Abstract

Currently, anti-resorptive drug therapy is the cornerstone of fracture prevention. Anti-resorptive drugs decrease bone remodelling, allowing the remaining bone to increase secondary mineralisation, and, with denosumab, also allowing periosteal bone modelling.

Teriparatide is currently the only available bone-forming drug, which increases bone formation more than bone resorption, and has been shown to reduce the risk of vertebral and non-vertebral fractures.

Recently, two randomized clinical trials have been published on the effect of new bone forming agents on the risk of fracture.

Abaloparatide is a 1–34 fragment of PTHrP, with different pharmacokinetics and potential different signalling mechanisms compared to teriparatide. It increases bone formation more than bone resorption, both to a lesser degree than teriparatide. In the double blind, randomised placebo-controlled 18-month ACTIVE study, abaloparatide significantly reduced the risk of vertebral (-86%), clinical (-43%), non-vertebral (-43%) and major fractures (-70%). In a parallel randomised exploratory open-label comparison with teriparatide, bone density increased significantly more with abaloparatide, but the anti-fracture effect was similar, except for a significantly better result on prevention of major fractures.

Romosozumab is a monoclonal antibody that binds sclerostin, which is an inhibitor of bone formation. In contrast to other bone forming agents, it disconnects the increase in bone formation from a decrease in bone resorption. In the double-blind placebo-controlled FRAME study, romosozumab significantly reduced the risk of vertebral (-63%) and clinical fractures (-36%) during the first year, an effect that was maintained by transitioning to one-year denosumab treatment.

The effect on non-vertebral fractures was not significant, but geographic interaction was found. When excluding patients from South America, in whom fracture risk was low, one-year treatment with romosozumab significantly decreased the risk of non-vertebral fractures by 42%.

Abaloparatide and romosozumab are new bone forming agents, with different effects on bone remodelling and remodelling and early effects on clinical fractures. This opens new perspectives in individualised treatment of patients with high fracture risk and for fracture prevention in patients with low bone turnover, multiple vertebral fractures, very low BMD and fractures or bone loss during anti-resorptive treatment.