The denosumab discontinuation dilemma
Lyu H, Yoshida K, Zhao SS, et al. Delayed denosumab injections and fracture risk among patients with osteoporosis: a population-based cohort study. Ann Intern Med. 2020;173:516-526.
Tripto-Shkolnik L, Fund N, Rouach V, et al. Fracture incidence after denosumab discontinuation: real-world data from a large healthcare provider. Bone. 2020;130:115150.
Denosumab, marketed under the brand name Prolia, is a human monoclonal antibody that blocks the binding of RANK ligand and inhibits development and activity of osteoclast, thus decreasing bone resorption and increasing BMD. In the original pivotal clinical trial of denosumab, almost 7,900 women between the ages of 60 and 90 (average age, 73) with osteoporotic T-scores were enrolled.8 The women were randomly assigned to receive 60 mg of denosumab subcutaneously every 6 months or placebo for a total of 3 years. In that trial, the denosumabtreated group, relative to the placebo group, showed a statistically significant decrease in radiographic vertebral fracture, hip fracture, and nonvertebral fracture.
An open-label extension study looked at denosumab use for a total of 10 years.9 That study found that denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. Thus, denosumab appeared to be an extremely safe and effective agent for treating postmenopausal women with osteoporosis.
Denosumab cessation leads to rebound vertebral fractures
As opposed to bisphosphonates, denosumab does not incorporate into bone matrix, and bone turnover is not suppressed after cessation of its use. Reports have implied that denosumab discontinuation may lead to an increased risk of multiple vertebral fractures.10 One theory is that unlike atypical femoral fractures that seem to emerge from failure of microdamage repair in cortical bone with long-term antiresorptive treatment, denosumab rebound–associated vertebral fractures seem to originate from the synergy of rapid bone resorption and accelerated microdamage accumulation in trabecular bone triggered by the discontinuation of this highly potent reversible agent.11
Post hoc analysis of the denosumab placebo-controlled trial and its extension reported that the vertebral fracture rate increased after denosumab discontinuation to the level observed in untreated patients.12 Further, a majority of participants who did sustain vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with the risk being greatest in participants who had a prior vertebral facture. This caused those authors to suggest that patients who discontinued denosumab should rapidly transition to an alternative antiresorptive treatment.
Effect of dose delays, discontinuation on vertebral fracture rate
Lyu and colleagues recently described their population-based cohort study of the United Kingdom’s Health Improvement Network primary care database between 2010 and 2019. They found that delayed administration of a subsequent denosumab dose by more than 16 weeks was associated with an increased risk for vertebral fracture compared with on-time dosing. They noted, however, that the evidence was insufficient to conclude that fracture risk at any other anatomic sites is increased with such a delay.
In a similar study, Tripto-Shkolnik and colleagues examined an Israeli database of 2.3 million members in a state-mandated health organization. They identified osteoporotic patients with at least 2 denosumab prescription dispenses and defined treatment discontinuation as a refill gap of 3 months or more. Fractures were identified by an osteoporosis registry, including fractures that occurred within 1 year from discontinuation in denosumab discontinuers as well as from the second year of treatment forward for persistent users. They identified 1,500 denosumab discontinuers (average age, 72) and 1,610 persistent users (average age also 72). At baseline, the groups were comparable in fracture history, smoking, and bone density.
In the discontinuation group, 0.8% had multiple vertebral fractures versus 0.1% in the persistent users (P = .006); the overall rate of fractures per 100 patient-years of follow-up was 3 times higher in the discontinuation group than in the persistent user group, and the rate of vertebral fractures was almost 5 times higher in the discontinuation group.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
Denosumab is an extremely safe and effective treatment for postmenopausal osteoporosis. Discontinuation or even delay in dosing seems to result in a “rebound” effect of increased vertebral fractures and even multiple vertebral fractures, especially in those with history of a previous vertebral fracture. This is extremely important in this era of COVID-19, in which patients—especially elderly patients who are perceived to be at the greatest risk—often delay management of chronic disease to limit their potential exposure to the virus. Further, even in normal, nonpandemic times, clinicians need to make patients receiving denosumab aware of the importance of timely administration of doses as scheduled. If such dosing is not possible, then clinicians and patients need to be aware of the potential need for instituting other antiresorptive therapies. In addition, the need to ostensibly continue denosumab therapy for long periods of time and indefinitely may make it a less desirable choice for younger patients.
Denosumab is an extremely safe and effective treatment for postmenopausal osteoporosis. Discontinuation or even delay in dosing seems to result in a “rebound” effect of increased vertebral fractures and even multiple vertebral fractures, especially in those with history of a previous vertebral fracture. This is extremely important in this era of COVID-19, in which patients—especially elderly patients who are perceived to be at the greatest risk—often delay management of chronic disease to limit their potential exposure to the virus. Further, even in normal, nonpandemic times, clinicians need to make patients receiving denosumab aware of the importance of timely administration of doses as scheduled. If such dosing is not possible, then clinicians and patients need to be aware of the potential need for instituting other antiresorptive therapies. In addition, the need to ostensibly continue denosumab therapy for long periods of time and indefinitely may make it a less desirable choice for younger patients.
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