PTH1 receptor agonists for fracture risk: a systematic review and network meta-analysis

Osteoporosis, defined by reduced bone mineral density and macro- and micro-architectural degradation, leads to increased fracture risk, particularly in aging populations. While randomized controlled trials (RCTs) demonstrate that PTH1 receptor agonists, teriparatide and abaloparatide, are effective at reducing fracture risk, real-world evidence (RWE) remains sparse. This study reviews and compares the anti-fracture efficacy of these agents, against each other and against other osteoporosis treatments using both RCTs and RWE. We systematically searched Medline, Embase, and Cochrane up to May 2024, focusing on RCTs and RWE studies reporting reduction in vertebral, non-vertebral, hip, or all fractures as primary endpoint. A network meta-analysis (NMA) was conducted, first through pairwise meta-analyses of teriparatide versus abaloparatide, then a Bayesian NMA comparing each to other treatments. Safety assessments included adverse events classified by MedDRA, with a particular attention to hypercalcemia and cardiac events. Seventeen studies (11 RCTs, 6 RWE) met inclusion criteria. Teriparatide and abaloparatide were effective in reducing vertebral and non-vertebral fractures in all pairwise meta-analyses versus placebo. Abaloparatide showed an advantage over teriparatide for non-vertebral fractures (OR: 0.87, 95% CI: 0.80-0.95) and hip fractures (OR: 0.81, 95% CI: 0.71-0.93). In the NMA model, teriparatide and abaloparatide were superior to placebo, raloxifene, and calcitonin in reducing vertebral fracture while teriparatide was further superior to denosumab and risedronate. For non-vertebral fracture, abaloparatide was better than any other treatment while teriparatide was only superior to alendronate or placebo. PTH1 analogs were better than placebo at reducing all fractures while no difference was observed for the risk of hip fracture. Both abaloparatide and teriparatide demonstrate comparable safety to other osteoporosis treatments, with no increased cardiovascular risk. This review highlights that PTH1 receptor agonists effectively reduce fracture risk, with abaloparatide offering enhanced benefits for non-vertebral and hip fractures compared to teriparatide. Both agents exhibit acceptable safety profiles, suggesting their valuable role in managing osteoporosis, particularly for high-risk patients.