Dkk-1 In Patients Research Articles

Study of serum and synovial fluid Dickkopf-1 levels in patients with primary osteoarthritis of the knee joint in correlation with disease activity and severity

BackgroundOsteoarthritis (OA) is a typical complex degenerative articular ailment that shows focal cartilage loss, new bone formation with involvement of entire joint tissues. Dkk-1 assumes a job in controlling the pattern of bone repair and regeneration in both OA and RA. This study aimed to determine serum and synovial fluid levels of Dickkopf-1 (Dkk-1) in patients with primary OA of the knee joint and study their correlations with disease activity and severity. This study included 45 patients, 30 of them were diagnosed as primary knee OA. Fifteen rheumatoid arthritis patients as well as 15 healthy subjects were enrolled in the study as control groups, serum and synovial levels of Dkk-1 were estimated utilizing the ELISA technique.ResultsSerum levels of Dkk-1 were significantly higher in OA patients than healthy subjects (p < 0.001), although it was even significantly higher in RA patients than OA patients (p < 0.001). There was a highly significant decrease in the median synovial level of Dkk-1 in OA patients compared to the RA control group (p < 0.001). There was a highly statistically significant inverse correlation between circulating as well as synovial fluid Dkk-1 levels and radiological disease grading in knee OA (p < 0.001). There was a statistically significant decrease in serum levels of Dkk-1 in patients with severe OA (grade 3, 4) compared to those with mild OA (Grade 2) (p < 0.001).ConclusionDkk-1 is an interesting marker that is related to articular disease .It could play an important role in decelerating the degenerative process of OA and can reflects radiographic severity of the disease as well.

Correlation between magnetic resonance imaging (MRI) findings and the new bone formation factor Dkk-1 in patients with spondyloarthritis

In recent years, MRI has been regarded as a major diagnostic tool for spondyloarthritis (SpA), and anti-TNF therapy has been widely confirmed as an effective treatment strategy. This study was designed to investigate the correlation between the secreted protein dickkopf-1 (Dkk-1) and abnormal findings on magnetic resonance imaging (MRI) through a prospective study of 30 cases of SpA. Thirty patients with active SpA were included, all treated with recombinant human tumor necrosis factor (TNF) receptor-antibody fusion protein (YiSaiPu) injection at 50 mg/week for 6 months. All patients were also examined for their clinical, serological, and imaging manifestations of the condition before and after treatment. In patients receiving TNF inhibitor treatment, the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and clinical activity indices BASDAI, BASFI, BASMI, ASDAS-CRP were significantly decreased (p < 0.01). Serum Dkk-1 concentration was also significantly decreased (p < 0.05), as were the scores of bone marrow edema of the sacroiliac joints and the spine (p < 0.05). The score of sacroiliac joint backfill was significantly increased (p < 0.05), and the baseline and changes in the serum Dkk-1 concentration were significantly correlated with the baseline and changes in spinal bone marrow edema levels. Inhibition of the level of serum Dkk-1 by TNF inhibitors may be the molecular basis for inhibiting the formation of new bone in SpA patients. In addition, spinal marrow edema may have significance for predicting new bone formation.

Chemotherapy-induced Dkk-1 expression by primary human mesenchymal stem cells is p53 dependent.

Mesenchymal stem cells (MSCs) are abundant throughout the body and regulate signaling within tumor microenvironments. Wnt signaling is an extrinsically regulated pathway that has been shown to regulate tumorigenesis in many types of cancer. After evaluating a panel of Wnt activating and inhibiting molecules, we show that primary human MSCs increase the expression of Dkk-1, an inhibitor of Wnt signaling, into the extracellular environment following chemotherapy exposure in a p53-dependent manner. Dkk-1 has been shown to promote tumor growth in several models of malignancy, suggesting that MSC-derived Dkk-1 could counteract the intent of cytotoxic chemotherapy, and that pharmacologic inhibition of Dkk-1 in patients receiving chemotherapy treatment for certain malignancies may be warranted.

Increased serum and bone matrix levels of the secreted Wnt antagonist DKK-1 in patients with growth hormone deficiency in response to growth hormone treatment.

