Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension

Abstract

Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above-baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued denosumab during the FREEDOM study or its Extension. Participants received ≥2 doses of denosumab or placebo Q6M, discontinued treatment, and stayed in the study ≥7 months after the last dose. Of 1001 participants who discontinued denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1, similar to participants who received and then discontinued placebo (n = 470; 8.5 per 100 participant-years). Among participants with ≥1 off-treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued denosumab (60.7%) than placebo (38.7%; p = 0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping denosumab were 3.9 (2.1-7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3-1.9) times higher with each additional year of off-treatment follow-up; among participants with available off-treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1-1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant-years) of nonvertebral fractures during the off-treatment period were similar (2.8, denosumab; 3.8, placebo). The vertebral fracture rate increased upon denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue denosumab should rapidly transition to an alternative antiresorptive treatment. Clinicaltrails.gov: NCT00089791 (FREEDOM) and NCT00523341 (Extension). © 2017 American Society for Bone and Mineral Research.

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition

“…(147,148) It also has broad antifracture efficacy, particularly for preventing vertebral fractures, which it reduces by approximately 70% over 3 years. (64,151) Depending on individual medical circumstances and other factors, the anabolic agents teriparatide, abaloparatide, and romosozumab may also be useful front-line therapies. (20,64,149,150) Unlike bisphosphonates, denosumab is not incorporated into the bone matrix and its antiresorptive effects do not continue after treatment is discontinued; rapid transition to another therapy after discontinuation of denosumab is recommended to prevent the risk of fractures from subsequently increasing.…”

“…(64,151) Use of the anabolic drugs teriparatide and abaloparatide for more than 2 cumulative years during a patient's lifetime is not recommended, primarily because of the potential risk of osteosarcoma (based on rodent studies) (86,162) and use of romosozumab is limited to 1 year. (64,151) Use of the anabolic drugs teriparatide and abaloparatide for more than 2 cumulative years during a patient's lifetime is not recommended, primarily because of the potential risk of osteosarcoma (based on rodent studies) (86,162) and use of romosozumab is limited to 1 year.…”

An Essential Warning

“…(1)(2)(3) In the setting of this uncertainty, the timely article by Cummings and colleagues in the current issue of JBMR, in which they present a post hoc analysis of their randomized placebocontrolled FREEDOM Trial, should have an immediate clinical impact. (4) In this report, Cummings and colleagues compare the rates of new or worsening vertebral fractures in postmenopausal osteoporotic women who discontinued denosumab with those who discontinued placebo. The fundamental finding of this analysis is that the incidence of vertebral fractures, which was reduced during ongoing denosumab therapy, rapidly returns to rates observed in placebo-treated patients when the drug is stopped.…”

Fasciola helminth defense molecule‐1 protects against experimental arthritis by inhibiting osteoclast formation and function without modulating the systemic immune response

“…4 However, RANKL is the most potent osteoclastogenic cytokine. 8 Osteoclasts degrade bone by creating an acidic microenvironment in the resorption lacunae that dissolves mineral and activates matrix digesting acid proteases to degrade the organic matrix. In phase 2 clinical trial, denosumab in combination with MTX increased BMD and improved microstructure of the trabecular and cortical bones, which underscored the advantage of targeting osteoclasts as an add-on strategy to treat RA.…”