https://orcid.org/0000-0002-1372-4417
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Serge Ferrari, Zoledronate Following Denosumab Discontinuation: Partial Reassurance but No Confidence, Journal of Bone and Mineral Research, Volume 35, Issue 7, 1 July 2020, Pages 1205–1206, https://doi.org/10.1002/jbmr.4022
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Blockade of RANK ligand (RANKL) by denosumab results in a complete inhibition of osteoclast development and activity, continuous BMD gains, and short‐term and long‐term fracture risk reductions.1 Upon cessation of therapy, a transient rebound in bone turnover and rapid BMD loss occur. This has been known since the early days of denosumab therapy,2 and was pointed out as potentially clinically relevant3 many years before the first vertebral fracture upon cessation of denosumab was identified. Indeed, 1% to 10% of patients interrupting therapy may experience vertebral fractures. This rate depends on whether only clinical or morphometric fractures are evaluated, as well as on the baseline risk profile,4, 5 and probably on other parameters, such as previous exposure to bisphosphonates (BPs), which may temperate the intensity of the bone turnover rebound.6 Yet the mechanisms of this rebound remain speculative. One is the probable overexpression of RANK/RANKL and the targeting of a growing pool of osteoclast precursors or “recycled,” but inactive, osteoclasts that will engage into synchronized differentiation. Another is a mechanostatic reset to a lower bone mass. Finally, it could also be a targeted repair of accumulated microdamage leading to a transient decrease in bone strength.7
