Denosumab discontinuation in the clinic: implications of rebound bone turnover and emerging strategies to prevent bone loss and fractures

Denosumab is a highly effective treatment for osteoporosis, and its long-term use is associated with incremental gains in BMD and sustained fracture risk reduction. Stopping denosumab, however, results in a rebound increase in bone turnover, loss of treatment-associated BMD gains, and in the worst case, spontaneous vertebral fractures (VFs). Insights into the risk factors, the underlying mechanisms for rebound-associated bone loss, and true incidence of rebound VFs are emerging. Conventional strategies using bisphosphonates to mitigate post-denosumab rebound display mixed success. Bisphosphonates may preserve bone density following short-term denosumab but the optimal sequential approach after longer-term denosumab remains elusive. Patients at particular risk of are those with prevalent VFs or greater on-treatment BMD gains. To greater understand these risks and strategies to preserve bone after denosumab, an emerging body of translational and preclinical work is shedding new light on the biology of RANKL inhibition and withdrawal. Discovering an effective "exit strategy" to control rebound bone turnover and avoid bone loss after denosumab will improve confidence among patients and clinicians in this highly effective and otherwise safe treatment for osteoporosis. This perspective characterizes the clinical problem of post-denosumab rebound, provides a comprehensive update on human studies examining the use of bisphosphonates following denosumab and explores mechanistic insights from preclinical studies that will be critical in the design of definitive human trials.