Metabolička bolest kostiju u Crohnovoj bolesti [Metabolic bone disease and Crohn's disease]

Turk, Nikša (2008) Metabolička bolest kostiju u Crohnovoj bolesti [Metabolic bone disease and Crohn's disease]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Objective The high incidence of bone disease and increasing evidence for Crohn´s disease (CD) affecting bone status in corticosteroid users and non-users suggest that bone metabolism is affected by inflammatory process. This study aimed to determine comparative serum levels of proinflammatory cytokines, markers of bone formation and resorption, and regulatory molecules of osteoclast biogenesis RANKL and osteoprotegerin (OPG), in CD patients with and without metabolic bone disease. Patients and Methods The study included 95 patients; 15 of them newly diagnosed and untreated, and 80 patients with long-standing Crohn´s disease. Serum sRANKL, OPG, TNF-α, IL-1β, IL-6, osteocalcin and C-telopeptide I were measured by immunoassay. Bone status was evaluated, in parallel, by calcaneal quantitative ultrasound (QUS), and dual-energy x-ray absorptiometry (DXA) scanned spine (L1-L4) and hip bone mineral density (BMD). Results Decreased BMD at diagnosis was found in 53% and low bone mass in 72% of the study population. The newly diagnosed, untreated patients showed correlation between TNF-α and sRANKL (r=0.6; p=0.027), and this positive relationship also persists in the unselected study population of long-standing CD patients (n=80) (r=0.3; p=0.009). Multiple regression identified TNF-α as the best predictor of sRANKL (p<0.001). Analysis of the OPG and sRANKL relationship according to subgroups showed absence of correlation in patients with healthy skeleton, and an inverse relationship in those with decreased BMD (r=-0.36; p=0.003). In naïve patients with reduced BMD t-score≤-1.0, the correlation between sRANKL and OPG was highly inverse (r=-0.8; p=0.02) and Abstract 79 these patients were characterized by lower BMI, significantly higher level of proinflammatory cytokines, elevated CRP and increased activity of free sRANKL and OPG. The sensitivity of QUS to identify bone disease was 93%; indicating 7% of patients with verified bone disease to be misclassify as false negative. The specificity of 63% showed that 37% of individuals with normal bone status were QUS classified as false positive. The sensitivity of QUS to detect osteopenia was 84% and 72% for osteoporosis. Conclusions Bone disease that accompanies CD at diagnosis suggests that bone metabolism is affected by the underlying inflammatory process per se, as probably confirmed by our finding of the central proinflammatory cytokine TNF-α being strongly associated with the osteoclastogenic mediator RANKL, and inversely with bone density. Calcaneal QUS showed poor agreement with bone status scanned by DXA and a low discriminatory power between osteopenia and osteoporosis. However, QUS successfully identified patients with previous fragile fractures.

Abstract in Croatian

Svrha/Ciljevi Metabolička bolest kostiju je učestala ekstraintestinalna manifestacija Crohnove bolesti. Patogeneza nije u potpunosti jasna, no kako se javlja u bolesnika koji jesu, ali i u onih koji nisu liječeni kortikosteroidima, prepostavlja se da sam upalni proces ima značajnog upliva na koštani metabolizam. Stoga je cilj ovog istraživanja bio komparativno evaluirati proupalne citokine, biljege koštane izgradnje i razgradnje, te regulatorne molekule u biogenezi osteoklasta RANKL i osteoprotegerin (OPG), u skupinama bolesnika s Crohnovom bolesti sa i bez metaboličke bolesti kostiju. Bolesnici i metode Ispitivanu skupinu od 95 bolesnika činilo je njih 80 s dugogodišnjim trajanjem Crohnove bolesti i 15 bolesnika u kojih je bolest tek dijagnosticirana. Koncentracije sRANKL, OPG, TNF-α, IL-1β, IL-6, osteokalcina i C-telopeptida u serumu, odreñivane su imunološkim metodama. Koštani je status mjeren metodom dvostruke apsorpciometrije X-zraka (DXA) odreñivanjem mineralne gustoće kostiju (BMD) lumbalne kralješnice i kuka, te uporedo, metodom kvantitativnog ultrazvuka petne kosti (QUS). Rezultati U skupini s tek dijagnosticiranom Crohnovom bolesti 53% bolesnika ima sniženu mineralnu koštanu gustoću, dok je u bolesnika s dugogodišnjim trajanjem bolesti osteoporoza prisutna u njih 26%. U naïvnih je bolesnika zabilježena vrlo dobra korelacija izmeñu središnjeg proupalnog citokina TNF-α i osteoklastičnog posrednika sRANKL (r=0.6; p=0.027), a ta je pozitivna korelacija ostala nepromjenjenom i u skupini bolesnika s višegodišnjim trajanjem bolesti (r=0.3; p=0.009). Koncentracije slobodnog RANKL-a i njegovog receptora OPG koreliraju negativno u bolesnika sa sniženom mineralnom gustoćom kostiju (r=- Sažetak 77 0.36; p=0.003), dok u bolesnika sa zdravim skeletom nema meñusobne povezanosti. U naïvnih bolesnika s reduciranom mineralnom gustoćom kostiju (T-vrijednost ≤-1.0), korelacija izmeñu RANKL-a i OPG je izrazito visoka, ali s negativnim predzakom (r=-0.8; p=0.02). Tu podskupinu bolesnika ujedno karakterizira niži indeks tjelesne mase, značajno viša koncentracija proupalnih citokina, visoka razina CRP i pojačane aktivnosti RANKL i OPG. Nalazi kvantitativnog ultrazvuka petne kosti nisu pokazali dobru podudarnost s DXA mjerenjima (specifičnost 63%). Osjetljivost QUS metode u detekciji osteopenije je 84%, a 72% za osteoporozu. Meñutim QUS petne kosti je uspješnija metoda u identificiraju bolesnika s rizikom koštanih prijeloma. Zaključci Rezultati ove studije snažno podupiru hipotezu da upalni proces per se u Crohnovoj bolesti ima primarnu ulogu u razvijanju i napredovanju metaboličke bolesti kostiju. U prilog izrečenom govori podatak da središnji proupalni citokin TNF-α vrlo pozitivno korelira s osteoklasičnim posrednikom RANKL, a negativno s mineralnom koštanom gustoćom. Klinički se to ogleda u činjenici da 50% naïvnih bolesnika već pri dijagnozi ima nižu koštanu gustoću. Kvantitativni ultrazvuk petne kosti prema rezultatima prikazanog istraživanja nije pouzdana zamjena za metodu klasične denzitometrije, no može poslužiti kao komplementarna opcija jer se pokazalo da je dobar prediktivni parametar za rizik na koštane prijelome.

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