Abaloparatide (acetate)

Abaloparatide is a synthetic derivative of human parathyroid hormone-related protein (PTHrP) (1-34) and an agonist of parathyroid hormone receptor type 1 (PTH1R).¹ It selectively binds to the G protein-dependent (RG) conformation of PTH1R over the G protein-independent (R₀) conformation (IC₅₀s = 0.2 and 316.23 nM, respectively). It induces cAMP signaling more transiently than PTH (1-34) , PTHrP (1-36), or the long-acting PTH/PTHrP hybrid peptide analog LA-PTH (EC₅₀s = 0.08, 0.44, 0.46, and 0.21 nM, respectively). Abaloparatide (5 and 20 µg/kg per day for six weeks) increases areal bone mineral density in the lumbar spine, total femur, and femur diaphysis in ovariectomized osteopenic rats.² It also increases bone strength in the femur diaphysis, femur neck, and L4 vertebra in the same model. Abaloparatide increases the incidence of focal osteoblast hyperplasia, benign osteoblastoma, and osteosarcoma in rats in a time- and dose-dependent manner when administered at doses greater than or equal to 10 µg/kg per day for up to two years.³ Formulations containing abaloparatide have been used in the treatment of osteoporosis in postmenopausal women at high risk for bone fracture.

1.Hattersley, G., Dean, T., Corbin, B.A., et al.Binding selectivity of abaloparatide for PTH-type-1-receptor conformations and effects on downstream signalingEndocrinology157(1)141-149(2016) 2.Bahar, H., Gallacher, K., Downall, J., et al.Six weeks of daily abaloparatide treatment increased vertebral and femoral bone mineral density, microarchitecture and strength in ovariectomized osteopenic ratsCalcif. Tissue Int.99(5)489-499(2016) 3.Jolette, J., Attalla, B., Varela, A., et al.Comparing the incidence of bone tumors in rats chronically exposed to the selective PTH type 1 receptor agonist abaloparatide or PTH(1-34)Regul. Toxicol. Pharmacol.86356-365(2017)