This post is part of a series on bone markers standardization from the Committee on Bone Metabolism of the International Federation of Clinical Chemistry
Bone metabolism is a dynamic process which can be determined by measuring a number of circulating biomarkers related to the bone remodeling process. The joint Committee for Bone Metabolism (C-BM) of the International Federation of Clinical Chemistry (IFCC) and the International Osteoporosis Foundation (IOF) recommend a formation marker serum procollagen of type I collagen propeptide (s-PINP) and a resorption marker serum C-terminal cross-linking telopeptide of type I collagen (sCTx) as reference markers to be measured by standardized assays in research studies (1). These markers are used in clinical practice for monitoring efficacy of and adherence to treatment for osteoporosis and as a diagnostic tool when evaluating patients for secondary osteoporosis. They are also gaining increased interest in selection of treatment and monitoring offset of effect during interruption of antiresorptive treatments.
However, novel biochemical markers reflecting bone turnover may provide additional and valuable information on bone metabolism. Measurement of circulating sclerostin levels may potentially provide such information. Sclerostin is a 22 kDa glycoprotein produced primarily by osteocytes. It is encoded by the SOST gene and is regulated by cytokines, mechanical loading, and endocrine factors. It acts as an inhibitor of the Wnt-beta-catenin signaling pathway. Sclerostin inhibits proliferation, differentiation, and activity of the bone forming osteoblasts leading to decreased formation and mineralization of bone matrix. In contrast, it stimulates formation and activity of bone degrading osteoclasts, thereby increasing bone resorption. Its levels increase with age in both sexes and studies have found a positive correlation between circulating sclerostin levels and bone mineral density. This is counterintuitive when considering the effects of sclerostin on bone formation and resorption and no definitive explanations for this phenomenon have been found. Patients with type 2 diabetes have increased circulating sclerostin levels combined with low bone turnover (low PINP and CTX). In patients with chronic kidney disease sclerostin levels are negatively associated with glomerular filtration rate (GFR) as sclerostin increases when GFR decreases. This may either be caused by impaired renal clearance, increased skeletal production or even extra-skeletal production, but this is still debated (2).
In addition to the skeletal effects of sclerostin it has also been proposed as a marker of vascular calcification. Expression of sclerostin has been demonstrated in atherosclerotic plaques and sclerostin seems to decrease expression of genes involved in matrix degradation and calcification. Moreover, a number of human studies in patients with rheumatoid arthritis (3), chronic kidney disease and type 2 diabetes have indicated that it could be a marker of vascular calcification but whether the increased levels of sclerostin are causative to the calcification or are increased as a protective response from the body to inhibit further calcification is not yet fully determined (4).
One point that may have influenced the somewhat conflicting results from clinical studies measuring sclerostin is the lack of standardization of assays. Very little is known about what the different assays actually measure. In a recent study by Delanaye and colleagues (5), three different commercial enzyme-linked immunosorbent assays; Biomedical (BM), TECOmedical (TE), R&D (RD) and enzyme immunoassay MesoScaleDiscovery (MSD) were compared and circulating sclerostin levels were correlated to biochemical and clinical determinants. The results showed notable differences between assays both in median sclerostin levels but also in the correlation to GFR, where only two of the four assays showed the above-mentioned negative correlation with GFR. Also, associations with age, sex, weight and PTH were different depending of the assay used. Whether this is due to one or more of the assays measuring different fragments of the molecule and/or the specificity of the antibody used is different, is not known, Newer assays are on the market, called intact sclerostin and bioactive sclerostin (6,7). These are an automated chemiluminescent sclerostin assay from DiaSorin on the LIAISON® analysis platform and the bioactive sclerostin assay from BioMedica which utilizes a recombinant monoclonal antibody that binds to the second loop of the sclerostin core region capturing all sclerostin protein, which is able to bind to the LRP 5/6 complex of the Wnt signaling pathway. However, similar results were observed between the assays so it is inconvenient to comment on only one assay. The lack of a reference method such as mass spectrometry definitely hampers the measurements as none of the available methods can currently be considered as a reference method.
Much is known about the important role of sclerostin in regulating bone metabolism and studies where circulating sclerostin levels are measured can teach us about the osteocyte activities and distinguish the bone compartments that they might be helpful for exploring the physiological and pathological links between the bone and other organs, and to monitor systemic diseases. Thus, it may be a promising biomarker in assessing bone health both in the general population and bone metabolism related systemic diseases. However, more studies are still needed before we can interpret changes in sclerostin levels and use sclerostin as a biomarker in clinical practice. Also, the intriguing results from the studies in vascular calcification may also pave the way for the use of sclerostin as a marker of cardiovascular disease. However, more studies are still necessary before it can be applied clinically. Yet, the first and most important issue is the lack of an established reference method and even more important the lack of standardization of the biochemical assays for measuring sclerostin. Thus, this is definitely in urgent need of attention before the full potential of sclerostin as a biomarker for bone and cardiovascular disease can unfold.
- Cavalier, E., Eastell, R., Jørgensen, N.R. et al. A Multicenter Study to Evaluate Harmonization of Assays for C-Terminal Telopeptides of Type I Collagen (ß-CTX): A Report from the IFCC-IOF Committee for Bone Metabolism (C-BM). Calcif Tissue Int 2021. 108, 785–797. https://doi.org/10.1007/s00223-021-00816-5
- Bouquegneau A, Evenepoel P, Paquot F, Malaise O, Cavalier E, Delanaye P. Sclerostin within the chronic kidney disease spectrum. Clinica Chimica Acta,. 2020 March 502: 84-90
- Paccou J, Mentaverri R, Renard C, Liabeuf S, Fardellone P, Massy Z. A. Brazier M, Kamel S, The Relationships Between Serum Sclerostin, Bone Mineral Density, and Vascular Calcification in Rheumatoid Arthritis,The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 12, December 2014, Pages 4740–4748,https://doi.org/10.1210/jc.2014-2327
- Catalano A, Bellone F, Morabito N, Corica F. Sclerostin and Vascular Pathophysiology. Int J Mol Sci. 2020 Jul 6;21(13):4779. doi: 10.3390/ijms21134779. PMID: 32640551; PMCID: PMC7370046.
- Delanaye P, Paquot F, Bouquegneau A, Blocki F, Krzesinski JM, Evenepoel P, Pottel H, Cavalier E. Sclerostin and chronic kidney disease: the assay impacts what we (thought to ) know. Nephrol Dial Transplant. 2018 Aug 1;33(8):1404-1410. doi: 10.1093/ndt/gfx282.
- Drake MT, Fenske JS, Blocki FA, Zierold C, Appelman-Dijkstra N, Papapoulos S, Khosla S. Validation of a novel, rapid, high precision sclerostin assay not confounded by sclerostin fragments. Bone. 2018 Jun;111:36-43. doi: 10.1016/j.bone.2018.03.013. Epub 2018 Mar 14. PMID: 29550267; PMCID: PMC5924723.
- Kerschan-Schindl K, Föger-Samwald U, Gleiss A, Kudlacek S, Wallwitz J, Pietschmann P. Circulating bioactive sclerostin levels in an Austrian population-based cohort. Wien Klin Wochenschr. 2021 Feb 5. doi: 10.1007/s00508-021-01815-0. Epub ahead of print. PMID: 33544208.