Abaloparatide (Tymlos, Eladynos)

概览

Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture.

作用机制

Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G and G, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G-protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation.

适应症

Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy.

• Osteoporosis