Abaloparatide

Abstract

SummaryAbaloparatide is an investigational analog of human PTHrP (1-34) being developed for the treatment of osteoporosis. The amino-acid sequence of abaloparatide is identical to that of PTHrP in the first 20 amino-acids, while over half of the remaining amino-acids are different. Some studies in animals and in humans reported that abaloparatide presented a potent anabolic activity with reduced effects on bone resorption as compared to that observed with teriparatide. This may be due to a more transient signaling response of abaloparatide related to differing affinities of the two drugs to the specific conformations of the PTH1 receptor. In the ACTIVE study, a phase 3 fracture prevention trial, 2460 postmenopausal osteoporotic women at high risk for fracture were randomized to receive 18-months of either daily abaloparatide 80 μg s.c., placebo or teriparatide 20 μg s.c. The reduction in vertebral fracture rate with respect to placebo was 86% in the abaloparatide group and 80% in the teriparatide group. Abaloparatide also produced a significant 43% reduction in the rate of nonvertebral fractures (2.7 vs 4.0% with placebo, p=0.04) whereas teriparatide determined a 28% reduction (2.9 vs 4.0% with placebo, p=NS). Abaloparatide or teriparatide showed similar increases in BMD at lumbar spine, while the patients of the abaloparatide group showed significantly greater increases in BMD at both total hip (4.18 vs 3.26%) and femoral neck (3.60 vs 2.66%). Therefore, if the preliminary data of the AC-TIVE study is confirmed, abaloparatide may become an important option for the anabolic treatment of postmenopausal osteoporosis.

Osteoanabolic and dual action drugs

“…Abaloparatide (ABL), a new drug for osteoporosis, is identical to PTHrP through the first 22 residues but, thereafter, several substituent amino acids render this molecule very different in terms of its interactions at the receptor level . Both TPTD and ABL act on the same receptor but in different ways . The difference in activity between the two molecules may be explained, at least in part, by the way in which these two peptides interact at the two conformational configurations of the PTHR1 receptor, namely R0 and RG .…”

Proteolytic Regulation of Parathyroid Hormone-Related Protein: Functional Implications for Skeletal Malignancy

“…Such approaches have already proven beneficial for the treatment of osteoporosis, such as the development and FDA approval of abaloparatide. The abaloparatide sequence shares the first 20 N-terminal amino acids in common with PTHrP, but approximately half of the remaining amino acids are modified to ensure predominantly anabolic properties [44,143].…”

Profile of Abaloparatide and Its Potential in the Treatment of Postmenopausal Osteoporosis

“…The molecular mechanisms by which abaloparatide exerts its effects on bone are not fully understood but may be related to the conformation-selective binding of the PTH1 receptor relative to other ligands including PTH and PTHrP [ 6 - 9 ]. Despite sharing some sequence homology, each hormone (PTH and PTHrP) plays a distinct role in bone physiology.…”

“…While both hormones act on the same receptor, recent studies have shown that continuous PTHrP administration stimulates bone formation preferentially, whereas continuous administration of PTH leads to more bone resorption than formation [ 6 , 9 ]. Both abaloparatide and teriparatide showed an increased messenger ribonucleic acid (RNA) expression level for the receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor in a human osteoblastic cell line; however, these effects were rapidly reversed after the removal of abaloparatide from the culture media, while the effects were sustained in the teriparatide-treated cells [ 6 , 9 ]. Thus, PTHrP may cause transient stimulation of osteoblast cAMP production, which may result in lower osteoblast-derived RANKL expression and, therefore, less stimulation of bone resorption.…”

“…Thus, PTHrP may cause transient stimulation of osteoblast cAMP production, which may result in lower osteoblast-derived RANKL expression and, therefore, less stimulation of bone resorption. Although the molecular mechanisms underlying the differences between abaloparatide and teriparatide are not well understood, the mechanisms may be related to conformational differences based on the affinities of the drugs to the PTHR1 receptor [ 6 - 9 ].…”