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Sclerostin: Function, Role and Therapy

Sclerostin is a protein produced by bone cells that inhibits new bone formation. It plays a key role in regulating bone metabolism and is a target for osteoporosis therapy.

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Things worth knowing about "Sclerostin"

Sclerostin is a protein produced by bone cells that inhibits new bone formation. It plays a key role in regulating bone metabolism and is a target for osteoporosis therapy.

What is Sclerostin?

Sclerostin is a glycoprotein primarily secreted by osteocytes – the bone cells embedded within the bone matrix. It belongs to the DANS protein family and acts as a key negative regulator of bone formation. The gene encoding sclerostin is called SOST.

Mechanism of Action

Sclerostin inhibits bone formation by blocking the Wnt signaling pathway, which is essential for the activation and differentiation of osteoblasts – the cells responsible for building new bone.

Sclerostin binds to the co-receptors LRP5 and LRP6 (Low-Density Lipoprotein Receptor-related Protein 5 and 6) on the surface of osteoblast precursors.
This binding prevents Wnt ligands from activating the signaling cascade.
Without active Wnt signaling, fewer osteoblasts are formed and activated, leading to reduced bone formation.
Sclerostin can also indirectly promote bone resorption by osteoclasts.

Through this dual mechanism – inhibiting bone formation and promoting bone resorption – sclerostin significantly influences bone mineral density and bone architecture.

Physiological Importance

In a healthy body, sclerostin serves as a critical regulatory protein that maintains the balance between bone formation and bone resorption (bone remodeling). Mechanical loading of the skeleton – such as through physical exercise – suppresses sclerostin production in osteocytes, which in turn stimulates bone formation. Conversely, reduced mechanical loading (e.g., during immobilization or spaceflight) increases sclerostin levels, contributing to bone loss.

Clinical Relevance

Rare Genetic Conditions

The importance of sclerostin was first discovered through rare genetic disorders:

Sclerosteosis: Loss-of-function mutations in the SOST gene lead to a complete absence of sclerostin, resulting in massive, progressive bone overgrowth, very high bone density, and complications such as nerve compression.
Van Buchem Disease: Similar to sclerosteosis, caused by a regulatory deletion near the SOST gene, leading to progressive bone overgrowth with similar clinical features.

Osteoporosis

In osteoporosis – a condition characterized by low bone density and increased fracture risk – serum sclerostin levels are often elevated. This makes sclerostin an attractive therapeutic target. By inhibiting sclerostin, the Wnt signaling pathway can be reactivated, thereby stimulating bone formation and reducing fracture risk.

Other Associated Conditions

Elevated sclerostin levels have also been associated with:

Chronic kidney disease (renal osteodystrophy)
Rheumatoid arthritis
Type 2 diabetes mellitus
Cardiovascular disease (vascular calcification)

Therapeutic Application: Anti-Sclerostin Antibody

The understanding of sclerostin biology led to the development of an innovative drug: romosozumab (brand name: Evenity®). This monoclonal antibody specifically binds to and neutralizes sclerostin, thereby promoting bone formation and reducing bone resorption simultaneously.

Approval: Romosozumab is approved in the EU, the US, and other countries for the treatment of severe osteoporosis in postmenopausal women at high risk of fracture.
Administration: Monthly subcutaneous injection over a period of twelve months.
Efficacy: Clinical trials (ARCH and FRAME studies) demonstrated a significant reduction in vertebral and hip fractures.
Safety considerations: An increased cardiovascular risk was observed in one pivotal trial; therefore, romosozumab is contraindicated in patients with a prior myocardial infarction or stroke.

Sclerostin as a Biomarker

Serum sclerostin levels can be measured as a biomarker of bone metabolism. Elevated levels may indicate increased bone resorption activity, while lower levels are associated with greater bone formation. However, sclerostin measurement is not yet part of routine clinical diagnostics.

References

Padhi, D. et al. - Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. Journal of Bone and Mineral Research, 2011.
Saag, K.G. et al. - Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. New England Journal of Medicine, 2017.
Baron, R. & Gori, F. - Targeting WNT signaling in the treatment of osteoporosis. Current Opinion in Pharmacology, 2018.

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