Study of bone metabolism in children and adolescents with type I diabetes mellitus: the role of sclerostin

Introduction: Diabetes Mellitus (DM) is a risk factor for reduced bone mass. Several bone metabolic pathways seem to be disrupted in patients with type 1 diabetes mellitus (T1DM), leading to the observed reduced Bone Mineral Density (BMD). Sclerostin and dickkopf-1 are inhibitors of the Wnt/b-catenin bone metabolic pathway. Increased sclerostin and dickkopf-1 levels and have been documented in adult patients with Diabetes Mellitus (DM), predominantly in those with T2DM. No relevant data exist on childhood T1DM. Furthermore, Osteoprotegerin (OPG) has been found higher in young T1DM patients, while Receptor Activator of Nuclear factor-KappaB Ligand(s-RANKL) has been found with comparable levels to controls.Aims Our aim was to study plasma sclerostin, dickkopf-1, OPG and s-RANKL concentration in children and adolescents with T1DM and controls and to correlate their levels with metabolic bone markers and BMD.Materials and Methods: We evaluated 40 children and adolescents with T1DM (mean±SD age 13.04±3.53 years, mean±SD T1DM duration 5.15±3.33years) and 40 healthy age- and gender-matched controls (mean±SD age 12.99±3.3years). Sclerostin, dickkopf-1, OPG, s-RANKL, Osteocalcin, C-telopeptide crosslinks-CTX, electrolytes, PTH, total alkaline phosphatise (ALP) and 25(OH)D were measured. Lumbar spine and total body Bone Mineral Density(BMD) were evaluated with dual energy X-ray absorptiometry (DXA). Results: Patients had significantly lower BMD than controls (L1-L4 BMD Z-score -0.17SD vs 0.23SD, p=0.03, total body BMD Z-score 0.23SD vs 0.56SD, p=0.04). Patients had significantly higher levels of OPG (6.15±1.56 vs 5.01±1.5 pmol/L, p<0.001), s-RANKL(logS-RANKL 5.97±0.63 vs 5.51±0.84, p=0.004) and ALP and lower levels of PTH and magnesium. Patients and controls had comparable 25(OH)vitD levels, while one third of both groups had low 25(OH)vitD levels(<20ng/ml). Osteocalcin was highly correlated with CTX in both groups (r=0.75, p<0.001), indicating coupling of bone resorption and formation but lower levels of both markers in patients could indicate lower bone turnover and osteoblastic disorder. OPG and s-RANKL were associated in controls (R2=0.15, p=0.021) but not in patients (R2=0.006, p=0.64), possibly indicating an osteoclastic disorder . Sclerostin levels in patients and controls were comparable (51.56±12.05 vs 50.98±13.55 pmol/L, p=0.84). Lower values were found in girls (49.1±12.7 vs 53.9±12.3 pmol/L, p=0.05) and in prepubertal children (47.3±11.6 vs 53.3±12.9 pmol/L, p=0.02). Sclerostin values significantly and gradually increased in children through pubertal Tanner stages 1 to 3, then reduced in stage 4 adolescents and increased again in pubertal stage 5 adolescents (ANOVA F=4.56, p=0.0024). Sclerostin levels were positively correlated with logCTX, logOsteocalcin and BMD Z-scores. Dickkopf-1 levels were found higher in patients(13.56±5.34 vs 11.35±3.76 pmol/L, p=0.0194), in boys (13.36±4.04 vs 11.72±5.14 pmol/L, p=0.02) and prebubertal children (13.61±4.87 vs 11.83±4.56 pmol/L, p=0.05). Dickkopf-1 was positively associated with logCTX, logOsteocalcin and IGF-1 in both groups, while in