Changes in RANKL and TRAcP 5b after discontinuation of denosumab suggest RANKL mediated formation of osteoclasts results in the increased bone resorption

Summary In patients discontinuing long-term denosumab, RANKL levels are high 6 months after the last denosumab injection. Nine and 12 months after the last denosumab injection RANKL levels are lower, but TRAcP 5b levels are higher, suggesting that accumulated RANKL increases the number of active osteoclasts. Purpose The rapid increase in bone turnover occurring when discontinuing long-term treatment with denosumab (DMAB), an antibody that neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) is not fully understood. We aimed to investigate the mechanisms underlying the rebound activation of bone resorption by measuring tartrate-resistant acid phosphatase 5b (TRAcP 5b), RANKL, osteoprotegerin (OPG), C-terminal collagen crosslinks (CTX), and procollagen type I N-propeptide (P1NP) in patients discontinuing long-term DMAB. Methods Sixty-one patients with BMD T-score > − 2.5 at the spine and hip discontinuing long-term DMAB were randomized to treatment with zoledronate (ZOL) 6 months (6 M group, n = 20), 9 months (9 M group, n = 20) or 12 months after the last DMAB injection or when bone turnover was high (12 M group, n = 21). Bone turnover markers were measured immediately before initiation of ZOL treatment. Results We found higher CTX and PINP in the 9 M and 12 M groups compared to the 6 M group ( p < 0.001). In the 6 M group, TRAcP 5b was lower and RANKL higher than in the other two groups ( p < 0.001). TRAcP 5b correlated negatively with RANKL ( R = − 0.54), and time since the last DMAB injection correlated positively with CTX ( R = 0.56), PINP ( R = 0.72), TRAcP 5b ( R = 0.51) and negatively with RANKL ( R = − 0.70) ( p < 0.001 for all). We found no difference in OPG between groups. Conclusion Following discontinuation of long-term DMAB, we find high levels of RANKL, which most likely result in an increase in the number of active osteoclasts (illustrated by TRAcP5b) causing an increased bone turnover.