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Targeting sclerostin as potential treatment of osteoporosis
1Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. m.v.iken@lumc.nl
Abstract:
In recent years, study of rare bone diseases has led to the identification of signalling pathways that regulate bone formation and provided targets for the development of novel therapeutic agents to stimulate bone formation in patients with osteoporosis. Studies of two bone sclerosing dysplasias, sclerosteosis and van Buchem disease led to the identification of sclerostin, a negative regulator of bone formation. Sclerostin binds to LRP5/6 and inhibits Wnt signalling, but its precise molecular mechanism of action is not yet known. Its expression is restricted in the skeleton to osteocytes and is modified by mechanical loading and parathyroid hormone treatment. Sclerostin deficiency reproduces the findings of the human diseases in mice, while sclerostin excess leads to bone loss and reduced bone strength. An antibody to sclerostin increased bone formation dramatically at all bone envelopes in ovariectomised rats and intact monkeys, without affecting bone resorption and improved bone strength. In initial human studies, a single injection of the antibody to postmenopausal women increased serum P1NP and transiently decreased serum CTX. Clinical phase II studies with this antibody are currently underway.
Insights
Researchers identified sclerostin, a protein inhibiting bone formation, and developed an antibody to block it. This antibody significantly increased bone formation in animal models and early human trials, offering a promising new treatment for osteoporosis.
Area of Science:
- Bone biology and endocrinology
- Skeletal dysplasias and osteoporosis research
- Signalling pathways in bone metabolism
Background:
- Rare bone diseases have elucidated key signalling pathways regulating bone formation.
- Sclerosteosis and van Buchem disease led to the identification of sclerostin, a negative regulator of bone formation.
- Sclerostin inhibits Wnt signalling by binding to LRP5/6, but its exact mechanism remains unclear.
Purpose of the Study:
- To investigate the role of sclerostin in bone formation and its potential as a therapeutic target.
- To evaluate the efficacy of a sclerostin antibody in stimulating bone formation and improving bone strength.
Main Methods:
- Studies involved analyzing sclerostin's expression and function in mouse models.
- An antibody targeting sclerostin was administered to ovariectomized rats and intact monkeys.
- Initial human studies involved administering the antibody to postmenopausal women.
Main Results:
- Sclerostin deficiency in mice mimics human sclerosing bone diseases; excess sclerostin causes bone loss.
- Sclerostin antibody treatment dramatically increased bone formation across all skeletal envelopes in animal models.
- The antibody improved bone strength without altering bone resorption.
- Early human studies showed increased P1NP and transiently decreased CTX levels post-injection.
Conclusions:
- Sclerostin is a critical regulator of bone formation, and targeting it holds therapeutic potential for osteoporosis.
- A sclerostin antibody demonstrates significant bone-building effects and improved bone strength in preclinical and early clinical studies.
- Further clinical trials are warranted to confirm the efficacy and safety of sclerostin antibodies for osteoporosis treatment.
