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Abstract Number: 1887

Ten-Year Continued Nonvertebral Fracture Reduction in Postmenopausal Osteoporosis with Denosumab Treatment

S Ferrari1, PW Butler2, DL Kendler3, Paul D Miller4, C Roux5, AT Wang2, Rachel B. Wagman2 and EM Lewiecki6, 1Geneva University Hospital, Geneva, Switzerland, 2Amgen Inc., Thousand Oaks, CA, 3University of British Columbia, Vancouver, BC, Canada, 4Colorado Center for Bone Research, Lakewood, CO, 5Paris Descartes University, Paris, France, 6New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: denosumab, fractures and osteoporosis

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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
DMAb Treatment

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)
     p-value

1.98 (1.67–2.34)

[Referent]

1.54 (1.29–1.83)

0.79 (0.62–1.00)
p = 0.046

1.44 (1.24–1.66)

0.74 (0.60–0.93)
p = 0.008

Cross-over Subjects
(N = 1731)

123 Fractures

91 Fractures

—

Fracture Rate (95% CI)

Rate Ratio (95% CI)
      p-value

2.37 (1.97–2.84)

[Referent]

1.52 (1.24–1.87)

0.65 (0.50–0.86)
p = 0.002

—

—

Long-term and
Cross-over Subjects Combined
(N = 4074)

263 Fractures

217 Fractures

—

Fracture Rate (95% CI)

Rate Ratio (95% CI)
       p-value

2.15 (1.90–2.43)

[Referent]

 

1.53 (1.34–1.75)

0.72 (0.61–0.86)
p < 0.001

—

—

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.

 


Disclosure: S. Ferrari, MSD,UCB Pharma, 2,Agnovos, Amgen, Labatec, UCB Pharma, 5,Amgen, Sandoz, UCB Pharma, 8,Novartis Pharmaceutical Corporation, 9; P. Butler, Amgen Inc., 1,Amgen Inc., 3; D. Kendler, Amgen, Astellas, AstraZenica, Eli Lilly, 2,Amgen, Eli Lilly, Pfizer, 5,Amgen, Eli Lilly, Pfizer, 8; P. D. Miller, Amgen, Lilly, Merck, Radius Health, Ultragenyx, 2,Amgen, Alexion, Merck, Lilly, Radius Health, Ultragenyx, 5; C. Roux, Ultragenyx, 2,Alexion, Amgen, Eli Lilly, UCB Pharma, 5; A. Wang, Amgen, 1,Amgen, 3; R. B. Wagman, Amgen, 1,Amgen, 3; E. Lewiecki, Amgen, 2,Amgen, Radius, 5.

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 .
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