Growth hormone (GH) substitution of adult-onset growth hormone deficiency (aoGHD) patients partially reverses unfavorable body composition profile. Wnt signaling pathway has being acknowledged as an important modulator of bone mass and of energy metabolism in adipose tissue and in β-cells. To assess the role of selected Wnt antagonists in bone and glucose metabolism before and after GH replacement in aoGHD. Patients from two randomized placebo-controlled studies of GH replacement in aoGHD were used. In study 1, 39 patients received GH or placebo for 9 months with 4 months wash-out. In study 2, iliac bone biopsies were obtained before and after GH or placebo (n = 10 each) for 12 months. Body composition and serum (study 1) and bone matrix (study 2) levels of Wnt antagonists (DKK-1, sFRP-3, WIF-1, and SOST) were quantified before and after GH. In vitro effect of GH and IGF-1 on DKK-1 secretion and expression of Wnt signaling modulators was assessed in human osteoblasts and mature adipocytes. GH replacement increased circulating and bone matrix levels of DKK-1, but not sFRP-3, WIF-1, and SOST. Furthermore, DKK-1 secretion increased in human osteoblasts stimulated by GH in vitro, with no effects on other cells. At baseline and after treatment, circulating DKK-1 was negatively associated with bone mass, but not fat mass or measures of insulin resistance, in aoGHD patients. An increase in DKK-1 may limit the effects of GH on bone mass, but does not seem to impact the increase in insulin resistance following GH substitution.

FRI0513 Decreased Skin Expression but Normal Circulating Levels and Function of Dickkopf-1 in Patients with Systemic Sclerosis

BackgroundThe critical question of what drives fibroblast activation in systemic sclerosis (SSc) remains unanswered. The Wnt pathway, a known regulator of osteoblastogenesis, has also emerged as a crucial mediator of...

FRI0149 Dikkopf-1 (DKK-1) Serum Levels in Axial Spndyloarthritis (AXSPA) Are Related to Disease Duration

BackgroundTumor necrosis factor (TNF) alpha is responsible for induction of dkk-1 which down-regulates bone formation. Therefore, it was expected that TNF-blocker therapy would inhibit radiographic progression in patients with axSpA...

Dickkopf-1: As a Diagnostic and Prognostic Serum Marker for Early Hepatocellular Carcinoma

The aim of the present study was to evaluate serum Dickkopf-1 (Dkk-1) as a marker for early detection of hepatocellular carcinoma (HCC), as well as for prognostic prediction of early HCC after hepatic resection. One-hundred and four cases of matched fresh tissue specimens of early HCC and adjacent non-tumorous liver tissue (ANLT) were obtained for RT-PCR, qRT-PCR, western blot and immunohistochemistry assays. Sera were collected from patients with early HCC (n=184), benign liver tumors (n=29), cirrhosis (n=174), non-cirrhotic hepatitis B (n=193), and from healthy individuals (n=202). The levels of Dkk-1 and alpha fetoprotein (AFP) were measured. The Dkk-1 mRNA and protein levels were both upregulated in early HCC. Serum levels of Dkk-1 in patients with early HCC were significantly higher than in the other 4 groups (p<0.001). Dkk-1 had a better sensitivity and accuracy than AFP (p<0.05). More importantly, 73.1% of the patients negative for AFP could be diagnosed with early HCC using Dkk-1. A combination of Dkk-1 and AFP further improved the diagnostic efficacy. Patients with a high serum Dkk-1 level had poorer overall and relapse-free survivals than those with a low Dkk-1 level (p=0.028 and p=0.045, respectively). These results were shown in a testing cohort and confirmed in a validation cohort of patients. Univariable and multivariable Cox regression analyses showed serum Dkk-1 level to be an independent prognostic factor for overall survival. Our data show that Dkk-1 is a diagnostic and prognostic serologic marker for early HCC.

AB0557 Effects of tocilizumab on bone homeostasis and DICKKOPF-1 in rheumatoid arthritis

BackgroundTocilizumab (TCZ) is a humanized monoclonal anti-IL-6 receptor antibody. TCZ has demonstrated efficacy in moderate to severe active rheumatoid arthritis (RA) with inadequate clinical response to disease-modifying anti-rheumatic drugs (DMARD)...

