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

Abstract 1010

Osteoporosis 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.