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.

Bone involvement in the early stages of Parkinson’s disease: a case–control study

“…27,28 Several studies investigated the prevalence of osteoporosis in PD, typically including patients with worse Hoehn & Yahr scores compared to the current population. [22][23][24][25][26][27][28][29] A previous study found a high prevalence of bone loss in patients with PD at the early stages based on quantitative parameters (i.e. BMD); reporting osteopenia and osteoporosis in 41.4% and 11.8% of patients, respectively.…”

“…24 Regarding other therapeutic strategies, including denosumab, a monoclonal antibody that inhibits osteoclast maturation by binding to receptor activator of nuclear factor j B ligand (RANKL), anabolic agents such as parathyroid hormonerelated protein analogues (teriparatide and abaloparatide) and dual-action drugs such as romosozumab, a monoclonal antibody sclerostin inhibitor, these have demonstrated efficacy in improving bone density and in reducing risk of fragility fractures in people affected by osteoporosis. 25,26 However, it should be noted that denosumab and romosozumab seem to reduce the risk of falls by 20% in the general population, but otherwise only limited evidence is available about the effectiveness of these drugs in PD patients. 27,28 Several studies investigated the prevalence of osteoporosis in PD, typically including patients with worse Hoehn & Yahr scores compared to the current population.…”

Molecular and Cellular Mechanisms of Osteoporosis

“…The most well-known sclerostin inhibitor, approved by the FDA and approved in clinical trials, is romosozumab. This preparation increases the number of osteoblasts, improves mechanical strength by increasing bone mass, improves structural and architectural characteristics, and optimizes the composition of bone tissue [163,164]. However, romosozumab has a limited period of effectiveness, which requires concomitant antiresorptive therapy [164].…”

Association of serum sclerostin levels with marrow adiposity in postmenopausal women with glucocorticoid-induced osteoporosis

“…Sclerostin, derived from osteocytes, navigates through canalicular networks to reach bone surfaces. Upon reaching these surfaces, sclerostin impedes the canonical Wnt-beta-catenin pathway, thereby reducing osteoblastogenesis and accelerating osteoclastogenesis [ 1 – 3 ]. In 2019, the European Medicines Agency approved romosozumab, an anti-sclerostin antibody, for osteoporosis treatment [ 4 ].…”

“…One of the key mechanisms by which glucocorticoids diminish the production of osteoblasts is through the antagonism of the Wnt/β-catenin signaling pathway [ 8 ]. Additionally, sclerostin acts as a Wnt signaling inhibitor, obstructing osteogenic differentiation and impeding the acquisition of bone mass [ 3 , 8 , 9 ]. Fascinatingly, treatments with sclerostin-neutralizing antibodies demonstrated the ability to reduce overall marrow adiposity in both a time-dependent and dose-dependent fashion [ 5 ].…”