Cardiovascular Safety of Abaloparatide in Postmenopausal Women With Osteoporosis: Analysis From the ACTIVE Phase 3 Trial

Abstract

Context Abaloparatide is an FDA-approved PTHrp analog for treatment of osteoporosis in postmenopausal women at high risk of fracture. Objectives We assessed the cardiovascular safety profile of abaloparatide. Design Review of heart rate (HR), blood pressure (BP), and cardiovascular-related adverse events (AEs), including major adverse cardiovascular events (MACE) and heart failure (HF) from: (a) ACTIVE (NCT01343004), a phase 3 trial that randomized 2463 postmenopausal women with osteoporosis to abaloparatide, teriparatide, or placebo for 18 months; (b) ACTIVExtend (NCT01657162), where participants from the abaloparatide and placebo arms received alendronate for 2 years; and (c) a pharmacology study in 55 healthy adults. Results Abaloparatide and teriparatide transiently increased HR relative to placebo. Following first dose, mean (SD) HR change from pre-treatment to 1 hour post treatment was 7.9 (8.5) bpm for abaloparatide, 5.3 (7.5) for teriparatide, and 1.2 (7.1) for placebo. A similar pattern was observed over subsequent visits. In healthy volunteers, HR increase resolved within 4 hours. The corresponding change in mean supine systolic and diastolic BP 1 hour post treatment was -2.7/-3.6 mmHg (abaloparatide), -2.0/-3.6 (teriparatide), and -1.5/-2.3 (placebo). The percentage of participants with serious cardiac AEs was similar among groups (0.9‒1.0%). In a post hoc analysis, time-to-first incidence of MACE + HF was longer with abaloparatide (P = 0.02 versus placebo) and teriparatide (P = 0.04 versus placebo). Conclusions Abaloparatide was associated with transient increases in HR and small decreases in BP in postmenopausal women with osteoporosis, with no increase in risk of serious cardiac AEs, MACE, or HF.

Abaloparatide Increases Lumbar Spine and Hip BMD in Japanese Patients With Osteoporosis: The Phase 3 ACTIVE-J Study

“…In the present study, no safety concerns other than those reported in the ACTIVE study were identified ( 6 ). In a detailed analysis of cardiovascular adverse events associated with abaloparatide, Cosman et al ( 11 ) reported that no increased risks of serious cardiac adverse events were observed, while a transient increase in heart rate was observed immediately after injection of abaloparatide compared with placebo and resolved within 4 hours after administration. This increase in heart rate after abaloparatide injection was weakly associated with small but significant decreases in mean supine and standing systolic and diastolic blood pressures.…”

“…In the present study, although heart rate was not monitored during the observation period after injection, 7 participants had palpitations and 1 participant had orthostatic hypotension in the abaloparatide group compared with 1 participant with palpitations and none with orthostatic hypotension in the placebo group. These symptoms appear to be related to the vasodilator activity of abaloparatide and possibly a direct effect on the sinoatrial node, which is known to be slightly stronger for abaloparatide than teriparatide ( 11 , 12 ). Nevertheless, none of those events were serious, and as a recent meta-analysis suggested ( 13 ), both teriparatide and abaloparatide have no effect on cardiovascular risk and overall mortality.…”

Cardiovascular Safety of Antifracture Medications in Patients With Osteoporosis: A Narrative Review of Evidence From Randomized Studies

“…At the request of the FDA, investigators of the “Abaloparatide Comparator Trial in Vertebral Endpoints” (ACTIVE) study performed a comprehensive post hoc cardiovascular safety study of trial participants. ( 75 ) Heart rates, blood pressure, and adverse events presumed related to increased heart rates were recorded. Overall rates of treatment‐emergent adverse events were higher in participants receiving study medications as expected.…”

“…• PTH-analogues may have autonomic heart rate effects of clinical importance At the request of the FDA, investigators of the "Abaloparatide Comparator Trial in Vertebral Endpoints" (ACTIVE) study performed a comprehensive post-hoc cardiovascular safety study of trial participants (75) . Heart rates, blood pressure and adverse events presumed related to increased heart rates were recorded.…”

Therapeutic Treatments for Osteoporosis—Which Combination of Pills Is the Best among the Bad?

“…Although ABL had no significantly improved effect, it was well tolerated for women with postmenopausal osteoporosis at high risk of fracture [143]. Clinical III phase studies showed that ABL was associated with increased heart rate and small decreases in blood pressure in postmenopausal women with osteoporosis, but no increased risks of serious cardiac adverse events, major adverse cardiovascular events, and heart failures [144]. In 2019, it was reported that the supporting effect of ABL in (mouse) chondrogenesis of mesenchymal stem cells was due to the inhibition of reactive oxygen species (ROS) production [145].…”