( PDF ) Rev Osteoporos Metab Miner. 2013; 5 (4): 125-6

Olmos JM, Hernández JL

Departamento de Medicina Interna – Hospital Universitario Marqués de Valdecilla-IFIMAV – Universidad de Cantabria – RETICEF – Santander

Correspondencia: José M. Olmos – Departamento de Medicina Interna – Hospital Universitario Marqués de Valdecilla – Avda. Valdecilla s/n – 39008 Santander (España)

 

The association between an excess of glucocorticoids and osteoporosis was indicated more than 80 years ago by Harvey Cushing when describing the disease which takes his name. Subsequently, after the introduction of the glucocorticoids as anti-inflammatory drugs, it was confirmed that exogenous hypercortisolism was also detrimental to the skeleton, in such a way that steroidal osteoporosis is now considered to be the most common form of secondary osteoporosis in our ambit1. Osteopenia induced by corticoids affects predominantly trabecular bone and is most intense during the first months of treatment, when more than 10% of bone mass may be lost2. In addition to inducing the loss of bone, the glucocorticoids alter its quality, which would explain the notable increase in fractures (nearly 75%) during the first three months of treatment, even before bone mineral density falls.

The mechanisms which are involved in the reduction in the quantity and quality of bone tissue are various. The glucocorticoids act directly on the osteoblasts, inhibiting their replication, differentiation and functional activity, and favouring both their apoptosis and that of the osteocytes3,4. They also act on the osteoclasts, reducing their proliferation but prolonging their survival3,5. On the other hand, the glucocorticoids exert an indirect effect on the generation of osteoblast cells by suppressing the expression of bone morphogenetic proteins (BMP), and of the Runx2 transcription factor, which is required to induce osteoblast differentiation from the mesenchymal mother cells6. In addition, these drugs increase the expression of PPARγ, which favours the differentiation mother cells into adipocytes and slows their differentiation into osteoblasts, contributing to an increase in fat in the bone marrow at the expense of the osteoblasts and of trabecular bone7.

Finally, the corticoids may also intervene in the Wnt (wingless) pathway, which acts to modulate the differentiation and activity of bone cells. This complex signalling pathway is made up of a number of components, including ligands, membrane receptors, intracellular and antagonist effectors8. The best known mechanisms for transmission of the signal of the Wnt ligands are those included in what is called the canonical pathway, in which β-catenin plays a central role, although there are other alternative or non-canonical pathways which use different mediators9. The Wnt ligands are glucoproteins capable of bonding with their receptor and initiating the activity of the pathway. The membrane receptors are made up of frizzled proteins and proteins related to the receptor of low density lipoproteins type 5 and 6 (LRP5 and LRP6). Finally, various types of molecules have been described with an inhibitory action on the Wnt pathway. In some cases these are molecules which act as decoys which bond with to the Wnt ligands and thus compete with its bonding to the receptor. This is the case for some soluble proteins of the frizzled type which are secreted into the extracellular environment. Another inhibitor molecule is sclerostin, a glucoprotein of 190 amino-acids coded by the SOST gene which is expressed in the osteocytes and which bonds to LRP5/6, impeding the formation of the LRP 5/6-frizzled-Wnt complex. The sclerostin is released into the blood circulation, making it possible to determine its blood concentration [10]. There is a strong correlation between the content of sclerostin in the bone and its level in the blood, which would indicate that the production of this protein occurs in the bone and that its measurement in the blood may reflect its activity in the tissue11.

Other molecules capable of antagonising the Wnt signals by bonding themselves to the LRP 5/6 and Kremen co-receptors are those of the dickkopf family. There are at least four members of this family of which the type 1 (Dkk-1) is especially significant in the bone9,12,13. Similarly to sclerostin, Dkk-1 may also be determined in the blood, with a higher concentration of this antagonist having been described in postmenopausal women or those with low bone mass. It has also been suggested that the reduction in the effect of teriparatide may be related to an increase in the concentrations of this antagonist14.

