Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma

Abstract

Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM

SOST, an LNGFR target, inhibits the osteogenic differentiation of rat ectomesenchymal stem cells

“…SOST is a vital negative regulator of bone formation. It has recently been reported that SOST inhibition increases bone formation in several disorders . Delgado‐Calle et al have shown that SOST inhibition augmented osteoblast numbers, promoted new bone formation and decreased osteoclast number in multiple myeloma‐colonized bone .…”

Mechanisms of bone destruction in multiple myeloma

“…In one study, there were no significant differences in sclerostin expression by osteocytes in MM patients when compared with healthy controls, suggesting that higher sclerostin levels could be secreted directly by myeloma cells rather than by osteocytes (Giuliani et al, 2012). The inhibition the osteocyteproduced sclerostin led to an increase in the bone mass, to prevention of bone destruction and to fracture resistance in mice myeloma models (Delgado-Calle et al, 2017;McDonald et al, 2017). The inhibition the osteocyteproduced sclerostin led to an increase in the bone mass, to prevention of bone destruction and to fracture resistance in mice myeloma models (Delgado-Calle et al, 2017;McDonald et al, 2017).…”

Preventing and Repairing Myeloma Bone Disease by Combining Conventional Antiresorptive Treatment With a Bone Anabolic Agent in Murine Models

“…More recently, deletion of the sclerostin gene ( Sost ) or administration of an anti‐sclerostin antibody prevented bone disease in murine models of myeloma . Furthermore, when an anti‐sclerostin treatment was used in combination with Zol in preclinical models of myeloma, using a preventative regimen, they showed superior effects on fracture resistance compared with Zol alone . However, sclerostin's effectiveness on established osteolytic bone disease has not yet been assessed in murine models or in patients with myeloma.…”