. Jergas M, Uffman M, Escher H et al Interobserver variation in the
detection of osteopenia by radiography and comparison with dual x-ray
absorptiometry (DXA) of the lumbar spine, Skeletal Radiol 1994, 23:
195-199
19. Genant H, Engelke K, Fuerst T et al Noninvasive assessment of bone
mineral and structure: state of art, J Bone Miner Res 1996, 11: 707-730
20. Will R, Bhalla AK, Palmer R et al Osteoporosis in early ankylosing
spondylitis: a primary pathological event ? Lancet 1989, 2: 14831485
21. Will R, Palmer R, Bhalla AK et al Bone loss as well as bone formation
is a feature of progressive ankylosing spondylitis, Br J Rheumatol 1999,
29: 498-499
22. Devogelaer JP, Maldague B, Malghem J et al Appendicular and
vertebral bone mass in ankylosing spondylitis. A comparison of plain
radiographs with single- and dual-photon absorptiometry and with
quantitative computed tomography, Arthritis Rheum 1992, 35: 1062-1067
23. Donnelly S, Doyle DV, Denton A et al Bone mineral density and
vertebral compression fracture rates in ankylosing spondylitis, Ann Rheum
Dis 1994, 53: 117121
24. Mulaji AB, Upadhyay SS, Ho EKW Bone mineral density in ankylosing
spondylitis. DEXA comparison of control subjects with mild and advanced
cases, J Bone Joint Surg Br 1994, 76: 660-665

160

25. Singh A, Bronson W, Walker SE et al Relative value of femoral and

lumbar bone mineral density assessments in patients with ankylosing
spondylitis, South Med J 1995, 88: 939943
26. Maill-efert JF, Aho LS, El Maghraoui A, et al Changes in bone
density in patients with ankylosing spondylitis: a two-year follow-up study,
Osteoporos Int 2001, 12: 605-609
27. 27.Capaci K, Hepguler S, Argin M et al Bone mineral density in mild
and advanced ankylosing spondylitis, Yonsei Med J 2003, 44: 379-384
28. Baek HJ, Kang SW, Lee YJ et al Osteopenia in men with mild and
severe ankylosing spondylitis, Rheumatol Int 2005, 26: 3034
29. Bronson WD, Walker SE, Hillman LS et al Bone mineral density and
biochemical markers of bone metabolism in ankylosing spondylitis, J
Rheumatol 1998, 25: 929-935
30. Gigil E, Kacar C, Tuncer T et al The association of syndesmophytes
with vertebral bone mineral density in patients with ankylosing spondylitis,
J Rheumatol 2005, 32: 292-294
31. Lee YS, Schlotzhauer T, Ott SM et al Skeletal status of men with early
and late ankylosing spondylitis, Am J Med 1997, 103: 233-241
32. Lange U, Kluge A, StrunkJ et al Ankylosing spondylitis and bone
mineral density. What is the ideal tool for measurement? Rheumatol Int
2005, 26: 115-120
33. Karberg K, Zochling J, Sieper J et al Bone loss is detected more
frequently in patients with ankylosing spondylitis with syndesmophytes J
Rheumatol 2005, 32: 1290-1298
34. Bessant R, Keat A How should clinicians manage osteoporosis in
ankylosing spondylitis? J Rheumatol 2002, 29: 1511-1519
35. Wedling D Bone loss in ankylosing spondylitis: can we put the puzzle
togheter? J Rheumatol 2005, 32: 1184-1186
36. Ralston SH, Urquhart GD, Brzeski M Prevalence of vertebral
compression fractures due to osteoporosis in ankylosing spondylitis, Br
Med J 1990, 300: 563 565
37. Sarikaya S, Barasan A, Tekin Y et al Is osteoporosis generalized or
localized to central skeleton in ankylosing spondylitis? J Clin Rheumatol
2007, 13: 2024
38. Albanese CV, Diessel E, Gennant HK et al Clinical application of body
composition measurements using DXA, J Clin Densitom 2003, 6: 75-85
39. El Maghraoui A, Borderie D, Cherruau B et al Osteoporosis, body
composition, and bone turnover in ankylosing spondylitis, J Rheumatol
1999, 26: 2205-2209
40. Toussirot E, Michel F, Wendling D Bone density, ultrasound
measurements and body composition in early ankylosing spondylitis, J
Rheumatology 2001, 40: 882-888
41. Hans D, Dargent Molina P, Schott AM et al Ultrasonographic heel
measurements to predict hip fracture in elderly women: the EPIDOS
prospective study, Lancet 1996, 348: 511-514
42. Gonnelli S, Cepollaro C, Gennari L et al Quantitative ultrasound and
dual-energy X-ray absorptiometry in the prediction of fragility fracture in
men, Osteoporos Int 2005, 16: 963-968
43. Speden DJ, Calin AI, Ring FJ Bone mineral density, calcanean
ultrasound, and bone turnover markers in women with ankylosing
spondylitis, J Rheumatology 2002, 29: 516-521
44. Jansen TL, Aarts MH, Zanen S Risk assessment for osteoporosis
by quantitative ultrasound of the heel in ankylosing spondylitis, Clin Exp
Rheum 2003, 21: 599-604
45. World Health Organization Assessment of fracture risk and its
application to screening for postmenopausal osteoporosis. WHO
Technical Report Series 843. Geneva: WHO, 1994
46. Melton LJ, Atkinson EJ, OConnor MK et al Bone density and fracture
risk in men, J Bone Miner Res 1998, 13:1915-1923
47. Meirelles ES, Borelli A, Camargo OP Influence of disease activity
and chronicity on ankylosing spondylitis bone mass loss, Clin. Rheumatol
1999, 18: 364-368
48. Reid DM, Nicoll JJ, Kennedy NSJ et al Bone mass in ankylosing
spondylitis, J Rheumatol 1986, 13: 932935
49. Szenjfeld VL, Monier-Faugere MC, Bognar BJ et al Systemic
osteopenia and mineralization defect in patients with ankylosing
spondylitis, J Rheumatol 1997, 24: 683-688
50. Looker AC, Bauer DC, Chesnut III CH Clinical use of biochemical
markers of bone remodeling: Current status and future directions,
Osteoporos Int 2000, 11: 467-480
51. Mitra D, Elvis DM, Collins AJ Biochemical markers of bone
metabolism in mild ankylosing spondylitis and their relantionship with
bone mineral density and vertebral fractures, J Rheumatol 1999, 26:
2201-2204

