The anti-RANKL therapy Denosumab (Dmab) is an effective agent for the treatment of osteoporosis. However rapid bone loss and increased risk of fracture have been associated with treatment withdrawal. We hypothesised that a rebound increase in osteoclast activity occurs following removal of Dmab therapy. To examine this in vivo, we utilised OPG:Fc to mimic Dmab in growing mice.
Following 2 weeks of OPG:Fc treatment, trabecular bone volume (BV/TV) was increased 57%, associated with decreased serum TRAP (p<0.01). This persisted 3 weeks following OPG:Fc withdrawal. 9 weeks following withdrawal, BV/TV remained significantly elevated compared to saline control (p<0.01), although 3/7 mice showed reduced BV/TV compared to control, suggesting the beginning of rebound bone loss. Consistent with increased osteoclast activity at 9 weeks following OPG:Fc withdrawal, serum TRAP was elevated 56% and osteoclast number was elevated over 2-fold (vs saline control p<0.01).
To further detail the timeline of rebound, longitudinal DXA and serum TRAP analysis were examined following OPG:Fc withdrawal. The 2 week OPG:Fc treatment increased BMD by 10%, which increased to 13%, 3 weeks following withdrawal. These bone changes were associated with decrease in serum TRAP at treatment withdrawal (2-fold, p<0.01) and 3 weeks after withdrawal (p<0.01). At 6 weeks after withdrawal, BMD remained elevated at 12%, however serum TRAP was elevated by 72% compared to control (p=0.06), indicating that rebound had initiated by this time.
Taken together, our results suggest that rebound-induced increase in osteoclast activity does occur following withdrawal of RANKL inhibition. This pathological elevation of osteoclast activity is evident in serum markers, prior to the development of bone loss. This suggests that serial serum biomarkers of osteoclast activity could predict Dmab rebound bone loss, allowing for early preventative intervention.