Multiple vertebral fractures after denosumab discontinuation:​ FREEDOM and FREEDOM extension trials additional post hoc analyses

Cosman, Felicia<sup>1</sup>; Huang, Shuang<sup>2</sup>; McDermott, Michele<sup>2</sup>; Cummings, Steven R.<sup>3</sup>

Affiliations

¹Division of Endocrinology/Department of Medicine, Columbia University, New York, NY, USA

²Amgen Inc., Thousand Oaks, CA, USA

³San Francisco Coordinating Center, California Pacific Medical Center Research Institute and University of California, San Francisco, CA, USA

Abstract and keywords

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.

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

Links

DOI: 10.1002/jbmr.4705

PubMed: 36088628

WoS: 000866285200001

History

Received: 2021-10-20

Revised: 2022-09-02

Accepted: 2022-09-05

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Cited By (2)

Year	Entry
2023	Coropciuc R, Coopman R, Garip M, Gielen E, Politis C, Van den Wyngaert T, Beuselinck B. Risk of medication-related osteonecrosis of the jaw after dental extractions in patients receiving antiresorptive agents: a retrospective study of 240 patients. Bone. May 2023;170:116722.
2023	Liebich G, Lamy O, Aubry-Rozier B, Gonzalez-Rodriguez E. Maintenance of bone resorption markers in the low premenopausal range during the year following denosumab discontinuation is associated to bone density preservation: the ReoLaus study. Bone. July 2023;172:116764.