REVISTA ROMN DE REUMATOLOGIE VOL. XIX NR. 3, AN 2010

52. Franck H, Keck E Serum osteocalcin and vitamin D metabolites in

patients with ankylosing spondylitis, Ann Rheum Dis 1993, 52: 343 -346
53. Franck H, Meurer T, Hofbauer LC Evaluation of bone mineral density,
hormones, biochemical markers of bone metabolism, and osteoprotegerin
serum levels in ankylosing spondylitis, J Rheumatol 2004, 31: 2236-2241
54. Lange U, Jung O, Teichmann J et al Relationship between disease
activity and serum levels of vitamin D metabolites and parathyroid
hormone in ankylosing spondylitis, Osteoporos Int 2001, 12: 1031-1035
55. Lange U, Teichmann J, Strunck J et al Association of 1, 25 vitamin D3
deficiency, disease activity and low bone mass in ankylosing spondylitis,
Osteoporos Int 2005, 12: 1999-2004
56. Marhoffer M, Stracke H, Masoud I et al Evidence of impaired cartilage/
bone turnover in patients with ankylosing spondylitis, Ann Rheum Dis
1995, 54: 556-559
57. Toussirot E, Ricard-Blum S, Dumoulin G et al Relationship between
urinary pyridinium cross-links, disease activity and disease subsets of
ankylosing spondylitis, Rheumatology 1999, 26: 2201-2204
58. Acebes C, de la Piedra C, Traba ML et al Biochemical markers of
bone remodeling and bone sialoprotein in ankylosing spondylitis, Clin
Chim Acta 1999, 289:99-110
59. Yilmaz N, Ozaslan J Biochemical bone turnover markers in patients
with ankylosing spondylitis, Clin Rheumatol 2000, 19: 92-98
60. Lange U, Teichmann J, Stracke H Correlation between plasma
TNF-alpha, IGF1, biochemical markers of bone metabolism, markers of
inflammation/disease activity, and clinical manifestations in ankylosing
spondylitis, Eur J Med Res 2000, 29:,507-511
61. Borman P, Bodur H, Bingl N et al Bone mineral density and bone
turnover markers in a group of male ankylosing spondylitis patients:
relationship to disease severity, J Clin Rheumatol 2001, 7: 315-321
62. Marhoffer W, Schatz H, Stracke H et al Serum osteocalcin levels in
rheumatoid arthritis: A marker for accelerated bone turnover in late onset
rheumatoid arthritis, J Rheumatol 1991, 18: 1158 1162
63. El Maghraoui A, Tellal S, Chaouir S et al Bone turnover markers,
anterior pituitary and gonadal hormones, and bone mass evaluation
using quantitative computed tomography in ankylosing spondylitis, Clin
Rheumatol 2005, 24: 346-351
64. Falkenbach A, Herold M Osteocalcin: a marker of disease activity in
ankylosing spondylitis, Ann Rheum Dis 2002, 61: 92
65. Sheehan NJ, Slavin BM, Kind PRN et al Increased serum alkaline
phosphatase activity in ankylosing spondylitis, Ann Rheum Dis 1983, 42:
563565
66. Toussirot E, Nyugen NU, Dumoulin G et al Insulin-like growth factor-I
and insulin-like growth factor binding protein-3 serum levels in ankylosing
spondylitis, Br J Rheumatol 1998, 37:1172-1176
67. Toussirot E, Racadot E, Nyugen NU et al Absence of relation between
TGF1 serum levels and bone mass in ankylosing spondylitis patients.
68. Allali F, Breban M, Porcher R et al ncrease in bone mineral density of
patients with spondyloarthropathy treated with anti-tumour necrosis factor
, Ann Rheum Dis 2003, 62: 347-349
69. Briot K, Garnero P, Henanff A L et al Body weight, body composition,
and bone turnover changes in patients with spondyloarthropathy receiving
anti-tumour necrosis factor treatment, Ann Rheum Dis 2005, 64: 11371140
70. Delmas PD Markers of bone turnover for monitoring treatment of
osteoporosis with antiresorptive drugs, Osteoporos Int 2000, suppl 6:
S66-S76
71. Cairns AP, Wright SA Taggart AJ et al, An open study of pulse
