ECTS Abstracts (2015) 1 P94

Targeting sclerostin prevents bone loss in a murine model of multiple myeloma

Michelle McDonald1, Jenny Down1, Rachael Terry1, Jessica Pettitt1, Natasa Kovacic1, Tri Phan1, Ina Kramer2, Michaela Kneissel2 & Peter Croucher1

1The Garvan Institute of Medical Research, Sydney, NSW, Australia; 2Novartis Pharma, Basel, Switzerland.

Multiple myeloma (MM) is a neoplastic disease of plasma cells associated with a progressive and highly destructive osteolytic bone disease, severe bone pain and pathological fractures. The bone disease is a result of both increased bone resorption and decreased bone formation. Anti-resorptive agents do limit fractures, however, the disease often progresses and no approaches exist to repair bone lesions. The Wnt/β-catenin pathway plays a critical role in the regulation of bone formation. Soluble wnt antagonists such as Dkk1 and Sclerostin, inhibit bone formation. Anti-Dkk1 treatment improves outcomes in pre-clinical models of MM, and is under clinical trials in MM patients. The role of sclerostin in MM is however unknown. C57BLKalwRij mice were injected with 5TGM1eGFP murine myeloma cells or saline (Naïve) and treated with anti-sost (weekly, 100 mg/kg) or control antibody (cont-Ab), until harvest day on 21. FACS analysis revealed no difference in tumour burden with anti-sost treatment. MicroCT analysis demonstrated that 5TGM1eGFP caused an 11% reduction in cortical bone volume and a 27% reduction in cancellous bone volume/total volume (BV/TV) (p<0.01). Anti-sost treatment prevented this bone loss, increasing cortical bone volume by 20% and cancellous BV/TV by 26% compared with cont-Ab treated tumour bearing mice (p<0.05). This was such that cortical BV and cancellous BV/TV were equivalent to the naïve cont-ab group. Taken together, these data suggest that sclerostin has a role in multiple myeloma induced bone loss. Further analysis of bone cell activity will confirm the mechanism of bone loss prevention was through enhanced bone formation, increasing the thickness of cortical and cancellous bone structures. Anti-sost is in clinical trials for the treatment of bone loss in osteoporotic patients. Our data suggest a potential new application for anti-sost treatment in patients with MM.

Disclosure: The authors declared no competing interests. This work was funded by IBMS/CABS Greg Mundy Fellowship.

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