Anti-sclerostin antibodies: a new frontier in fragility fractures treatment

Abstract

Bone fragility is the determinant of the increased risk of minimal trauma fracture and must be treated with a multimodal approach that includes pharmacological therapy, physical exercise, and adequate nutrition. Pharmacological therapy, to date based on the administration of antiresorptive drugs, such as bisphosphonates and denosumab, or osteoanabolic drugs, such as teriparatide and abaloparatide, has shown to be effective in reducing the risk of fracture in osteoporotic patients. In the context of the cellular and molecular mechanisms that regulate bone metabolism, the discovery of the Wnt signaling pathway and its role in bone tissue homeostasis has allowed the identification of sclerostin as an inhibitor of osteoblastic activity and simultaneously as a stimulator of osteoclastic activity. Therefore, the use of a monoclonal antibody, romosozumab, against this protein has been tested as a potential drug with a dual action, stimulating bone neo-apposition and inhibiting bone resorption. The efficacy of romosozumab has been demonstrated in numerous clinical trials against both placebo and other drugs commonly used in the treatment of patients affected by osteoporosis. The advantages of this drug lie above all in its rapid action which makes it particularly suitable in clinical situations where it is necessary to improve bone strength very quickly due to the imminent risk of fragility fracture. Clinical studies and guidelines suggest romosozumab as an initial drug in an ideal sequential approach from osteoanabolic to antiresorptive drugs. Some aspects of cardiovascular safety remain to be fully investigated, therefore its use in osteoporotic patients at high cardiovascular risk should be avoided until further data become available.

Keywords: fragility fractures; osteoporosis; risk of falls; romosozumab; sclerostin.

Figure 1.

Lumbar spine BMD changes during treatment with anti-osteoporotic drugs at 1-year follow-up. FRAME investigated efficacy of romosozumab on fracture risk in postmenopausal osteoporosis; FIT investigated efficacy of alendronate on fracture risk in postmenopausal osteoporosis; MORE investigated efficacy of raloxifene on fracture risk in postmenopausal osteoporosis; VERT investigated efficacy of risedronate on fracture risk in postmenopausal osteoporosis; HORIZON investigated efficacy of zoledronate on fracture risk in postmenopausal osteoporosis; FREEDOM investigated efficacy of denosumab on fracture risk in postmenopausal osteoporosis; ACTIVE investigated efficacy of abaloparatide on fracture risk in postmenopausal osteoporosis; PTH (parathyroid hormone); FPT [PTH (1–34) 20 µg, PTH (1–34) 40 µg)] investigated efficacy of alendronate on fracture risk in postmenopausal osteoporosis. ACTIVE, Abaloparatide Comparator Trial in Vertebral Endpoints; BMD, bone mineral density; FIT, Fracture Intervention Trial; FPT, Fracture Prevention Trial; FRAME, Fracture Study in Postmenopausal Women with Osteoporosis; FREEDOM, Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months; HORIZON, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly; MORE, Multiple Outcomes of Raloxifene Evaluation; VERT, Vertebral Efficacy with Risedronate Therapy.

Figure 2.

Femoral neck BMD changes during treatment with anti-osteoporotic drugs at 1-year follow-up. FRAME investigated efficacy of romosozumab on fracture risk in postmenopausal osteoporosis; FIT investigated efficacy of alendronate on fracture risk in postmenopausal osteoporosis; MORE investigated efficacy of raloxifene on fracture risk in postmenopausal osteoporosis; VERT investigated efficacy of risedronate on fracture risk in postmenopausal osteoporosis; HORIZON investigated efficacy of zoledronate on fracture risk in postmenopausal osteoporosis; FREEDOM investigated efficacy of denosumab on fracture risk in postmenopausal osteoporosis; ACTIVE investigated efficacy of abaloparatide on fracture risk in postmenopausal osteoporosis; FPT [PTH (1–34) 20 µg, PTH (1–34) 40 µg)], investigated efficacy of alendronate on fracture risk in postmenopausal osteoporosis. ACTIVE, Abaloparatide Comparator Trial in Vertebral Endpoints; BMD, bone mineral density; FIT, Fracture Intervention Trial; FPT, Fracture Prevention Trial; FRAME, Fracture Study in Postmenopausal Women with Osteoporosis; FREEDOM, Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months; HORIZON, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly; MORE, Multiple Outcomes of Raloxifene Evaluation; VERT, Vertebral Efficacy with Risedronate Therapy.