Oral Presentation 30th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2020

Multi-targeting DKK1 and LRP6 prevents myeloma-induced bone disease (#7)

Marija K Simic 1 2 , Sindhu T Mohanty 1 , Ya Xiao 1 , Tegan L Cheng 3 , Feng Cong 4 , Michael Daley 4 , Peter I Croucher 1 2 , Michelle M McDonald 1 2
  1. Healthy Ageing, Bone Biology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia
  3. Centre for Children's Bone and Musculoskeletal Health, The Children's Hospital at Westmead, Westmead, NSW, Australia
  4. Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America

An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Wnt-targeted therapeutic agents have the potential to address these skeletal complications, where they could rebuild lost bone and improve bone strength in affected individuals. We have demonstrated an anti-LRP6 agent, which potentiates Wnt signalling through binding the Wnt receptor LRP6, prevented the development of myeloma-induced bone loss primarily through preventing bone resorption. However, since MM patients present with both increased bone resorption and decreased bone formation, we hypothesised that combining anti-LRP6 with the bone anabolic anti-DKK1 (100mg/kg twice weekly i.v.) would lead to more robust improvements in bone structure than single treatment approaches. MicroCT demonstrated a 74% increase in femoral bone volume per tissue volume (BV/TV) in naïve mice given the combination treatment compared to control agents (p<0.0001). Mice injected with 5TGM1eGFP murine myeloma cells had a 34% reduction in femoral BV/TV compared to naïve controls (p<0.0001). Combination treatment drastically improved BV/TV in 5TGM1-bearing mice by 111% (p<0.0001), which was also superior to anti-LRP6 single treatment (p<0.001). Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1eGFP-bearing mice treated with the combination strategy (p<0.001). Consequently, this combination significantly improved resistance to fracture in lumbar vertebrae in 5TGM1eGFP-bearing mice compared to their controls (p<0.001), and it provided greater protection against fracture compared to anti-LRP6 single agent treatment. Importantly, tumour activity was not altered with either single or combination strategies. This study defines a therapeutic strategy superior to current approaches, which will reduce fractures and improve quality of life in patients with MM.