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Τhe story of sclerostin inhibition: the past, the present, and the future

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Abstract

Sclerostin inhibits osteoblast activity by hampering activation of the canonical Wnt signaling pathway and simultaneously stimulates osteoclastogenesis through upregulation of the receptor activator of NFκB ligand (RANKL). Thus, antibodies against sclerostin (Scl-Abs), besides promoting bone formation, suppress bone resorption and dissociate bone formation from resorption. This dual action results in remarkable increases of bone mineral density which are of a greater magnitude compared to the other antiosteoporotic treatments and are accompanied by decreases of fracture risk at all skeletal sites. The anabolic effect subsides after the first few months of treatment and a predominantly antiresorptive effect remains after this period, limiting its use to 12 months. Furthermore, these effects are largely reversible upon discontinuation; therefore, subsequent treatment with antiresorptives is indicated to maintain or further increase the bone gains achieved. Romosozumab is currently the only Scl-Ab approved for the treatment of severe postmenopausal osteoporosis. Indications for use in other populations, such as males, premenopausal women, and patients with glucocorticoid-induced osteoporosis, are pending. Additionally, the efficacy of Scl-Abs in other bone diseases, such as osteogenesis imperfecta, hypophosphatasia, X-linked hypophosphatemia, and bone loss associated with malignancies, is under thorough investigation. Cardiovascular safety concerns currently exclude patients at high cardiovascular risk from this treatment.

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Authors and Affiliations

  1. Department of Endocrinology, 424 Military General Hospital, Ring Road, 564 29 N. Efkarpia, Thessaloniki, Greece

    Athanasios D. Anastasilakis

  2. Department of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany

    Elena Tsourdi

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Conception of the hypothesis of the study: ADA and ΕΤ. Design of the study: ADA and ΕΤ. Acquisition, analysis, and interpretation of data: ADA, ΕΤ. Drafting the manuscript: ADA and ΕΤ. Revising the work critically for important intellectual content: ADA and ΕΤ. Final approval of the submitted version: ADA and ΕΤ. Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: ADA and ΕΤ.

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Athanasios D. Anastasilakis reports lecture fees from Amgen, Bianex, Eli-Lilly, Galenica, ITF, Unifarma, and UCB; E. Tsourdi received honoraria for lectures and advisory boards from Amgen, UCB, Takeda, Kyowa Kirin, and educational grants from Takeda and UCB.

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Anastasilakis, A.D., Tsourdi, E. Τhe story of sclerostin inhibition: the past, the present, and the future. Hormones (2024). https://doi.org/10.1007/s42000-023-00521-y

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