Anti-sclerostin antibody treatment prevents myeloma bone disease and increases bone strength — ASN Events
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Anti-sclerostin antibody treatment prevents myeloma bone disease and increases bone strength (#30)

Michelle M McDonald 1 , Michaela R Reagan 2 , Scott E Youlten 1 , Sindhu T Mohanty 1 , Anja Seckinger 3 , Rachael L Terry 1 , Jessica A Pettitt 1 , Marija K Simic 1 , Tegan L Cheng 4 , Alyson Morse 4 , Lawrence MT Le 1 , David Abi-Hanna 1 , Ina Kramer 5 , Carolyne Falank 2 , Heather Farifield 2 , Irene M Ghobrial 6 , Paul A Baldock 1 , David G Little 4 , Michaela Kneissel 5 , Karin Vanderkerken 7 , John HD Bassett 8 , Graham R Williams 8 , Oyajobi O Babatunde 9 , Dirk Hose 3 , Tri G Phan 1 , Peter I Croucher 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Maine Medical Center Research Institute, Scarborough, ME, USA
  3. Universitätsklinikum Heidelberg, Medizinische Klinik V, Labor für Myelomforschung, Ruprecht-Karls-Universiät, Heidelberg, Germany
  4. Centre for Children’s Bone and Musculoskeletal Health,, The Children’s Hospital at Westmead, Sydney, NSW, Australia
  5. Novartis Pharma, Basel, Switzerland
  6. Dana Faber Cancer Institute, Boston, MA, USA
  7. Frei University, Brussels, Belgium
  8. Imperial College, London, UK
  9. University of Texas Health Science Centre, San Antonio, Texas, USA

Multiple myeloma is a plasma cell cancer that causes bone destruction and fractures, which result from increased bone resorption and decreased bone formation. Anti-resorptive drugs prevent further bone loss but fail to influence bone formation, so patients continue to fracture. Development of drugs that stimulate bone formation and prevent fracture are a priority. Sclerostin is a soluble Wnt antagonist that inhibits bone formation with expression restricted to osteocytes. We hypothesized that anti-sclerostin antibody would prevent bone disease and increase fracture resistance in myeloma. Sclerostin was not expressed in plasma cells isolated from 630 patients with myeloma, or 54 human myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM or MM1.S myeloma cells, demonstrated significant bone loss (32%, 36% and 69%, p<0.01, respectively) caused by increased osteoclastic bone resorption (182%, p<0.01) and suppressed bone formation (92%, p<0.001), when compared to naive mice. Bone loss in the vertebrae resulted in decreased bone strength in 5TGM1 (37%, p<0.01), 5T2MM (30%, p<0.05) and MM1.S (51%, p<0.01) tumour bearing mice. Anti-sclerostin treatment (100mg/kg weekly) increased bone volume in 5TGM1 (54%, p<0.01), 5T2MM (516%, p<0.01) and MM1.S (110%, p<0.05) tumour-bearing mice, returning bone volume to control levels. Anti-sclerostin treatment also reduced the number of osteolytic bone lesions (p<0.02). Anti-sclerostin treatment increased osteoblast numbers (663% p<0.05) and bone formation rate (91%, p<0.01), but did not alter osteoclastic resorption or tumour burden. Anti-sclerostin antibody increased vertebral strength in mice bearing 5TGM1, 5T2MM and MM1.S cells to levels in control naïve mice. Combining anti-sclerostin antibody, to stimulate bone formation, with zoledronic acid, to suppress bone resorption, led to increases in bone volume (112% p<0.001) and bone strength (114% p<0.001) beyond zoledronic acid treatment alone. This study defines a therapeutic strategy superior to current approaches, which will reduce fractures, enhance quality of life and ultimately improve survival in patients with myeloma.