Serum sclerostin and Dkk1 in patients with parathyroid disorders

Serum sclerostin and Dkk1 in patients with parathyroid disorders

Dickkopf-1 in ankylosing spondylitis: Relation to spinal dysmobility and radiographic findings

Back groundDickkopf-1 (DKK-1) is an inhibitory molecule that regulates Wnt pathway, which is critically important in osteoblastic new bone formation, therefore it may play a role in the process of new bone formation in Ankylosing Spondylitis (AS). Aim of the workTo measure serum level of DKK-1 in AS patients and study the relation between these levels with disease activity, spinal dysmobility and radiographic findings. Patients and methodsThirty AS patients as well as 20 healthy subjects as a control group were included in this study. DKK-1 serum levels were measured using ELISA technique, disease activity was assessed using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score, radiographic assessment by Bath Ankylosing Spondylitis Radiology Index-spine (BASRI-s) and modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). ResultsDKK-1 was not correlated to ESR, CRP or BASDAI (p>0.05) and was negatively correlated to BASRI-s and mSASSS (p<0.001), though DKK-1 serum level was unexpectedly higher in patients versus control (p<0.001). On comparing HLA-B27 positive and HLA-B27 negative patients, there were a significant increase in BASRI-s and mSASSS and decrease in DKK-1 level in those with positive HLA-B27 (p<0.05). On comparing patients received anti TNF therapy and those not received anti TNF therapy, there was no significant difference in DKK-1 level (p>0.05). ConclusionOur finding suggests dysfunction of DKK-1 in patient with AS.

Circulating Dickkopf-1 in acute ischemic stroke and clinically stable cerebrovascular disease

ObjectivesPrevious data suggest that Dickkopf-1 (Dkk-1), an inhibitor of the canonical/β-catenin cascade of the Wnt pathway, is upregulated in carotid atherosclerosis and acute myocardial ischemia. It is currently unclear if such upregulation also occurs in cerebral ischemia. MethodsWe measured plasma levels of Dkk-1 in patients with acute ischemic stroke (n=57) within 24h from symptom onset, in patients with clinically stable cerebrovascular disease (n=29) and in healthy controls (n=29). Stroke severity on admission was determined by the National Institutes of Stroke Scale (NIHSS). The modified Rankin Scale (mRS) served to define outcome at day 90. Ischemic stroke subtype and cause was determined by the Oxfordshire Community Stroke Project (OCSP) criteria and the Causative Classification of Stroke System (CCS). ResultsDkk-1 plasma levels were significantly higher in acute stroke patients (median 727.1pg/ml) as compared to patients with stable cerebrovascular disease (median 534.2pg/ml; p=0.017) or healthy controls (median 371.3pg/ml; p<0.001). The difference of Dkk-1 levels between patients with stable cerebrovascular disease and healthy controls was also significant (p=0.005). No significant differences in Dkk-1 plasma levels were found between different causes or subtypes of ischemic stroke. No correlation of Dkk-1 levels was found with stroke severity on admission and outcome at day 90. ConclusionOur study provides for the first time evidence for a release of Dkk-1 into the circulation in patients with acute ischemic stroke and also in patients with clinically stable cerebrovascular disease.

High Circulating Levels of Sclerostin Correlate with Bone Mineral Density In Patients with Thalassemia and Osteoporosis: The Role of the Wnt Signaling In the Pathogenesis of Bone Loss In Thalassemia

