Abaloparatide

Abaloparatide is a 34-amino acid synthetic analog of parathyroid hormone-related protein (PTHrP) approved by the FDA under the brand name Tymlos for treating osteoporosis in postmenopausal women and men at high fracture risk. It is an anabolic agent that preferentially stimulates bone formation with minimal increase in bone resorption, distinguishing it from antiresorptive therapies. FDA approval was granted in 2017.

Abaloparatide acts as a selective agonist at the PTH1 receptor (PTH1R), activating the Gs-protein–mediated cyclic adenosine monophosphate (cAMP) signaling pathway in osteoblasts. Compared to teriparatide (PTH 1-34), abaloparatide shows greater selectivity for the RG conformation of PTH1R, which is associated with transient cAMP signaling and predominantly anabolic bone effects. This selectivity reduces prolonged receptor activation that drives osteoclast coupling and bone resorption. The net result is increased osteoblast activity, stimulation of new bone formation on trabecular and cortical surfaces, and improved bone mineral density (BMD) with a relatively favorable bone formation-to-resorption ratio compared to teriparatide.

The pivotal ACTIVE trial (n=2,463) demonstrated abaloparatide 80 mcg daily reduced vertebral fracture risk by 86% and non-vertebral fracture risk by 43% versus placebo over 18 months. Head-to-head comparison with teriparatide showed significantly greater improvements in total hip and femoral neck BMD. The ACTIVExtend extension study confirmed durable fracture protection after transitioning to alendronate. Markers of bone formation (P1NP) increased rapidly, while resorption markers (CTX) showed a lesser rise than with teriparatide, supporting the favorable anabolic window hypothesis.