New therapeutic targets for osteoporosis.

New anti-osteoporotic agents have been developed, potentially enriching the therapeutic armamentarium. Currently available osteoanabolic therapies are the parathyroid hormone (PTH) and PTH-related peptide (PTHrP) synthetic analogues, teriparatide and abaloparatide. Daily administration at doses of 20 and 80 μg, respectively, in contrast to continuous PTH secretion, leads to increased bone formation and reduces vertebral and non-vertebral fracture risk. Teriparatide is more effective than bisphosphonates (alendronate, risedronate) in increasing bone mineral density (BMD), improving bone architecture and reducing fracture risk. Abaloparatide leads to greater BMD gain, has greater anti-fracture efficacy regarding major osteoporotic fractures (upper arm, wrist, hip or clinical spine) compared with teriparatide (without a difference in morphometric vertebral and non-vertebral fractures), and has a lower risk of hypercalcaemia. Romosozumab, a sclerostin inhibitor, both induces bone formation and suppresses bone resorption. Administered at monthly subcutaneous doses of 210 mg, it reduces vertebral, non-vertebral and hip fracture risk compared with either placebo or alendronate. However, concerns have arisen about increased cardiovascular risk, which has suspended its approval by the FDA. Anabolic therapy should always be followed by administration of an anti-resorptive agent, such as bisphosphonates or denosumab, which preserves and may further increase BMD gain. Denosumab provides the greatest benefit for BMD when administered sequentially after its combination with teriparatide for 24 months and constitutes a reasonable option for patients at high risk of fracture. However, longitudinal data are needed to confirm the efficacy and safety of these therapeutic interventions.