Multiple Vertebral Fractures After Denosumab Discontinuation: FREEDOM and FREEDOM Extension Trials Additional Post Hoc Analyses

Abstract

It is uncertain whether the risk of vertebral fracture (VF) and multiple vertebral fractures (MVFs; ≥2 VFs) after denosumab (DMAb) discontinuation is related to treatment duration. A prior analysis of Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) and FREEDOM Extension trials did not find a relationship with DMAb duration and may have underreported MVF incidence because it included women who did not have radiographs. In this post hoc exploratory analysis, the crude incidence and annualized rates of VF and MVF were determined in patients with ≥7 months' follow-up and ≥1 spine radiograph after discontinuing placebo or DMAb. A multivariate analysis was performed to identify predictors of MVF. Clinical characteristics of patients with ≥4 VFs were explored. This analysis included women who discontinued after placebo (n = 327) or DMAb either from FREEDOM or FREEDOM Extension (n = 425). The DMAb discontinuation group was subsequently dichotomized by treatment duration: short-term (≤3 years; n = 262) and long-term (>3 years; n = 213) treatment. For any VF, exposure-adjusted annualized rates per 100 patient-years (95% confidence interval [CI]) were 9.4 (95% CI, 6.4-13.4) for placebo, 6.7 (95% CI, 4.2-10.1) for short-term DMAb, and 10.7 (95% CI, 7.4-15) for long-term DMAb. Annualized rates for MVF were 3.6 (95% CI, 1.9-6.3), 2.9 (95% CI, 1.4-5.4), and 7.5 (95% CI, 4.8-11.1), respectively. Annualized rates for ≥4 VFs were 0.59 (95% CI, 0.1-2.1), 0.57 (95% CI, 0.1-2.1), and 3.34 (95% CI, 1.7-6.0), respectively. In a multivariate regression model, DMAb duration was significantly associated with MVF risk (odds ratio 3.0; 95% CI, 1.4-6.5). Of 15 patients with ≥4 VFs, 13 had DMAb exposure (mean ± standard deviation [SD], 4.9 ± 2.2 years). The risk of MVF after DMAb discontinuation increases with increased duration of DMAb treatment. Patients transitioning off DMAb after 3 years may warrant more frequent administration of zoledronic acid or another bisphosphonate to maintain bone turnover and bone mineral density (BMD) and prevent MVF. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Keywords: ANTIRESORPTIVES; CLINICAL TRIALS; FRACTURE PREVENTION; OSTEOPOROSIS; THERAPEUTICS.

Fig. 1

Patient disposition. Flow diagram shows disposition of patients from FREEDOM or its Extension through treatment discontinuation and follow‐up. The off‐treatment follow‐up period begins from the last dose plus 7 months through the end of study. DMAb = denosumab; EXT = extension; FU = follow‐up; Pbo = placebo.

Fig. 2

Exposure‐adjusted annualized rates of (A) any vertebral fracture, (B) multiple vertebral fractures, and (C) ≥4 vertebral fractures in Pbo and DMAb Discontinuation groups categorized by duration ≤3 years versus >3 years. Bar graphs show exposure‐adjusted annualized rates (per 100 patient‐years) of any vertebral fracture, multiple vertebral fractures, and ≥4 vertebral fractures in Pbo Discontinuation (n = 327), DMAb Discontinuation ≤3 years (n = 262), and DMAb Discontinuation >3 years (n = 213) groups. Number in parentheses represents the number of patients with fracture. DMAb = denosumab; Pbo = placebo.