AbstractAbstract 1010Osteoporosis represents an important cause of morbidity in adult patients with thalassemia. Osteoclast activity is elevated in thalassemia-induced osteoporosis, and thus bisphosphonates have been used for its management. Moreover, osteoblasts are also deregulated in thalassemia patients but there is very limited data for the underlying mechanisms of this deregulation. Osteocyte seems to be a key cell for the control of bone remodeling. Sclerostin is a secreted inhibitor of the wingless-type and integrase 1 (Wnt) canonical pathway which is produced by osteocytes and has inhibitory effects on bone formation by preventing the activation of lining cells as well as by inhibiting the function of active osteoblasts. The aim of this study was to evaluate, for the first time, the circulating levels of sclerostin in patients with thalassemia and osteoporosis who received therapy with zoledronic acid (ZOL) and explore possible correlations with clinical and laboratory data in an attempt to clarify if there is any role of sclerostin in the pathogenesis of bone loss in thalassemia. Sixty-six patients (22M/44F, median age 42 years) with thalassemia-induced osteoporosis who participated in a phase 2, randomized, placebo-controlled trial, which was previously published, were studied. In summary, patients were blindly randomized to receive ZOL at a dose of 4 mg, iv, in 15 min infusion, every 6 months (group A, n=23) or every 3 months (group B, n=21), or to receive placebo every 3 months (group C, n=22) for a 12-month period (Voskaridou et al, Hametologica 2006;91:1193-202). 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 before and 12 months post-ZOL treatment. Circulating sclerostin was measured in the serum of all patients at baseline and after 12 months of therapy, using an ELISA methodology developed by BDF for Biomedica Medizinprodukte (Vienna, Austria), along with a series of serum bone indices: i) bone resorption markers [C-terminal telopeptide of collagen type-1 (CTX) and tartrate resistant-acid phosphatase (TRACP-5b)]; ii) bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin and C-terminal propeptide of collagen type-I (CICP)]; iii) osteoclast regulators [RANKL, osteoprotegerin (OPG) and osteopontin] and iv) dickkopf-1 (Dkk-1), which is another inhibitor of Wnt signaling, as previously described (Voskaridou et al, Haematologica 2009;94:725-8). The above bone markers were also evaluated in 30, age- and gender-matched, healthy controls (11M/19F, median age 44 years), while sclerostin was also measured in 62 women with post-menopausal osteoporosis (median age 63 years). At baseline, patients with thalassemia and osteoporosis had elevated circulating levels of sclerostin (median: 605 pg/mL, range: 22–1227 pg/mL) compared to healthy controls (250 pg/mL, 0–720 pg/mL, p<0.001) and reduced levels of sclerostin compared with postmenopausal women with osteoporosis (840 pg/mL, 181–1704 pg/mL, p<0.001). Patients with thalassemia had also increased values of CTX (p<0.001), Dkk-1 (p<0.001), bALP (p<0.001), CICP (p=0.003), TRACP-5b (p<0.01), and sRANKL/OPG ratio (p=0.001). Sclerostin levels correlated with BMD in all studied sites L1-L4 (r=0.454, p<0.001), R (r=0.324, p=0.01) and FN (r=0.268, p=0.035). Similar results were obtained for post-menopausal women with osteoporosis for L1-L4 BMD (r=0.501, p<0.001). The other Wnt inhibitor, Dkk-1 also correlated with BMD of L1-L4 (r=-0.290, p=0.022) and R (r=-0.415, p=0.001). Patients who received ZOL did not alter their sclerostin levels after 12 months of therapy, but reduced their circulating Dkk-1 (from 39.6±16.6 to 28.9±16.3 pmol/L, p=0.004). In contrast, placebo group patients showed an increase of sclerostin levels (p=0.01) and a borderline increase of Dkk-1 (p=0.08). In conclusion, the results of this study show that circulating sclerostin is elevated in thalassemia patients with osteoporosis and correlated with their BMD. Furthermore, the high Dkk-1 serum levels and their association with BMD observed in these patients support the notion of a disrupted Wnt signaling in patients with thalassemia and osteoporosis which leads, in turn, to osteoblast deregulation. These findings give the rationale for the use of novel drugs targeting sclerostin and Dkk-1 in patients with thalassemia-induced osteoporosis. Disclosures:No relevant conflicts of interest to declare.

Levels of DKK1 in patients with acute myocardial infarction and response to atorvastatin

The Wnt-LPR5 signalling pathway plays an important role in skeletal homeostasis, especially in regulating osteoblastic activity. Activation of this pathway is regulated by various inhibitors, including DKK1. The objective of this study was to evaluate DKK1 levels in patients with ischemic heart disease, the response to atorvastatin and the relationship with bone mass. Twenty-one patients with acute myocardial infarction and twenty-three controls with a mean age of 61 ± 9 years with acute coronary syndrome were included. Patients were allocated to low (10-20mg) and high doses (40-80 mg) of atorvastatin according to baseline levels of cholesterol and triglycerides and the index of vascular risk. Patients were studied at hospital admission (baseline) and at 12 months of follow up. DKK1 was determined in all patients at baseline and at 12 months of follow up. Densitometric studies were conducted in the lumbar spine (L2-L4) and the femoral neck and trochanter using an X-ray densitometer. Patients had higher levels of DKK1 than controls, (111 ± 41 nmol/l versus 84 ± 27 nmol/l, p=0.014). Osteoporotic patients had higher levels of DKK1 (137.5 ± 33 nmol/l versus 95.4 ± 36 nmol/l, p=0.021). Analysis of the response to atorvastatin showed reduced DKK1 levels. In conclusion, in patients with acute coronary syndrome, atorvastatin decreases DKK1 levels. This may be a previously unreported mechanism of action of atorvastatin on bone, stimulating the Wnt signalling pathway and increasing bone mass.

