Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: Reduction post‐bortezomib monotherapy

Abstract

Sclerostin is a Wingless and Int-1 inhibitor, which is produced by osteocytes and inhibits osteoblast-driven bone formation. Sclerostin is implicated in the pathogenesis of bone loss in metabolic bone disorders but there is no information for its effect on multiple myeloma (MM)-related osteolytic disease. We evaluated circulating sclerostin in 157 newly diagnosed patients with symptomatic myeloma, in 25 with relapsed myeloma who received bortezomib monotherapy, in 21 patients with monoclonal gammopathy of undetermined significance (MGUS), and in 21 healthy controls. Patients with active myeloma had elevated circulating sclerostin compared to MGUS patients and controls (p < 0.01). MM patients who presented with fractures at diagnosis (n 5 34) had very high levels of circulating sclerostin compared with all others (p < 0.01), whereas sclerostin correlated negatively with bone specific alkaline phosphatase (a bone formation marker; r 5 20.541, p < 0.0001) and positively with C-telopeptide of collagen type-1 (a bone resorption marker; r 5 0.524, p < 0.0001). Patients with International Staging System (ISS)-3 disease had higher circulating sclerostin compared to ISS-1 and ISS-2 MM (p 5 0.001). Furthermore, patients with high sclerostin (upper quartile, n 5 40) had a median survival of 27 months versus 98 months of all others (p 5 0.031). Relapsed MM patients had higher levels of circulating sclerostin even compared to newly diagnosed patients (p < 0.01). Bortezomib monotherapy resulted in a reduction of sclerostin by almost 50% in both responders and non-responders. These results suggest that patients with active myeloma have elevated circulating sclerostin, which correlated with advanced disease features including severe bone disease. Our study indicates sclerostin as a possible target for the development of novel therapies to enhance osteoblast function in myeloma.Osteolytic bone disease is one of the most common and devastating complications of multiple myeloma (MM). Almost 80% of myeloma patients at baseline have evidence of bone loss. MM-related bone disease is due to increased osteoclast activity and reduced osteoblast function. The interactions between myeloma cells and bone marrow stromal cells lead to the overproduction of several chemokines and cytokines that are responsible for this imbalance between osteoclast and osteoblast activity.1 To-date, dickkopf-1 (Dkk-1) is considered as the main causative factor for the osteoblast exhaustion in MM. Dkk-1 is overproduced by myeloma cells and inhibits the canonical Wingless and Int-1 (Wnt) signaling, which is crucial for the osteoblast differentiation and activity. 2,3 Sclerostin is another Wnt inhibitor, specifically expressed by osteocytes, which inhibits osteoblast-driven bone formation and induces mature osteoblast apoptosis. 4 Sclerostin deficiency leads to the development of rare bone sclerosing disorders, including sclerosteosis and van Buchem disease. 5 However, during the last 2 years it has been reported that elevated sclerostin is implicated in the mech...

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

“…However, recent data show that circulating sclerostin levels are higher in MM patients as compared with MGUS and healthy controls with highest levels in those patients with advanced disease including bone fractures. 47 We can suppose that these high sclerostin levels could be derived directly from MM cells rather than from osteocytes because it has been reported that MM cells overexpress sclerostin. 48 Nevertheless, we cannot exclude that apoptotic osteocytes contribute to the increased sclerostin levels in MM patients because it has been reported that pro-apototic factors may induce sclerostin expression by osteocytes and OBs.…”

A Review of Osteocyte Function and the Emerging Importance of Sclerostin

“…Additional studies have revealed that myeloma cells also suppress osteoblasts by secreting sclerostin 91 . A positive correlation between severity of bone disease and circulating levels of serum sclerostin suggests multiple myeloma cells utilize sclerostin in the formation of osteolytic lesions 92 .…”

Mechanisms of multiple myeloma bone disease

“…87 Anti-DKK1 does not have direct anti-tumor effects, although anti-DKK1 may suppress tumor growth via its effects on osteoblast differentiation. 88,89 Sclerostin is an inhibitor of the downstream Wnt signaling pathway and is produced by osteocytes to inhibit osteoblast differentiation. Antibodies to sclerostin are potent inducers of bone formation in preclinical models.…”

“…90 Sclerostin levels correlate with the extent of bone destruction in patient with myeloma. 89 Giuliani and coworkers recently reported that osteocyte apoptosis occurs in myeloma, and apoptotic osteocytes may release both RANKL and sclerostin. 91 Transforming growth factor-␤ .…”