pamidronate treatment in severe ankylosing spondylitis, and its effect on
biochemical markers of bone turnover, Ann Rheum Dis 2005, 64: 338-339
72. Vosse D, van der Heijde D, Landew R et al Determinants of
hyperkyphosis in patients with ankylosing spondylitis, Ann Rheum Dis
2006, 65: 770774
73. Mitra D, Elvins DM, Speden DJ et al The prevalence of vertebral
fractures in mild ankylosing spondylitis and their relationship to bone
mineral density, Rheumatology 2000, 39: 8589
74. Sivri A, Kilinc S, Gokce-Kutsal Y et al Bone mineral density in
ankylosing spondylitis, Clin Rheumatol 1996, 15: 51-54
75. Cooper C, Carbone L, Michet CJ et al Fracture risk in patients with
ankylosing spondylitis: A population based study, J Rheumatol 1994, 21:
1877-1882
76. Feldtkeller E, Vosse D, Geusens P et al Prevalence and annual
incidence of vertebral fractures in patients with ankylosing spondylitis,
Rheumatol Int 2006, 26: 234-239

REVISTA ROMN DE REUMATOLOGIE VOL. XIX NR. 3, AN 2010

77. Finkelstein JA, Chapman JR, Mirza S Occult vertebral fractures in

ankylosing spondylitis, Spinal Cord 1999, 37:444 447
78. Olerud C, Frost A, Bring J Spinal fractures in patients with ankylosing
spondylitis, Eur Spine J 1996, 14: 51-55
79. Graham B, Van Peteghhem PK Fractures of the spine in ankylosing
spondylitis. Diagnosis, treatment, and complications, Spine 1998, 14:
803-807
80. Hitchon PW, From AM, Brenton MD et al Fractures of the
thoracolumbar spine complicating ankylosing spondylitis, J Neurosurg
2002, 97: 218-222
81. Vosse D, Feldtkeller E, Erlendsson J et al Clinical vertebral fracture in
patients with ankylosing spondylitis, J Rheumatol 2004, 31: 1981-1985
82. Thorngren KG, Liedberg E, Aspelin P Fractures of the thoracic and
lumbar spine in ankylosing spondylitis, Arch Orthop Traumat Surg 1981,
98:101-107
83. Hunter T, Dubo HIC Spinal fractures complicating ankylosing
spondylitis. A longterm follow-up study, Arthritis Rheum 1983, 26:
751 759
84. Meirelles ES, Borelli A, Camargo OP Influence of disease activity
and chronicity on ankylosing spondylitis bone mass loss, Clin Rheumatol
1999, 18: 364-368
85. Gratacos J, Collado A, Pons F et al Significant loss of bone mass
in patients with early, active ankylosing spondylitis. A follow-up study,
Arthritis Rheum 1999, 42: 23192324
86. Maillefert JF, Aho LS, El Maghraoui A et al Changes in bone density
in patients with ankylosing spondylitis: a two-year follow-up study,
Osteoporos Int 2001, 12: 605-609
87. Dos Santos FP, Constantin A, Laroche M Whole body and regional
bone mineral density in ankylosing spondylitis, J Rheumatol 2001, 28:
547-549
88. Mitra D, Elvins DM, Collins AJ Testosterone and testosterone free
index in mild ankylosing spondylitis. Relationship with bone mineral
density and vertebral fractures, J Rheumatol 1999, 26: 2414-2417
89. Straub RH, Struhrov J, Schlmerich J et al No alterations of serum
levels of adrenal and gonadal hormones in patients with ankylosing
spondylitis, Clin Exp Rheumatol 2002, 20 (Suppl 28):S52-S59
90. Ralston SH Genetic control of susceptibility to osteoporosis, J Clin
Endocrinol Metab 2002, 87: 2460-2466
91. Obermayer Pietsch BM, Lange U, Tauber G et al Vitamin D receptor
initiation codon polymorphism, bone density and inflammatory activity of
patients with ankylosing spondylitis, Osteoporos Int 2003, 14: 9951000
92. Schett G Erosive arthritis, Arthritis Res Ther 2007, 9 (Suppl1):S2
93. Walsh NC, Crotti TN, Goldring SR et al Rheumatic diseases: the
effects of inflammation on bone, Immunol Rev 2005, 208: 228251