Effects of bortezomib on bone disease in multiple myeloma

Bone disease is a well-recognized feature of multiple myeloma (MM), with skeletal-related complications (including pathologic fractures, spinal cord compression, hypercalcemia, and pain) affecting greater than 80% of patients. For many patients, a pathologic fracture or severe bone pain resulting from bone destruction within the marrow cavity is the sentinel event heralding a diagnosis of MM [1]. Importantly, bone disease in MM differs from that of other malignancies. Usually, osteoclast-mediated bone resorption is closely followed both spatially and temporally by osteoblastmediated bone formation. In MM, however, this coupling does not occur even following years of complete remission. Rather bone disease in MM results both from the increased proliferation and activation of osteoclasts and the suppression or absence of osteoblast activity [2]. This finding explains the clinical observation that bone scans (which detect bone formation) in approximately half of patients with MM are normal despite the presence of severe osteolytic disease. Intravenous bisphosphonates (pamidronate and zoledronic acid) bind to bone at sites of exposed hydroxyapatite to limit osteoclast-mediated bone resorption and are the current primary therapy for MM bone disease [3]. Despite bisphosphonate therapy, however, 50% of patients experience a skeletal-related event at the time of relapse [4]. Importantly, however, bisphosphonates target only mature osteoclasts and do not appear to affect osteoblast activity [5]. Further, bisphosphonate therapy is not without risk as MM patients have the highest incidence (among all groups of patients with malignancies receiving bisphosphonate therapy) of avascular osteonecrosis of the jaw [6]. Given these limitations, new strategies to improve skeletal-related outcomes are warranted. In this issue of the American Journal of Hematology, Pennisi et al. [7] demonstrate a skeletal anabolic effect for bortezomib, a first in class proteasome inhibitor with antineoplastic activity in both newly diagnosed and relapsed MM. The authors report that bortezomib (but not melphalan) treatment of immunodeficient mice engrafted with human myeloma cells increased bone formation in previously implanted nonfetal rabbit bone, as documented by both radiographic and bone histomorphometric analyses. The increase in bone formation was associated with an increase in osteoblast numbers along with a simultaneous reduction in the number of osteoclasts. Importantly, however, significant heterogeneity in both the skeletal anabolic and MM cell responses to proteasome inhibition was found. Thus, increases in bone mass were not uniformly found in all subjects treated with bortezomib, and changes in bone mass did not appreciably correlate with the changes in MM tumor cell burden (i.e., subjects with a significant anti-MM cell response to bortezomib may have had little or no bone anabolic response). Accordingly, though the data presented are interesting, it is important to place them in the context of our current understanding of MM bone disease. Over the past several years, the importance of the bone marrow microenvironment in the establishment and progression of MM and MM bone disease has received increasing attention. In this context, the report by Pennisi et al. follows a growing body of literature examining the role of bortezomib in modulating the activity of primary bone cells, namely osteoblasts and osteoclasts. Although the mechanism(s) by which proteasome inhibition leads to increased osteoblast activity has not been firmly established, previous work suggests that proteasome inhibition decreases proteolytic degradation of the Gli3 protein, leading to increased bone morphogenetic protein-2 (BMP-2) expression in osteoblastic cells [8]. Other studies have shown that proteasome inhibition can also increase the activity of the osteoblast transcription factor Runt-related transcription factor 2 (Runx2)/core binding factor a1 (Cbfa1) [9]. These studies are consistent with a recent report by Mukherjee et al. which demonstrated that in mice, bortezomib induces the Runx2/Cbfa1-dependent differentiation of mesenchymal stem/progenitor cells into osteoblasts, leading to new bone formation [10]. In addition, bortezomib also appears to decrease levels of the Wnt pathway inhibitor DKK-1 in patients with MM [11]. As demonstrated in preclinical mouse models of MM, increases in Wnt signaling (and hence osteogenic differentiation) lead to decreased MM bone disease and tumor growth within the bone marrow microenvironment [12,13]. In total, these results are consistent with the increases in bone formation markers demonstrated to occur in MM patients treated with bortezomib [14,15]. As further shown by Pennisi et al., bortezomib also appears to influence osteoclast activity. Although the molecular mechanism(s) by which bortezomib inhibition of proteasome activity leads to decreased osteoclast activity is somewhat unclear, inhibition of nuclear factor-kappa B (NFjB) signaling (perhaps through decreases in TNF Receptor Associated Factor 6 (TRAF6) levels [16] or stabilization of inhibitor of NF-jB (IjB) levels [17]) appears to be important. In turn, NF-jB inhibition serves to limit both the ability of osteoclast precursors to differentiate into mature osteoclasts and the capacity of mature osteoclasts to resorb bone [18]. Importantly, Terpos et al. have shown that bortezomib can reduce serum levels of receptor activator of NF-

