Effect of abaloparatide on vertebral, nonvertebral, major osteoporotic, and clinical fractures in a subset of postmenopausal women at increased risk of fracture by FRAX probability

Abstract

Summary We evaluated the efficacy of abaloparatide in women who were at increased risk for fracture, based on CHMP recommended risk thresholds, at the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) study baseline. Among patients at high risk based on FRAX probabilities, 18 months of abaloparatide significantly decreased risk for all fracture endpoints compared with placebo. Purpose Abaloparatide, a novel anabolic agent for the treatment of postmenopausal osteoporosis, significantly reduced the risk of vertebral and nonvertebral fractures in the ACTIVE study compared with placebo. In this post hoc analysis, we evaluated abaloparatide’s efficacy in a subset of women in the study at an increased risk of fracture at baseline, based on the Committee for Medicinal Products for Human Use (CHMP) recommended risk thresholds for inclusion in clinical trials. Methods Women with a baseline 10-year risk of major osteoporotic fracture ≥ 10% or hip fracture ≥ 5%, assessed using the FRAX® tool (including femoral neck bone mineral density), were included in the analysis. The proportion with one or more events of new morphometric vertebral fractures was calculated. Event rates for nonvertebral, major osteoporotic, and all clinical fractures were estimated using Kaplan-Meier analysis. Results Following 18 months of treatment, abaloparatide significantly reduced incident vertebral fractures compared with placebo (relative risk reduction = 91%; 0.5% versus 5.6%; p < 0.001). Abaloparatide treatment was also associated with significantly fewer nonvertebral, major osteoporotic, and clinical fractures compared with placebo: 2.7% versus 5.8%, p = 0.036; 1.3% versus 6.0%, p < 0.001; and 3.5% versus 8.2%, p = 0.006, respectively. The effect of abaloparatide on major osteoporotic fractures (78% reduction) was significantly greater than that seen with teriparatide (23% reduction, p = 0.007). Conclusion In a subset of postmenopausal women at increased risk of fracture as judged by CHMP guidance, abaloparatide significantly decreased the risk of all fracture endpoints compared with placebo.

Fracture risk assessment by the FRAX model

“…This information has also been used to determine whether treatment efficacy varies according to baseline fracture risk. Interventions studied include abaloparatide, raloxifene, bazedoxifene, clodronate, daily and weekly teriparatide, denosumab, alendronate, strontium ranelate and, most recently, romosozumab [43][44][45][46][47][48][49][50][51][52][53].…”

Abaloparatide: an anabolic treatment to reduce fracture risk in postmenopausal women with osteoporosis

“…A number of post hoc analyses of ACTIVE and ACTIVExtend have been conducted to further elucidate the efficacy of ABL in postmenopausal women with osteoporosis 53,[55][56][57][58][59][60][61][62][63][64][65][66][67][68] .…”

“…The fracture risk reduction and BMD increases observed in ACTIVE and ACTIVExtend were found to be consistent regardless of participant baseline fracture risk 64,66 (Figure 8). Fracture risk reduction was also similar across a wide range of baseline fracture probabilities, as assessed by FRAX in women from ACTIVE 62 , including in participants at high risk of fracture (N ¼ 1400) based on the Committee for Medicinal Products for Human Use (CHMP) guidelines for clinical trial enrollment (a baseline 10-year risk of major osteoporotic fracture !10% or hip fracture !5%) 60 . Fracture risk reduction with ABL was also consistent in participants from ACTIVE across geographic region subgroups (North America, South America, Europe, and Asia) and regardless of ethnicity subgroup (Hispanic or Latino or other) 67 .…”

“…The efficacy and safety of ABL are consistent with the overall ACTIVE/ACTIVExtend population in the following subpopulations Patient baseline fracture risk 64,66 BMD T-score of the lumbar spine, total hip, and femoral neck ( -2.5 versus >-2.5 and -3.0 versus >-3.0) History of nonvertebral fracture (yes versus no) Prevalent vertebral fracture (yes versus no) Age (<65 versus 65 to <75 versus !75 years) Fracture risk as assessed by FRAX 62 Fracture risk based on CHMP thresholds 60 Baseline 10-year risk of major osteoporotic fracture !10% or hip fracture !5% The elderly 55,63 Aged !80 years Patients with renal impairment 57 Baseline eGFR of !90 mL/min (stage I CKD) Baseline eGFR 60 mL/min to ˂90 mL/min (stage II CKD) Baseline eGFR 30 mL/min to <60 mL/min (stage III CKD) Patients with T2DM 59 Across geographic and ethnic subgroups 67 North and ACTIVExtend, in which the effectiveness of ABL treatment in ACTIVE was compared with ALN treatment in ACTIVExtend in postmenopausal women with osteoporosis 61 . Cross-group comparison of the incidence of new vertebral fractures between the ABL group during ACTIVE and the PBO/ALN group during ACTIVExtend showed a significant decrease with initial treatment with ABL versus initial treatment with ALN.…”

Economic implications of osteoporotic fractures in postmenopausal women

“…The difference in fracture risk reduction between abaloparatide and teriparatide was not statistically significant. 43 Oftentimes in clinical practice, patients are treated with bisphosphonates after 2 years of therapy with teriparatide or abaloparatide in order to preserve the increase in bone density. 44,45 If bisphosphonates cannot be used, clinicians may consider the use of raloxifene or denosumab.…”