Parathyroid hormone receptor agonists in the management of osteoporosis

Parathyroid hormone (PTH) regulates bone homeostasis. Intermittent exposure to PTH results in bone formation being greater than bone resorption, and this effect has been harnessed through the development of agonists of the PTH and PTH-related protein type 1 receptor (PTH1R) to treat osteoporosis. Teriparatide, an analogue of the first 34 amino acids of PTH, and abaloparatide, which resembles PTH-related protein (PTHrP) in structure, are PTH1R agonists currently in clinical use. Both medications have been shown to increase bone mineral density at the lumbar spine, femoral neck and total hip. Randomized controlled trials with teriparatide or abaloparatide have also provided evidence of reduction in vertebral and non-vertebral fractures. The ACTIVE trial suggested slightly greater efficacy for major osteoporotic fractures (as an exploratory end point) for abaloparatide than for teriparatide. A similar potential superiority was suggested for hip fracture in a real-world, observational study. Side effects of these medications are usually transient, and although a risk of osteosarcoma was suggested by studies using murine models, no such risk has been observed in extensive human studies. Overall, both teriparatide and abaloparatide have demonstrated convincing clinical effectiveness and cost-effectiveness, with a reassuring safety profile. Potential differences in their effects on bone mineral density and their antifracture effects offer avenues for differentiation but require further validation in appropriately designed studies. This Review summarizes clinical effectiveness, health economics and safety data on the parathyroid hormone receptor agonists teriparatide and abaloparatide, discussing potential strategies and drug combinations to achieve best outcomes in patients with osteoporosis.