In this edition of the Review of Osteoporosis and Mineral Metabolism Grifé et al.15 analysed the values of blood sclerostin and Dkk-1 in patients who has started treatment with glucocorticoids, confirming that, contrary to what occurs in experimental studies, steroid treatment is associated with a reduction in Dkk-1, while no changes are observed in concentrations of sclerostin. As the authors note, there are various reasons which may justify these findings. Sex, age, renal function, estrogenic status, the existence of associated diseases or the quantity of bone mass are determining factors in levels of sclerostin and probably also of Dkk-114,16,17. On the other hand, there is also the possibility that the blood values of both antagonists do not adequately reflect their expression in tissue. Moreover, contrary to what might be expected a priori, there was no relationship between the blood concentrations of the antagonists of the Wnt pathway and those of the markers for bone remodelling. However, it should be noted that the data published to date have been contradictory, with in some cases an inverse relationship between levels of sclerostin and some markers for formation having been described17, while in other studies this relationship has not been able to be confirmed16,18,19. In any case, the results of this excellent work invite further studies which analyse the effect of glucocorticoids on the Wnt pathway antagonists, as well as their relationship with bone mass and markers for remodelling, which would without doubt help to clarify the role the Wnt pathway antagonists play in the development of steroidal osteoporosis.

 

BIBLIOGRAPHY

1. Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: Pathophysiology and therapy. Osteoporos Int 2007;18:1319-28.

2. Weinstein RS. Glucocorticoid-induced bone disease. En: Rosen CJ. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 8th Ed. Iowa: Wiley & Sons Inc.; 2013. p.473-81.

3. Weinstein RS. Glucocorticoid-induced osteoporosis and osteonecrosis. Endocrinol Clin Metab North Am 2012;41:595-611.

4. O’Brien CA, Jia D, Plotkin LI, et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinol 2004;145:1835-41.

5. Jia D, O’Brien CA, Stewart SA, et al. Glucocorticoids act directly on osteoclasts to increase their lifespan and reduce bone density. Endocrinol 2006;147:5592-9.

6. Karsenty G, Kronenberg HM, Settembre C. Genetic control of bone formation. Annu Rev Cel Dev Biol 2009;25:629-48.

7. Abdallah BM, Kassem M. New factors controlling the balance between osteoblastogenesis and adipogenesis. Bone 2012;50:540-5.

8. Velasco J, Riancho JA. La vía Wnt y el hueso. Rev Esp Enf Metab Oseas 2008;17:5-9.

9. Baron R, Kneissel M. Wnt signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 2013;19:179-92.

10. McNulty M, Singh RJ, Li X, Bergstralh EJ, Kumar R. Determination of serum and plasma sclerostin concentrations by enzyme-linked immunoassays. J Clin Endocrinol Metab 2011;96:1156-62.

11. Alonso G, García-Martín A, Muñoz-Torres M. Vía Wnt y esclerostina como nuevas dianas para la evaluación y el tratamiento de la osteoporosis. Med Clin (Barc) 2012;139:634-9.

12. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003;349:2483-94.

13. Morvan F, Bouloukos K, Clemen-Lacroix P, Roman S, Suc-Royer I, Vayssier B, et al. Deletion of single allele of the Dk1 gene leads to increase in bone formation and bone mass. J Bone Miner Res 2006,21:934-45.

14. Gatti D, Viapiana O, Idolazzi L, Fracassi E, Rossini M, Adami S. The waning of teriparatide effect on bone formation markers in postmenopausal osteoporosis is associated with increasing serum levels of DKK1. J Clin Endocrinol Metab 2011;96:1555-9.

15. Grife L, Ruiz-Gaspa S, Monegal A, Nomdedeu B, Guañabens N, Peris P. Esclerostina y Dkk-1 séricos en pacientes que inician tratamiento con glucocorticoides. Resultados preliminares. Rev Osteoporos Metab Miner 2014;4:127-32.

16. García-Martín A, Reyes-García R, Rozas-Moreno P, Varsavsky M, Luque-Fernández I, Avilés-Pérez MD, et al. Variables que influyen en las concentraciones de esclerostina en los pacientes con diabetes mellitus tipo 2 y su asociación con el metabolismo óseo. Rev Osteoporos Metab Miner 2012;4:109-15.

17. Gaudio A, Pennisi P, Bratengier C, Torrisi V, Lidner B, Mangiafico RA, et al. Increased sclerostin levels associated with bone formation and resorption markers in patrients with immobilization-induced bone loss. J Clin Endocrinol Metab 2010;95:2248-53.

18. Möder UI, Clowes JA, Hoey K, Peterson JM, McCready L, Ousler MJ, et al. Regulation of circulating sclerostin levels by sex steroids in women and men. J Bone Miner Res 2011;26:27-34.

19. Mirza FS, Padhi ID, Raisz LG, Lorenzo JA. Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J Clin Endocrinol Metab 2010;95:1991-7.