Abaloparatide Treatment for Osteoporosis

Abstract

Abstract Parathyroid hormone related peptide (PTHrP) is a paracrine factor produced by osteoblast lineage cells, which has a role in the regulation of bone remodeling and fracture repair. Early preclinical and clinical studies indicated that exogenous administration of PTHrP could have anabolic activity on the skeleton similar to that seen with exogenous PTH, but had potent vasodilatory effects which limited its clinical utility. Abaloparatide (Abalo) is a synthetic PTHrP(1-34) analog with 70% homology to PTHrP and 40% homology with Parathyroid hormone (PTH). Like PTH and PTHrP, Abalo interacts with the PTH1 receptor, however Abalo has higher affinity for the RG subtype of the Receptor and lower affinity for the R0 conformation (vs. PTH), resulting in relatively greater stimulation of bone formation and lesser bone resorption in preclinical models. Short-term clinical studies confirmed that Abalo had potent dose dependent anabolic activity with increases in BMD at the higher doses that were equal to or larger than that seen with PTH. In the Abalo Pivotal Trial, 2463 postmenopausal women with osteoporosis were randomized to blinded daily subcutaneous Abalo vs. placebo or open label PTH1-34. At 18 months, spine BMD had increased similarly with Abalo and TPTD, however, hip BMD increments were faster and significantly larger with Abalo. Consistent with the BMD effects, over 18 months, Abalo reduced vertebral fracture incidence by 86% and nonvertebral fracture incidence by 43%. The fracture risk reductions were sustained after both groups transitioned to antiresorptive medication. Abalo is a potent anabolic agent for treatment of osteoporosis and can be considered as initial therapy in patients at high risk for fracture.