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01-04-2012 | Original Article

Long-term treatment with raloxifene, but not bisphosphonates, reduces circulating sclerostin levels in postmenopausal women

Authors: Y. E. Chung, S. H. Lee, S.-Y. Lee, S.-Y. Kim, H.-H. Kim, F. S. Mirza, S.-K. Lee, J. A. Lorenzo, G. S. Kim, J.-M. Koh

Published in: Osteoporosis International | Issue 4/2012

Abstract

Summary

We determined whether suppression of sclerostin levels by estrogen treatment was mediated by anti-resorptive effect. Raloxifene, but not bisphosphonates, suppressed circulating sclerostin concentration, suggesting that sclerostin may mediate the action of estrogen on bone metabolism, independently of their anti-resorptive effects.

Introduction

Circulating sclerostin concentrations are higher in postmenopausal than in premenopausal women, and estrogen treatment suppresses sclerostin levels in both men and women. We determined whether anti-resorptives may suppress the circulating sclerostin levels.

Methods

We conducted a retrospective observational study. Eighty postmenopausal women were treated with raloxifene for 19.4 ± 7.7 months (n = 16), bisphosphonates for 19.2 ± 6.7 months (n = 32), or were untreated (n = 32) for 17.1 ± 4.6 months. Plasma sclerostin concentrations were measured before and after treatment.

Results

Plasma sclerostin levels after treatment were significantly lower in the raloxifene than in the control group (55.8 ± 23.4 pmol/l vs. 92.1 ± 50.4 pmol/l, p = 0.046), but were similar between the bisphosphonate and control groups. Relative to baseline, raloxifene treatment markedly reduced plasma sclerostin concentration (−40.7 ± 22.8%, p < 0.001), with respect to both control (−7.5 ± 29.1%) and bisphosphonate (−3.1 ± 35.2%) groups. Changes in bone-specific alkaline phosphatase and osteocalcin levels showed reverse associations with sclerostin concentration changes in the raloxifene (γ = −0.505, p = 0.017) and control (γ = −0.410, p = 0.020) groups.

Conclusions

Raloxifene, but not bisphosphonates, significantly suppressed circulating sclerostin concentration, suggesting that sclerostin may mediate the action of estrogen on bone metabolism, independently of their anti-resorptive effects.

Riggs BL, Khosla S, Melton LJ 3rd (2002) Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279–302PubMedCrossRef

Garnero P, Sornay-Rendu E, Chapuy MC, Delmas PD (1996) Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res 11:337–349PubMedCrossRef

Bord S, Beavan S, Ireland D, Horner A, Compston JE (2001) Mechanisms by which high-dose estrogen therapy produces anabolic skeletal effects in postmenopausal women: role of locally produced growth factors. Bone 29:216–222PubMedCrossRef

Khastgir G, Studd J, Holland N, Alaghband-Zadeh J, Fox S, Chow J (2001) Anabolic effect of estrogen replacement on bone in postmenopausal women with osteoporosis: histomorphometric evidence in a longitudinal study. J Clin Endocrinol Metab 86:289–295PubMedCrossRef

Semenov M, Tamai K, He X (2005) SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem 280:26770–26775PubMedCrossRef

Glass DA 2nd, Bialek P, Ahn JD et al (2005) Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751–764PubMedCrossRef

Spencer GJ, Utting JC, Etheridge SL, Arnett TR, Genever PG (2006) Wnt signalling in osteoblasts regulates expression of the receptor activator of NFκB ligand and inhibits osteoclastogenesis in vitro. J Cell Sci 119:1283–1296PubMedCrossRef

Winkler DG, Sutherland MK, Geoghegan JC et al (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22:6267–6276PubMedCrossRef

Li X, Ominsky MS, Niu QT et al (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869PubMedCrossRef

10.

Balemans W, Ebeling M, Patel N et al (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537–543PubMedCrossRef

11.

Balemans W, Patel N, Ebeling M et al (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97PubMedCrossRef

12.

Li X, Ominsky MS, Warmington KS et al (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 24:578–588PubMedCrossRef

13.

