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Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma
Michelle M McDonald1,2, Michaela R Reagan3,4, Scott E Youlten1,2
1The Garvan Institute of Medical Research, Sydney, NSW, Australia.
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.
Insights
Inhibiting sclerostin, a bone formation blocker, prevents bone loss and fractures in multiple myeloma (MM). Combining anti-sclerostin therapy with zoledronic acid improves bone mass and fracture resistance more than current treatments.
Area of Science:
- Bone biology
- Cancer research
- Pharmacology
Background:
- Multiple myeloma (MM) causes significant bone destruction and fractures due to increased osteoclastic resorption and suppressed bone formation.
- Current treatments like bisphosphonates inhibit bone resorption but do not stimulate bone formation or reverse bone loss.
- Targeting tumor-derived factors to enhance bone formation has shown limited success in MM.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting sclerostin, an osteocyte-specific Wnt antagonist, to prevent and treat bone disease in multiple myeloma.
- To determine if anti-sclerostin antibody treatment can increase bone formation and fracture resistance in a preclinical model of MM.
- To evaluate the combination therapy of anti-sclerostin antibody and zoledronic acid for improving bone mass and fracture resistance in MM.
Main Methods:
- Sclerostin expression was analyzed in osteocytes and myeloma cells from preclinical models and patients.
- Murine models of MM were established by injecting myeloma cells.
- Mice were treated with anti-sclerostin antibody, zoledronic acid, or a combination, and bone loss, osteolytic lesions, and fracture resistance were assessed.
Main Results:
- Sclerostin was expressed in osteocytes but not in myeloma cells.
- Anti-sclerostin antibody treatment increased osteoblast numbers and bone formation rate.
- Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic lesions, and significantly increased vertebral fracture resistance.
- Combination therapy with anti-sclerostin antibody and zoledronic acid resulted in greater increases in bone mass and fracture resistance compared to zoledronic acid alone.
Conclusions:
- Inhibiting sclerostin is a promising therapeutic strategy for preventing and treating skeletal complications in multiple myeloma.
- Anti-sclerostin antibody treatment effectively stimulates bone formation and enhances fracture resistance in the context of MM.
- Combination therapy of anti-sclerostin antibody with bisphosphonates offers superior skeletal benefits compared to bisphosphonates alone for MM patients.
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