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

Duration of OPG:Fc treatment determines the extent of rebound bone loss following its cessation – insight into rebound bone loss  (#40)

Jad Zamerli 1 , Ya Xiao 1 , Shelley Ma 1 2 , Albert Kim 3 , Sindhu Mohanty 1 , Peter Croucher 1 , Jackie Center 1 4 , Christian Girgis 3 5 , Michelle M McDonald 1 4
  1. Bone, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. University of Technology, Sydney, NSW
  3. Endocrinology and Metabolism, Royal North Shore Hospital, Sydney, NSW, Australia
  4. University of New South Wales, Sydney, NSW, Australia
  5. Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW, Australia

Treatment cessation of the anti-resorptive denosumab (Dmab) can result in rebound loss in bone mineral density (BMD) and increased risk of pathological fracture. Bone turnover analysis reveals this results from increased osteoclast formation and activity, however predicting high-risk patients who will require preventative intervention is unclear. We hypothesized that a proportionality exists between treatment duration and magnitude of rebound. We aimed to compare Dmab-withdrawal rebound bone-loss following short-term and long-term therapy. Growing mice were treated thrice-weekly with osteoprotegerin (OPG:Fc) for 2 weeks (short-OPG) or 8-weeks (long-OPG) to mimic Dmab and bone mass changes assessed to 15 weeks post cessation.

Lower-limb BMD peaked at 6-weeks (short-OPG) and 8-weeks (long-OPG) post OPG cessation at 31% and 54% above vehicles, respectively (p<0.0001). 4-weeks later, BMD had normalized to vehicle levels for both groups. However, whilst short-OPG plateaued at control levels to 15 weeks, BMD continued to decline in the long-OPG group, reaching 13.5% below controls (p<0.01).

MicroCT at 15 weeks post treatment cessation confirmed normalization of femoral trabecular bone volume fraction (tbBV/TV) and cortical bone thickness (CBth) in the short-OPG group. However, despite BMD falling below vehicle levels at 15-weeks post-cessation, tbBV/TV remained elevated by 300% (p<0.0005) in long-OPG treated mice compared to vehicle (p<0.01). Conversely, CBth was reduced by 18% (p<0.0001) and CB-volume 15% in long-OPG mice compared to vehicles (p<0.01).

Our data indicates that longer OPG treatment led to greater BMD gains, however normalization time remained similar to short-OPG, indicating higher bone resorption rates. Longer treatment also led to rebound BMD below control levels, with cortical bone the primary contributor. Future analysis of bone turnover will confirm cellular mechanisms and mechanical testing will determine fracture resistance. Taken together, this data indicates treatment duration may be a factor in determining the magnitude of rebound bone loss and fracture-risk in patients ceasing Dmab.