161

94. Hofbauer LC, Schoppet M Clinical implication of the osteoprotegerin/

RANKL/RANK system for bone and vascular disease, JAMA 2004, 28:
490 495
95. Schett G, Landew R, van der Heijde D Tumour necrosis factor
blockers and structural remodelling in ankylosing spondylitis: what is
reality and what is fiction? Ann Rheum Dis 2007, 66: 709-711
96. Gratacos J, Collado A, Filella X et al Serum cytokines (IL-6, TNFalpha, IL-1 beta, and IFN-gamma) in ankylosing spondylitis: a close
correlation between serum IL-6 and disease activity and severity, Br J
Rheumatol 1994, 33: 927 931
97. Chung-Tei Chou, An-Ping Huo, Hsiao-Ning Chang Cytokine production
from peripheral blood mononuclear cells in ankylosing spondylitis and their
first degree relatives, Arch Med Res 2007, 38:190-195
98. Wendling D Bone and matrix remodeling markers: A new tool for
assessment of treatment efficacy in ankylosing spondylitis? J Rheumatol
2007, 34: 16471649
99. Kim HR, Kim HY, Lee SH Elevated serum levels of soluble receptor
activator of nuclear factor kappa B ligand (sRANKL) and reduced bone
mineral density in patients with ankylosing spondylitis, Rheumatology
Oxford 2006, 45:1197 1200
100. Grisar J, Bernecker PM, Aringer M et al Ankylosing spondylitis,
psoriatic arthritis, and reactive arthritis show increased bone resorption,
but differ with regard to bone formation, J Rheumatol 2002, 29:
14301436
101. Golmia RP, Sousa BD, Scheinberg MA Increased osteoprotegerin
and decreased pyridinoline levels in patients with ankylosing spondylitis:
comment on the article by Gratacos et al. Arthritis Rheum 2002,
46:33903391
102. Bessant R, Harris C, Keat A Audit of the diagnosis, assessment,
and treatment of osteoporosis in patients with ankylosing spondylitis, J
Rheumatology 2003, 30: 779 782
103. Haibel H, Braun J, Maksymowych WP Bisphosphonates Targeting
bone in treatment of spondyloarthritis, Clin Exp Rheumatol 2002, 20
(Suppl 28):S162 S166
104. Maksymowych WP, Jhangri GS, Fitzgerald AA et al A sixmonth
randomized, controlled, doubleblind, doseresponse comparison of
intravenous pamidronate (60 mg versus 10 mg) in the treatment of
nonsteroidal anti-inflammatory drugrefractory ankylosing spondylitis,
Arthritis Rheum 2002, 46: 766773
105. Braun J, Sieper J Biological therapies in the spondyloarthritides the
current state, Rheumatology 2004, 43: 10721084
106. MarzoOrtega H, McGonagle D, Haugeberg G Bone mineral density
improvement in spondyloarthropathy after treatment with etanercept, Ann
Rheum Dis 2003, 62: 10201021

Vizitai site-ul

SOCIETII ROMNE DE REUMATOLOGIE

www.srreumatologie.ro