Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration

Abstract

Terpos E. Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemiainduced osteoporosis. Reduction post-zoledronic acid administration. Haematologica 2009; 94:725-728. doi: 10.3324/haematol.2008 This is an open-access paper. ABSTRACTSerum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration Dkk1 was measured at baseline and after 12 months of therapy, using ELISA methodology (Biomedica Medizinprodukte, No. BI-20412, Gesellschaft GmbH, Wien, Austria; in this ELISA 1 pmol/L=28.68 pg/mL), along with a series of serum bone indices: i) bone resorption markers [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP5b)], ii) bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC) and C-terminal propeptide of collagen type-I (CICP)], and iii) osteoclast regulators [receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and osteopontin], as previously described. 4 Bone mineral density (BMD) of the lumbar spine (L1-L4), femoral neck (FN) and distal radius (R) was determined using Dual-Energy X-ray Absorptiometry (DXA; LUNAR, PRODIGY Version 8.60.006/SYSTEM GE medical system LUNAR USA 726, Heartland Trail, Madison, WI 53717, USA) before and 12 months post-ZOL treatment. 4 The above bone markers were also evaluated in 30, age-and gender-matched, healthy controls (11M/19F, median age 44 years, range: 21-55 years). All controls had BMD measurements (L1-L4/FN/R) to exclude osteopenia/osteoporosis of other etiology, and were examined to ensure that there was no evidence of bone disease (i.e. osteoarthritis) and no receipt of medication that could alter the normal bone turnover during the previous six months. Statistical analysisThe Mann-Whitney test and paired samples t-tests were applied to evaluate the differences between patients and controls while the Wilcoxon signed rank test was used to evaluate differences between baseline and values of the studied parameters at the various time points. Differences between patients of three groups were evaluated using the Mann-Whitney test and the one-way ANOVA. The correlation between changes of various biochemical parameters and BMD was evaluated with the Spearman's (rs) correlation coefficient. Variables found to be statistically significant at the p<0.05 level for the presence of severe osteoporosis (Z-score< -4.0) in at least one studied site were entered into a multivariate model using Cox regression analysis to identify the most statistically significant model. All p values are two sided, the level of significance is <0.05 and confidence intervals refer to 95% boundaries. © F e r r a t a S t o r t i F o u n d a t i o n Results and DiscussionAt baseline, thalassemia patients had increased serum levels of Dkk1 (mean±SD: 39±17.1 pmol/L) compared with controls (27.4±9.7 pmol/L; p<0.0001; Figure 1A Figure 1B) and R-BMD (r=-0.415, p=0.001...

High Circulating Sclerostin is Present in Patients with Thalassemia-associated Osteoporosis and Correlates with Bone Mineral Density

“…In contrast, placebo group patients showed an increase of sclerostin levels (from 628 ± 534 to 781 ± 429 pg/ml; p = 0.01) and a borderline increase of Dkk-1 (p = 0.08). In our thalassemia patients, after zoledronic acid treatment the correlations between sclerostin and BMD of the studied sites was not significant anymore, while a signifi cant negative correlation was observed between percentage change of Dkk-1 and percentage change of L1-L4 BMD (r = − 0.458, p < 0.01) and R-BMD (r = − 0.512, p < 0.01) in patients who received zoledronic acid, as reported previously [ 4 ] .…”

“…Linear regression analysis showed that age was strongly correlated with sclerostin levels (r = 0.759; p < 0.001) independent of the type of the disorder (thalassemia-associated osteoporosis or postmenopausal osteoporosis; p = 0.110). [ 4 ] . There was also a weak correlation between FN-BMD and serum Dkk1 (r = − 0.212, p = 0.072).…”

Effects of strontium ranelate on bone mass and bone turnover in women with thalassemia major-related osteoporosis

“…As previously reported by Voskaridou et al, subjects with TM-induced osteoporosis showed higher values of soluble DKK-1 and sclerostin (which are well-characterized receptor inhibitors of the Wnt pathway in bone) when compared with healthy controls [13,14]. In TM subjects, L1-L4 BMD was positively related to sclerostin, and this could be explained, at least in part, to the higher osteocyte number or osteocyte viability.…”

“…This pathway is modulated by a number of factors that include Dickkopf-1 (DKK-1) and sclerostin, which compete with Wnt/ β-catenin for binding to LRP5/6, disrupting (Dkk-1) or antagonizing (sclerostin) LRP5/6-mediated Wnt signaling. Recently, sclerostin and DKK-1 were found to be increased in TM patients, highlighting a possible role of the Wnt pathway in the pathogenesis of TM-induced osteoporosis [13,14].…”

Bleeding disorders and reduced bone density

“…The RBD in men is multi-factorial, factors such as advancing age, heredity, hypogonadism, chronic steroid use, alcohol, calcium and vitamin D intake, weight, chronic illness, smoking and restricted physical activity will impact bone mass [2,7]. High incidence of RBD has already been reported in some haematological disorders such as thalassemia and haematologic malignancies [8,9].…”