Cardiovascular Safety of Abaloparatide in Postmenopausal Women With Osteoporosis

Analysis From the ACTIVE Phase 3 Trial

Felicia Cosman; Linda R. Peterson; Dwight A. Towler; Bruce Mitlak; Yamei Wang; Steven R. Cummings

Disclosures

J Clin Endocrinol Metab. 2020;105(11) 

In This Article

Abstract and Introduction

Abstract

Context: Abaloparatide is a US Food and Drug Administration-approved parathyroid hormone-related peptide 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 (MACEs) 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 (standard deviation SD) HR change from pretreatment to 1 hour posttreatment was 7.9 (8.5) beats per minute (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 posttreatment 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 vs placebo) and teriparatide (P = 0.04 vs 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.

Introduction

In addition to the central role of parathyroid hormone-related peptide (PTHrP) in bone and cartilage development, PTH/PTHrP signaling is important in cardiovascular development and functioning.[1–3] PTHrP acts in a paracrine fashion to regulate local vascular tone, and it has been known for decades that acute administration of PTH and PTHrP causes vasodilatation of the coronary, renal, and other vascular beds.[3–5] In healthy volunteers, infusion of PTHrP increased heart rate (HR) and renal plasma flow without a significant effect on other hemodynamic parameters (arterial pressure, electromechanical systole corrected for HR [QS2c]).[2] In preclinical models, PTHrP improved the contractile function of myocardium subjected to ischemia-reperfusion,[6] and PTHrP protected cultured cardiomyocytes from oxidative stress.[7]

Abaloparatide is a synthetic analog of PTHrP and selective agonist of the PTH type 1 receptor (PTHR1) that is US Food and Drug Administration (FDA) approved for the treatment of osteoporosis in postmenopausal women at high risk for fracture.[8] The efficacy and safety of abaloparatide was established in the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial, in which 18 months of treatment with abaloparatide produced significantly greater reductions in risk of new vertebral and nonvertebral fractures versus placebo and significantly greater reductions in risk of major osteoporotic fracture versus placebo and teriparatide.[9] In the extension study (ACTIVExtend), where participants from the abaloparatide and placebo groups were treated with oral alendronate,[10,11] reductions in fracture risk and increased bone mineral density increments were sustained.

There were no differences in adverse events (AEs) between the treatment groups in ACTIVE. Nonserious AEs leading to study-drug discontinuation occurred more frequently with abaloparatide (nausea [1.6%], dizziness [1.2%], headache [1.0%], and palpitations [0.9%]) compared with placebo or open-label teriparatide.[9] During the first 6 months of treatment, a slightly greater number of participants withdrew from the abaloparatide group compared with the teriparatide or placebo groups, but from 6 months on, discontinuation was similar among groups.

At the request of a regulatory agency, a post hoc analysis of major adverse cardiovascular events (MACE) and MACE plus heart failure (HF) was conducted in ACTIVE and was further assessed during ACTIVExtend. The objective of the current analysis was to assess the cardiovascular safety profile of abaloparatide using HR, blood pressure (BP) measurements, and AEs potentially associated with changes in HR and BP from ACTIVE and to determine the frequency of MACE after abaloparatide treatment concluded. Further information on HR changes was examined in a clinical pharmacology study conducted in 55 healthy women and men.

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