Denosumab Safety and Efficacy Among Participants in the FREEDOM Extension Study With Mild to Moderate Chronic Kidney Disease

Abstract

Context: The effects of long-term exposure to denosumab in individuals with renal insufficiency are unknown.

Objective: This post hoc analysis evaluates the long-term safety and efficacy of denosumab in individuals with mild-to-moderate chronic kidney disease (CKD) (stages 2 and 3) using data from the pivotal phase 3, double-blind, 3-year FREEDOM (NCT00089791) and open-label, 7-year extension (NCT00523341) studies.

Participants and methods: Women age 60 to 90 years with a bone mineral density (BMD) T-score of less than -2.5 to greater than -4.0 at the total hip or lumbar spine were randomly assigned 1:1 to receive denosumab 60 mg subcutaneously every 6 months (long-term arm) or placebo (cross-over arm) in FREEDOM; eligible participants could enroll in the extension to receive denosumab 60 mg subcutaneously every 6 months. Change in estimated glomerular filtration rate (eGFR) from study baseline and annualized rates of fracture and adverse events (AEs) were the main outcome measures.

Results: Most participants (1259/1969 [64%] long-term arm; 1173/1781 [66%] crossover arm) with baseline CKD stage 2 or 3 remained within the same CKD subgroup at study completion; less than 3% progressed to CKD stage 4. Participants in all eGFR subgroups showed similar, persistent BMD gains over time and a low incidence of fractures. The percentage of participants reporting serious AEs was similar among renal subgroups (normal, CKD stage 2, CKD stage 3a, CKD stage 3b) both for the long-term (54% vs 52% vs 57% vs 58%) and crossover (43% vs 42% vs 43% vs 68%) arms, except CKD stage 3b subgroup, crossover arm.

Conclusion: The safety and efficacy of denosumab did not differ among participants with mild to moderate CKD.

Keywords: bone mineral density; chronic kidney disease; denosumab; fracture; safety.

Figure 1.

Annualized incidence rates of fractures by baseline estimated glomerular filtration rate (eGFR). A, Annualized incidence rate (%) of new vertebral fractures. B, Annualized cumulative incidence rate (%) of nonvertebral fractures based on Kaplan-Meier estimate. Bars (from left to right) show FREEDOM placebo arm, FREEDOM denosumab (DMAb)-treated arm, FREEDOM extension long-term denosumab-treated arm, and crossover denosumab-treated arm (randomly assigned to placebo in FREEDOM and received denosumab in the extension). Chronic kidney disease (CKD) stage was calculated according to eGFR at FREEDOM baseline, except for the crossover arm, where CKD stage was calculated according to eGFR at the extension baseline. Normal renal function = eGFR greater than or equal to 90 mL/min/1.73 m²; CKD stage 2 = eGFR 60 to 89 mL/min/1.73 m²; CKD stage 3a = eGFR 45 to 59 mL/min/1.73 m²; CKD stage 3b = eGFR 30 to 44 mL/min/1.73 m². VFx, vertebral fracture.

Figure 2.

Percentage change in lumbar spine and total hip bone mineral density (BMD) from baseline by baseline estimated glomerular filtration rate (eGFR) in the long-term and crossover arms. Graphs show the least square means and 95% CIs. Chronic kidney disease (CKD) stage was calculated according to eGFR at FREEDOM and extension baseline for the denosumab-treated long-term and crossover arms, respectively. Note that for the long-term arm, lumbar spine BMD was measured in a FREEDOM substudy at year 1 and 2 with a limited number of participants; lumbar spine BMD was measured in all participants at baseline and year 3 only. Normal renal function = eGFR greater than or equal to 90 mL/min/1.73 m²; CKD stage 2 = eGFR 60 to 89 mL/min/1.73 m²; CKD stage 3a = eGFR 45 to 59 mL/min/1.73 m²; CKD stage 3b = eGFR 30 to 44 mL/min/1.73 m². N = number of participants with an eGFR evaluation at study baseline; n = number of participants with observed data.

Figure 3.

Maximum postbaseline shift in hypocalcemia grade in the long-term and crossover arms. Chronic kidney disease (CKD) stage was calculated according to estimated glomerular filtration rate (eGFR) at FREEDOM and extension baseline for the denosumab-treated long-term and crossover arms, respectively. Normal renal function = eGFR greater than or equal to 90 mL/min/1.73 m²; CKD stage 2 = eGFR 60 to 89 mL/min/1.73 m²; CKD stage 3a = eGFR 45 to 59 mL/min/1.73 m²; CKD stage 3b = eGFR 30 to 44 mL/min/1.73 m². Hypocalcemia grade was based on the Common Terminology Criteria for Adverse Events, version 3.0: grade 1 = less than the lower limit of normal to 8.0 mg/dL (2.0 mmol/L); grade 2 = less than 8.0 to 7.0 mg/dL (< 2.0-1.75 mmol/L). N = number of participants with an eGFR evaluation at study baseline.