Denosumab Discontinuation and the Rebound Phenomenon: A Narrative Review

Abstract

Denosumab is a potent antiresorptive agent that substantially increases bone mineral density and reduces fracture rates at all skeletal sites for as long as it is administered. However, its favorable skeletal effects reverse quickly upon its discontinuation, because of a vast increase of osteoclast number and activity, which leads to a subsequent profound increase of bone turnover above pre-treatment values, a phenomenon commonly described as "rebound phenomenon". More importantly, most patients experience rapid, profound bone loss due to this burst of bone resorption that may lead in a minority of these patients to occurrence of fractures, especially multiple vertebral fractures. Therefore, subsequent antiresorptive treatment is mandatory, although the optimal regimen is yet to be clarified. In the present review, we outline what is currently known regarding the negative effects of denosumab discontinuation on different aspects of bone status, the factors that may affect them, and strategies to prevent them.

Keywords: denosumab; discontinuation; fracture; osteoporosis; rebound; turnover.

Figure 1

Schematic figure of Denosumab’s mechanism of action. (A) Normal bone remodeling. Normally, resorption of old bone matrix is followed by deposition of equal amount of newly formed bone. Osteocytes orchestrate this procedure by producing and secreting sclerostin and Dickkopf −1, and RANKL and OPG, which regulate osteoblastic bone formation and osteoclastic bone resorption, respectively. RANKL binds to its receptor RANK on the surface of osteoclasts and osteoclast precursors, activating these cells. OPG binds to RANKL, preventing it from interacting with RANK. Sclerostin and Dickkopf act as inhibitors of the Wnt intracellular signaling by binding to the frizzled /LRP 5 co-receptor in osteoblasts. (B) Treatment with denosumab. Denosumab binds the cytokine RANKL, preventing it from binding to its receptor RANK, and thus it prevents maturation of osteoclast precursors while it promotes apoptosis of mature, multinucleated osteoclasts. Osteoclast number and activity is declined along with bone formation due to the coupling effect. The number of empty lacunae is increased due to accumulation of dead osteocytes that are not replaced by newly embedded osteoblasts/preosteocytes during RANKL inhibition. (C) Denosumab discontinuation. Denosumab discontinuation abrogates the suppression on the cells of osteoclastic lineage, leading to increased osteoclastogenesis and subsequently increased osteoblastogenesis. Unmineralized bone is increased due to high bone remodeling rate while the number of osteopetrotic empty lacunae remain unchanged. RANK, receptor activator of nuclear factor kappa-Β; RANKL, receptor activator of nuclear factor kappa-Β ligand; OPG, osteoprotegerin; SOST, sclerostin; DKK-1, Dickkopf; FRP, frizzled related protein; LRP5, low-density lipoprotein receptor-related protein 5.