Inhibition of Sclerostin in Osteoporosis Therapy
Romosozumab, a subcutaneously administered antibody against sclerostin, is one of the most potent osteoanabolics and appears to be a highly effective modality in the treatment of postmenopausal women's osteoporosis. Essential information about the mechanism of action, insights from completed pivotal studies, and practical recommendations for romosozumab treatment are summarized in the following brief overview.
Balance in Bone Formation
Bone homeostasis is controlled by many signaling pathways. The Wnt protein-driven pathway (the Wnt/β-catenin cascade) plays a key role in osteoblast differentiation. Activation of this pathway leads to increased bone mass formation and reduced resorption. The signaling cascade is very complex and is influenced by many different molecules. One of these is the extracellular protein sclerostin, which is a natural antagonist of the Wnt pathway. Binding of sclerostin to low-density lipoprotein receptors (LRP) on the surface of osteoblasts leads to inhibition of this cascade.
Targeting treatment at the Wnt/β-catenin signaling pathway is a scientific challenge due to the wide range of functions of this cascade in different cell types, posing a risk of systemic side effects. Since sclerostin is mainly produced by osteocytes and primarily localized in adult bone tissue, it represents an ideal therapeutic target.
How to Promote Bone Mass Production?
Romosozumab is a humanized monoclonal antibody (IgG2) that binds to sclerostin and inhibits its function. After binding of romosozumab, the attachment of sclerostin to LRP-5 and LRP-6 receptors is not possible, resulting in the activation of the Wnt signaling pathway and stimulation of bone mass production by osteoblasts (see figure).
Figure. Mechanism of action of romosozumab
Romosozumab also inhibits bone resorption by causing changes in the expression of osteoclast mediators. Thanks to this dual mechanism of action, romosozumab treatment is faster and results in a significantly greater bone mineral density (BMD) increase than treatment with bisphosphonates, denosumab, or parathyroid hormone analogs.
Data from Pivotal Studies
The efficacy of romosozumab in treating postmenopausal women's osteoporosis has been substantiated by robust data from 2 key studies. The FRAME clinical trial involved 7180 postmenopausal women aged 55–90, who were randomized into two arms: the experimental group with one year of subcutaneous romosozumab treatment (210 mg once a month) followed by a year of denosumab treatment (once every 6 months) and the control arm placebo/denosumab. After 2 years of therapy, a 75% reduction in the occurrence of new vertebral fractures was observed in the experimental group compared to the control group.
The ARCH clinical trial included women at higher fracture risk (patients with at least one osteoporotic fracture in their history). The experimental group received romosozumab treatment followed by alendronate therapy, while the control group received only alendronate throughout the study. In the romosozumab-treated group, a 48% reduction in the occurrence of new vertebral fractures was observed. The osteoanabolic properties of romosozumab proved superior to alendronate concerning fracture risk reduction, increased bone density, and a faster onset of effect regarding fracture risk.
After one year of romosozumab therapy, the positive impact of administering an antiresorptive agent, contributing to the maintenance or further increase of BMD and reducing fracture risk even after treatment cessation, was demonstrated.
Clinical Recommendations
Administering romosozumab before antiresorptive treatment appears to be the ideal therapeutic sequence based on clinical trial outcomes, especially in highly at-risk patients or those with immediate fracture risk. Administration is contraindicated in patients who have had a myocardial infarction or stroke in the past year.
The introduction of romosozumab into clinical practice has expanded therapeutic options in the treatment of osteoporosis. This substance exhibits a strong osteoanabolic effect, improving bone structural integrity and strength. However, further data are needed to evaluate the optimal use of this drug and to assess its safety, particularly in patients with cardiovascular risks.
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