Session Information
Date: Monday, November 6, 2017
Title: Osteoporosis and Metabolic Bone Disease – Clinical Aspects and Pathogenesis
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Treatment with denosumab (DMAb) for 3 years significantly reduces the incidence of nonvertebral fractures (NVFx; Cummings NEJM 2009). While there are limited data describing the benefit/risk of long-term reduction in bone remodeling, recent findings show that subjects receiving DMAb for up to 7 years experience further decreases in NVFx risk (Ferrari OI 2015). To better characterize this observation, we evaluated the reproducibility of the 7-year findings in the FREEDOM Extension (EXT) cross-over (XO) group and assessed long-term fracture rates with 10 years of DMAb treatment in the EXT long-term (LT) group.
Methods: During FREEDOM, subjects were randomized to placebo or DMAb 60 mg every 6 months (Q6M) for 3 years. Subjects who missed ≤ 1 dose could enroll in the 7-year EXT, when all subjects were to receive open-label DMAb 60 mg Q6M; LT subjects could receive up to 10 years of DMAb and XO subjects could receive up to 7 years of DMAb. The NVFx rate in the first 3 years of DMAb was compared with 1) years 4-7 in LT and XO groups separately and combined, and 2) years 4-10 in the LT group. Adjusted rate ratios (RR, 95% confidence intervals [CIs]) between observational periods were computed by generalized estimating equation Poisson regression.
Results: Of 5,928 subjects eligible for the EXT, 4,550 (77%) enrolled (N = 2,343 LT; N = 2,207 XO). Baseline characteristics at FREEDOM and EXT and percent of subjects who completed the EXT were balanced between groups. The NFVx rate (95% CI) in the LT group was 1.98 (1.67-2.34) per 100 subject-years during the first 3 years of DMAb treatment and 1.54 (1.29-1.83) during years 4-7 (RR 0.79, p = 0.046; Table). To confirm this observation, the NVFx rate in the XO group was 2.37 (1.97-2.84) during the first 3 years of DMAb treatment and 1.52 (1.24-1.87) during years 4-7 (RR 0.65, p = 0.002). The NVFx rate in the combined LT + XO group was 2.15 (1.90-2.43) during the first 3 years and 1.53 (1.34-1.75) during years 4-7 (RR 0.72, p < 0.001). The LT group showed a NVFx rate of 1.44 (1.24-1.66) during years 4-10 (RR 0.74, p = 0.008). For 6,089 subjects exposed to DMAb in FREEDOM or the EXT, the rate of bone safety events (ONJ or AFF) was 4.2 per 10,000 subject-years.
Conclusion: Compared with the first 3 years of DMAb treatment, a longer duration of DMAb therapy was associated with a further decrease in NVFx rate through 10 years. Long-term reduction in bone remodeling is not only associated with continued increases in BMD (Bone ASBMR 2016), but also with a favorable benefit/risk profile for bone.
Table. Comparison of Nonvertebral Fracture Rates up to 10 Years of Denosumab Treatment
|
|
First 3 Years of DMAb Treatment |
Years 4-7 of |
Years 4–10 of DMAb Treatment |
|
Long-term Subjects (N = 2343) |
140 Fractures |
126 Fractures |
184 Fractures |
|
Fracture Rate (95% CI) Rate Ratio (95% CI) |
1.98 (1.67–2.34) [Referent] |
1.54 (1.29–1.83) 0.79 (0.62–1.00) |
1.44 (1.24–1.66) 0.74 (0.60–0.93) |
|
Cross-over Subjects |
123 Fractures |
91 Fractures |
— |
|
Fracture Rate (95% CI) Rate Ratio (95% CI) |
2.37 (1.97–2.84) [Referent] |
1.52 (1.24–1.87) 0.65 (0.50–0.86) |
— — |
|
Long-term and |
263 Fractures |
217 Fractures |
— |
|
Fracture Rate (95% CI) Rate Ratio (95% CI) |
2.15 (1.90–2.43) [Referent]
|
1.53 (1.34–1.75) 0.72 (0.61–0.86) |
— — |
|
N = number of subjects who completed FREEDOM (ie, completed their 3-year visit and did not discontinue IP), did not miss >1 dose of IP in FREEDOM, and who enrolled in the Extension. In addition, cross-over subjects completed 3 years of the extension and did not miss >1 dose of DMAb during the first 3 years of the Extension. Fracture rates and rate ratios were obtained using generalized estimating equation Poisson models; fracture rates are per 100 subject‑years. Rate ratios relative to the first 3 years of DMAb treatment were adjusted for age, total hip BMD T-score, weight, and history of nonvertebral fracture. In addition, the treatment group variable was included in the model for the combined analysis only. |
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To cite this abstract in AMA style:
Ferrari S, Butler P, Kendler D, Miller PD, Roux C, Wang A, Wagman RB, Lewiecki E. Ten-Year Continued Nonvertebral Fracture Reduction in Postmenopausal Osteoporosis with Denosumab Treatment [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/ten-year-continued-nonvertebral-fracture-reduction-in-postmenopausal-osteoporosis-with-denosumab-treatment/. Accessed .« Back to 2017 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/ten-year-continued-nonvertebral-fracture-reduction-in-postmenopausal-osteoporosis-with-denosumab-treatment/