patients it was associated with OPG and fasting plasma glucose. The lowest dickkopf-1 values were found in Tanner stage 3 adolescents. Conclusions: RANKL/OPG axis seems to be significantly activated in patients with T1DM. These changes could indicate abnormal osteoclast function, while lower bone turnover could indicate abnormal osteoblast function and both could be associated with the lower bone mass, found in T1DM patients. Children and adolescents with T1DM had similar sclerostin but higher levels of dickkopf-1 than controls, indicating a downregulated Wnt/b-catenin bone metabolic pathway. Dickkopf-1 association with OPG and plasma fasting glucose in patients could indicate dickkopf-1 implication in RANKL/OPG axis dysregulation in that group. The decrease in sclerostin values observed in pubertal stage 4 adolescents and dickkopf-1 values in pubertal stage 3 adolescents coincide with the concurrent growth spurt, and are consistent with sclerostin and dickkopf-1 physiology as inhibiting signals. The only current realistic measures against bone disease in patients with T1DM are optimal glycaemic control along with regular physical exercise.Εισαγωγή: Αρκετές οστικές μεταβολικές οδοί διαταράσσονται στους ασθενείς με Σακχαρώδη Διαβήτη τύπου 1(T1ΣΔ) με αποτέλεσμα να ανευρίσκεται μειωμένη οστική πυκνότητα(BMD). Η σκληροστίνη και ο dickkopf-1 είναι αναστολείς της μεταβολικής οδού Wnt/β-κατενίνης των οστών. Αυξημένα επίπεδα σκληροστίνης και dickkopf-1 έχουν τεκμηριωθεί σε ενήλικες Τ2ΣΔ ασθενείς, ενώ δεν υπάρχουν μελέτες στα παιδιά με Τ1ΣΔ. Ομοίως η Οστεοπροτεγερίνη(OPG) έχει βρεθεί αυξημένη στους νεαρούς ασθενείς με Τ1ΣΔ, ενώ ο παράγοντας Receptor Activator of Nuclear factor-KappaB Ligand (s-RANKL) δεν έχει βρεθεί να διαφοροποιείται σημαντικά.Σκοπός: Η μελέτη της σκληροστίνης, του dickkopf-1, της OPG, του s-RANKL, καθώς και η μελέτη δεικτών οστικού μεταβολισμού σε παιδιά και εφήβους με Τ1ΣΔ και σε φυσιολογικά παιδιά και η συσχέτιση των τιμών των αναφερθέντων παραμέτρων τόσο μεταξύ τους όσο και με την ΟΠ.Υλικό: Αξιολογήθηκαν 40 παιδιά και έφηβοι με T1ΣΔ (μέση τιμή±SD ηλικίας:13.04± 3.53 έτη, διάρκεια ΣΔ1: 5.15±3.33 έτη), και 40 υγιείς μάρτυρες (μέση τιμή±SD ηλικίας 12.99±3.3 έτη). Μέθοδος: Μετρήθηκαν η σκληροστίνη, ο dickkopf-1, η οστεοκαλσίνη, τα καρβοξυτελικά πεπτίδια αποδόμησης του κολλαγόνου-CTX, η OPG, ο παράγοντας s-RANKL,ηλεκτρολύτες, παραθορμόνη(PTH), ολική αλκαλική φωσφατάση (ALP) και 25(OH)D. Η ολόσωμη BMD (ΤΒ-ΒΜD) και η BMD οσφυϊκής μοίρας σπονδυλικής στήλης (L1-L4 BMD) αξιολογήθηκαν με απορρόφησιομέτρηση ακτίνων Χ διπλής ενέργειας(DXA).Αποτελέσματα: Η BMD ήταν σημαντικά χαμηλότερη στους ασθενείς από τους μάρτυρες (L1-L4 BMD Z-score -0.17 SD vs 0.23 SD, p=0.03, TB-BMD Z-score 0.23 SD vs 0.56 SD, p=0.04). Οι ασθενείς είχαν υψηλότερα επίπεδα OPG (6.15±1.56 vs 5.01±1.5 pmol/L, p<0,001), s-RANKL(logs-RANKL 5.97±0.63vs5.51±0.84, p=0.004), dickkopf-1 (13.56±5.34 vs 11.35±3.76 pmol/L, p=0.0194) και ALP και χαμηλότερα επίπεδα οστεοκαλσίνης, CTX, ΡΤΗ και μαγνησίου από τους μάρτυρες. Οι ασθενείς και οι μάρτυρες είχαν συγκρίσιμα επίπεδα 25(ΟΗ)VitD, ενώ το ένα τρίτο αμφοτέρων των ομάδων είχε χαμηλά επίπεδα 25(ΟΗ)VitD (<20ng/ml). H oστεοκαλσίνη και η CTX συσχετίζονταν σε αμφότερες τις ομάδες (r=0.75, p