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Inhibitors of sclerostin: emerging concepts
Matthew T Drake1, Joshua N Farr
1Division of Endocrinology, Metabolism, Nutrition and Diabetes, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Purpose Of Review:
Recent data suggest that inhibitors of sclerostin, an osteocyte-produced Wnt signaling pathway antagonist, can stimulate bone formation. This review provides rationale and summarizes recent evidence supporting this novel approach to skeletal anabolism.
Recent Findings:
Data from numerous preclinical models in rodents and monkeys consistently demonstrate that antisclerostin monoclonal antibody (Scl-Ab) treatment leads to improvements in bone mass and strength, as well as enhanced fracture repair. Delivery of Scl-Ab therapy either subcutaneously or intravenously in phase 1 and 2 human clinical trials demonstrates short-term anabolic responses in excess of those seen with teriparatide, the only currently available anabolic skeletal agent. Gains have been primarily at central (spine and hips) versus peripheral (wrist) sites. Strikingly, Scl-Ab treatment appears to both stimulate bone formation and inhibit bone resorption in humans. If proven, Scl-Ab would be the first pharmacologic agent with such dual properties. Data on fractures are not yet available.
Summary:
Scl-Ab therapy represents a novel pharmacologic approach to skeletal anabolism. Although many questions remain before Scl-Ab treatment can be introduced into clinical practice, phase 3 human clinical trials are currently underway and could provide the necessary data to bring this exciting class of skeletal anabolic agents to patient care.
Insights
Antisclerostin monoclonal antibody (Scl-Ab) therapy shows promise for stimulating bone formation and improving bone mass. Ongoing clinical trials may lead to a new treatment for skeletal anabolic conditions.
Area of Science:
- Bone biology and pharmacology
- Wnt signaling pathway modulation
- Skeletal anabolism
Background:
- Sclerostin is an osteocyte-derived antagonist of the Wnt signaling pathway.
- Inhibiting sclerostin has emerged as a potential strategy to stimulate bone formation.
Purpose of the Study:
- To review the rationale and evidence for sclerostin inhibitors as a novel approach to skeletal anabolism.
- To summarize preclinical and clinical data on antisclerostin monoclonal antibody (Scl-Ab) therapy.
Main Methods:
- Review of preclinical data from rodent and monkey models.
- Analysis of Phase 1 and 2 human clinical trial data for Scl-Ab therapy.
- Comparison of Scl-Ab effects with teriparatide.
Main Results:
- Preclinical studies consistently show Scl-Ab improves bone mass, strength, and fracture repair.
- Human trials demonstrate short-term anabolic responses exceeding teriparatide, primarily at central sites.
- Scl-Ab may possess dual action: stimulating bone formation and inhibiting resorption.
Conclusions:
- Scl-Ab therapy represents a novel pharmacologic approach for skeletal anabolism.
- Further Phase 3 clinical trials are necessary to confirm efficacy and safety for patient care.