Padhi D, Jang G, Stouch B, Fang L, Posvar E (2011) Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res 26:19–26PubMedCrossRef

14.

Mirza FS, Padhi ID, Raisz LG, Lorenzo JA (2010) Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J Clin Endocrinol Metab 95:1991–1997PubMedCrossRef

15.

Modder UI, Clowes JA, Hoey K et al (2011) Regulation of circulating sclerostin levels by sex steroids in women and in men. J Bone Miner Res 26:27–34PubMedCrossRef

16.

Drake MT, Srinivasan B, Modder UI et al (2010) Effects of parathyroid hormone treatment on circulating sclerostin levels in postmenopausal women. J Clin Endocrinol Metab 95:5056–5062PubMedCrossRef

17.

Paszty C, Turner CH, Robinson MK (2010) Sclerostin: a gem from the genome leads to bone building antibodies. J Bone Miner Res 25:1897–1904PubMedCrossRef

18.

Lane NE, Yao W (2010) Glucocorticoid-induced bone fragility. Ann New York Acad Sci 1192:81–83CrossRef

19.

Lopez-Ibarra PJ, Pastor MM, Escobar-Jimenez F et al (2001) Bone mineral density at time of clinical diagnosis of adult-onset type 1 diabetes mellitus. Endocr Pract 7:346–351PubMed

20.

Dobnig H, Piswanger-Sölkner JC, Roth M et al (2006) Type 2 diabetes mellitus in nursing home patients: effects on bone turnover, bone mass, and fracture risk. J Clin Endocrinol Metab 91:3355–3363PubMedCrossRef

21.

Terpos E, Dimopoulos MA (2011) Interaction between the skeletal and immune systems in cancer: mechanisms and clinical implications. Canc Immunol Immunother 60:305–317CrossRef

22.

Mosekilde L (2008) Primary hyperparathyroidism and the skeleton. Clin Endocrinol (Oxf) 69:1–19CrossRef

23.

Vosse D, de Vlam K (2009) Osteoporosis in rheumatoid arthritis and ankylosing spondylitis. Clin Exp Rheumatol 27:S62–S67PubMed

24.

Schindeler A, McDonald MM, Bokko P, Little DG (2008) Bone remodeling during fracture repair: the cellular picture. Semin Cell Dev Biol 19:459–466PubMedCrossRef

25.

Eastell R, Robins SP, Colwell T, Assiri AM, Riggs BL, Russell RG (1993) Evaluation of bone turnover in type I osteoporosis using biochemical markers specific for both bone formation and bone resorption. Osteoporos Int 3:255–260PubMedCrossRef

26.

Shang Y, Brown M (2002) Molecular determinants for the tissue specificity of SERMs. Science 295:2465–2468PubMedCrossRef

27.

Cremers S, Garnero P (2006) Biochemical markers of bone turnover in the clinical development of drugs for osteoporosis and metastatic bone disease: potential uses and pitfalls. Drugs 66:2031–2058PubMedCrossRef

28.

Leupin O, Kramer I, Collette NM et al (2007) Control of the SOST bone enhancer by PTH using MEF2 transcription factors. J Bone Miner Res 22:1957–1967PubMedCrossRef

29.

Modder UI, Hoey KA, Amin S et al (2011) Relation of age, gender, and bone mass to circulating sclerostin levels in women and men. J Bone Miner Res 26:373–379PubMedCrossRef

Title: Long-term treatment with raloxifene, but not bisphosphonates, reduces circulating sclerostin levels in postmenopausal women
Authors: Y. E. Chung
S. H. Lee
S.-Y. Lee
S.-Y. Kim
H.-H. Kim
F. S. Mirza
S.-K. Lee
J. A. Lorenzo
G. S. Kim
J.-M. Koh
Publication date: 01-04-2012
Publisher: Springer-Verlag
Published in: Osteoporosis International / Issue 4/2012
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-011-1675-1

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Long-term treatment with raloxifene, but not bisphosphonates, reduces circulating sclerostin levels in postmenopausal women

Abstract

Summary

Introduction

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusions

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