Abaloparatide, the second generation osteoanabolic drug: Molecular mechanisms underlying its advantages over the first-in-class teriparatide

Abaloparatide is an analog of human parathyroid hormone-related protein (PTHrP) that has recently been approved for the treatment of post-menopausal osteoporosis. Abaloparatide is a stimulator of bone formation similar to teriparatide (1-34 PTH/TPTD), the first-in-class osteoanabolic drug. Both PTH and PTHrP signal via the type 1 PTH receptor (PTH1R) however, the downstream signaling varies between the two ligands. Both ligands have a similar affinity for the R-G (GTP gamma S-sensitive) state of PTH1R, but, TPTD has a four-fold higher affinity for R-0 (GTP gamma S-insensitive) than PTHrP that results in a prolonged cAMP signaling. Consequently, a greater production from osteoblastic cells of a potent resorption inducer, receptor activator of nuclear factor kappa B ligand (RANKL) is caused by TPTD than PTHrP. TPTD causes an excess formation over resorption early on producing an anabolic "window" which is lost with time due to increased RANKL production causing resorption to catch up with the formation. Although highly labile, PTHrP has an osteogenic effect accompanied by lesser resorptive and hypercalcemic effects than TPTD because of faster PTHrP-PTH1R dissociation than PTH-PTH1R complex. Engineered from PTHrP (1-34), abaloparatide was made stable and overcame the loss of the anabolic window and hypercalcemia associated with TPTD. The receptor activating domain (1-21 amino acids) of both ligands is same but multiple substitutions between amino acids 22-34 of PTHrP were made to enhance the peptide's stability. In, women with osteoporosis, abaloparatide increased BMD faster than TPTD and decreased fracture risk at both vertebral and non-vertebral sites but unlike TPTD/PTH did not increase resorption or hypercalcemia.