Serum Dickkopf-1 Is Increased and Correlates with Bone Mineral Density in Patients with Thalassemia-Induced Osteoporosis. Reduction Post Zoledronic Acid Administration

Osteoporosis represents an important cause of morbidity in adult patients with thalassemia. Its pathogenesis is multifactorial, and includes mainly bone marrow expansion, endocrine dysfunction and iron overload. Bone metabolism is altered in thalassemia. Osteoclast function is elevated, while osteoblast activity seems to be reduced and thus the balance of bone remodeling is in favor of bone loss. The exact mechanisms of osteoblast dysfunction have not been fully clarified to-date. Wingless-type (Wnt) signaling is an important pathway for osteoblast differentiation. Dickkopf-1 (Dkk-1) protein is an inhibitor of Wnt pathway and is implicated in the pathogenesis of several bone disorders. Collagen type-I is the main structural protein of the bone. The collagen type-I alpha (COLIA)-1 specific protein (Sp)-1 polymorphism has been related to osteoporosis in thalassemia. The aim of this study was to evaluate the serum levels of Dkk-1 in patients with thalassemia-induced osteoporosis who receive therapy with zoledronic acid (ZOL) and evaluate possible correlations with clinical and laboratory data, including the COLIA-1 Sp1 polymorphism. Sixty-six patients (21M/45F; median age 35.5 years) with thalassemia and osteoporosis were studied. Patients were blindly randomized to receive ZOL at a dose of 4 mg, iv, in 15 min infusion, every 6 months (group A, n=23) or every 3 months (group B, n=21), or to receive placebo every 3 months (group C, n=22) for a period of one year. All patients received oral calcium (500 mg) during the treatment period. Dkk-1 was measured at baseline and after 12 months of therapy using ELISA methodology (Biomedica Medizinprodukte, Wien, Austria) along with a series of serum bone remodeling indices:bone resorption markers [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)],bone formation markers [bone-specific alkaline phosphatase (bALP), osteocalcin, and C-terminal propeptide of collagen type-I (CICP)], andosteoclast regulators [receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin (OPG), and osteopontin].The above bone markers were also evaluated in 30, age- and gender-matched, healthy controls. The G–>T mutation at base 1 of intron 1 at the binding site of the Sp1 transcription factor of the COLIA-1 gene was detected by polymerase chain reaction using mutagenesis primers followed by restriction enzyme analysis in all patients. BMD of the lumbar spine (L1-L4), femoral neck (FN) and wrist (W) was determined using DEXA, before and 12 months after treatment. At baseline, all patients had increased serum levels of Dkk-1 (mean±SD: 39±17.1 pmol/L) compared to controls (27.4±9.7 pmol/L; p<0.0001). Furthermore, thalassemia patients had increased values of CTX (p<0.0001), bALP (p<0.001), CICP (p=0.003), sRANKL (p=0.02), and OPG (p=0.001) compared to controls. Results for the COLIA-1 Sp1 polymorphism were available for 53 patients. Seventeen patients (32%) were G/T heterozygotes at the polymorphic Sp1 site (Ss), while 3 (5.6%) were T/T homozygotes (ss). Dkk-1 serum levels correlated with L1-L4 BMD (r=−0.290, p=0.022) and W-BMD (r=−0.415. p=0.001), but also with TRACP-5b (r=0.310, p=0.011) and bALP levels (r=−0.289, p=0.018). Ss and ss patients tended to have lower L1-L4 BMD compared with SS patients (p=0.09). No significant correlations were observed between Ss and ss patients with the measured bone markers or the response to ZOL. As reported previously, patients of group B experienced an increase of L1-L4 BMD, while no other alterations in BMD were observed in the 3 studied groups after 12 months of ZOL administration. Interestingly, patients of groups A+B showed a strong reduction of Dkk-1 after 12 months of ZOL (from 39.6±16.6 to 28.9±16.3 pmol/L; p=0.004); indeed they almost normalized Dkk-1 levels (no difference from control values). In contrast, patients of group C showed a borderline increase of Dkk-1 (from 33.1±16.8 to 40.1±23.2 pmol/L, p=0.08). These results show for the first time in the literature that Dkk-1 is increased in the serum of patients with thalassemia and osteoporosis, correlates with their BMD and is reduced post-ZOL therapy. This Dkk-1 elevation may be at least partially responsible for osteoblast dysfunction in thalassemia and reveal a novel possible target for the development of new agents for the management of bone loss in thalassemia patients.