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Effect of Sclerostin Inhibition on Cardiovascular Safety
Effect of Sclerostin Inhibition on Cardiovascular Safety for the Treatment of Severe Osteoporosis
Osteoporosis is a skeletal disorder characterized by diminished bone strength that is responsible for an increased fracture risk. The glycoprotein sclerostin acts as an inhibitor of bone formation. Therapies directed against this molecule have been developed. A humanized antibody against sclerostin has been approved for the treatment of severe osteoporosis in postmenopausal women in many parts of the world. A recent review by Langdahl BL and colleagues sumarizes the current knowledge of the effect of sclerostin inhibition on cardiovascular safety.
Cardiovascular Safety and Sclerostin Inhibition – a mini-review.
Langdahl BL, Hofbauer LC, Forfar JC. J Clin Endocrinol Metab. 2021 Mar 23:dgab193. doi: 10.1210/clinem/dgab193. Epub ahead of print. PMID: 33755157.
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RELATED Publications – Sclerostin Inhibition and Cardiovascular Safety
Bovijn J, Krebs K, Chen CY, Boxall R, Censin JC, Ferreira T, Pulit SL, Glastonbury CA, Laber S, Millwood IY, Lin K, Li L, Chen Z, Milani L, Smith GD, Walters RG, Mägi R, Neale BM, Lindgren CM, Holmes MV. Sci Transl Med. 2020 Jun 24;12(549):eaay6570. doi: 10.1126/scitranslmed.aay6570. PMID: 32581134; PMCID: PMC7116615.
Abstract
Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the SOST genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.