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• W3016940466 abstract "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 Accordingly, BPs, particularly zoledronate, have been recommended after denosumab to prevent a bone turnover rebound and maintain BMD gains.8 However, a first small study of patients receiving zoledronate after denosumab had pointed out that preservation of bone mass could be only partial,9 particularly if the infusion occurred at a time when resorbing areas had not yet been reactivated. In contrast, a recent reanalysis of the Denosumab-Alendronate Preference Study (DAPS) in patients crossing over from denosumab to alendronate showed no rebound in bone turnover after 6 and 12 months and preservation of BMD at 1 year, although this study is limited by the short exposure to denosumab (two injections).10 In this context, the observational study by Everts-Graber and colleagues11 published in this issue of the Journal of Bone Mineral Research (JBMR) provides some reassurance. A single infusion of zoledronate 6 months after the last denosumab injection partially preserved BMD gains—the post-zoledronate BMD remaining on average at two-thirds of the post-denosumab BMD gain—although the 95% CI indicates that some patients ended up lower than baseline. Clinical vertebral fractures were rare (1 per 100 patient-years) and apparently no one suffered from multiple vertebral fractures. These results are consistent with another recent randomized study of zoledronate post-denosumab also showing no BMD loss (on average) and very low vertebral fracture risk within 2 years.12 Note, however, that both studies were performed in subjects treated with denosumab for at most 2 to 3 years, and would therefore require confirmation in patients with longer periods of exposure. Indeed, with greater BMD gains upon long-term treatment, the intensity of the rebound and amount of BMD losses could be even greater. The study by Everts-Graber and colleagues11 actually shows some correlation between gains in spine BMD on denosumab and losses off denosumab, similar to the observations from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial.5 This might reflect the fact that BMD gains are initially dependent on the extent of the bone remodeling space—itself a reflection of the pretreatment level of bone turnover—therefore, patients with higher intrinsic levels of bone remodeling gain more bone on therapy and therefore lose more bone off therapy. Translated to the clinic it suggests that levels of bone turnover markers (BTMs) prior to therapy could be useful to identify subjects more susceptible to rapid bone loss off therapy, and for whom the efficacy of a single infusion of zoledronate, particularly if administered immediately 6 months after the last denosumab, could be insufficient. Those patients could therefore need to be treated longer with denosumab and/or more aggressively with BPs thereafter. Nevertheless, we should not be too confident at this stage because the study by Everts-Graber and colleagues11 has several limitations. First, of the 336 patients who stopped denosumab, only 120 could be included in the study. No information is provided on fracture rates in the remainder, so we do not know if the vertebral fracture incidence with zoledronate is actually lower than without. Second, the post-denosumab DXA was performed 1 to 4 years after zoledronate; hence, we cannot fully appreciate to which extent the early bone loss was prevented—although the average BMD in the patients re-measured between 12 and 23 months after zoledronate appeared similar to the BMD measured in some patients later on. Moreover, BTMs were available only in very few subjects and were collected late; hence, no real information on the capacity to block the bone turnover rebound is available. Third, 50% of the patients had previously been exposed to BPs. Although previous BP treatment within 2 years or more before denosumab appeared to make no difference on the final BMD level, no details regarding the duration and type of exposure are provided. Finally, morphometric vertebral fractures were not systematically assessed, which could have underestimated the risk. In summary, although the few available studies published so far suggest that a single infusion of zoledronate at 6 months after denosumab may partially prevent bone loss and is associated with a low risk of vertebral fractures, the individual need for BP therapy after denosumab may greatly vary depending on the baseline fracture risk, level of bone turnover, duration, recency of previous exposure to BPs, and duration of denosumab treatment, among other factors. Although the observational study of Everts-Graber and colleagues11 published in this issue of the JBMR has provided some further insights, prospective randomized controlled trials (RCTs) directed at determining the best alternative regimen after denosumab discontinuation are particularly needed. Consulting fees from AMGEN, UCB, Agnovos, Radius, Galapagos." @default.
• W3016940466 created "2020-04-24" @default.
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• W3016940466 date "2020-04-21" @default.
• W3016940466 modified "2023-10-18" @default.
• W3016940466 title "Zoledronate Following Denosumab Discontinuation: Partial Reassurance but No Confidence" @default.
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• W3016940466 doi "https://doi.org/10.1002/jbmr.4022" @default.
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