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

Michelle M. McDonald, Michaela R. Reagan, Scott E. Youlten, Sindhu T. Mohanty, Anja Seckinger, Rachael L. Terry, Jessica A. Pettitt, Marija K. Simic, Tegan L. Cheng, Alyson Morse, Lawrence M.T. Le, David Abi-Hanna, Ina Kramer, Carolyne Falank, Heather Fairfield, Irene M. Ghobrial, Paul A. Baldock, David G. Little, Michaela Kneissel, Karin Vanderkerken, J.H. Duncan Bassett, Graham R. Williams, Babatunde O. Oyajobi, Dirk Hose, Tri G. Phan and Peter I. Croucher

Key points

  • Anti-Sclerostin treatment increases bone mass and fracture resistance in multiple myeloma.

  • Anti-Sclerostin in combination with zoledronic acid is superior to zoledronic acid alone in increasing fracture resistance.

Abstract

Multiple myeloma 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. Treatment with bisphosphonates, which inhibit bone resorption, prevents 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 multiple myeloma. Sclerostin was expressed in osteocytes from bones from naïve 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 the fracture resistance in the vertebrae. Anti-sclerostin antibody treatment increased osteoblast numbers and bone formation rate, but did not inhibit bone resorption or reduce tumour burden. Anti-sclerostin treatment prevented myeloma-induced bone loss, reduced osteolytic bone lesions and increased fracture resistance. Combination treatment with anti-sclerostin and zoledronic acid increased bone mass and fracture resistance when compared to zoledronic acid treatment alone. This study defines a therapeutic strategy superior to the current standard of care, which will reduce fractures for patients with multiple myeloma.

  • Submitted March 14, 2017.
  • Accepted May 2, 2017.