Skip to main content
Top
Published in: Osteoporosis International 8/2016

01-08-2016 | Original Article

The circulating sphingosine-1-phosphate level predicts incident fracture in postmenopausal women: a 3.5-year follow-up observation study

Authors: S. J. Bae, S. H. Lee, S. H. Ahn, H.-M. Kim, B.-J. Kim, J.-M. Koh

Published in: Osteoporosis International | Issue 8/2016

Login to get access

Abstract

Summary

A high level of circulating sphingosine-1-phosphate (S1P) is associated with a high incidence of osteoporotic fracture and a high rate of an insufficient response to bisphosphonate therapy.

Introduction

Sphingosine-1-phosphate (S1P) is a significant regulator of bone metabolism. Recently, we found that a high plasma S1P level is associated with low bone mineral density (BMD), high levels of bone resorption markers (BRMs), and a high risk of prevalent vertebral fracture in postmenopausal women. We investigated the possibility that S1P is a predictor of incident fracture.

Methods

A total of 248 postmenopausal women participated in this longitudinal study and were followed up for a mean duration of 3.5 years (untreated [n = 76] or treated with bisphosphonate or hormone replacement therapy [n = 172]). The baseline plasma S1P level and prevalent and incident fracture occurrence were assessed.

Results

A high S1P level was significantly associated with a higher rate of prevalent fracture after adjusting for femoral neck (FN) BMD, BRM, and potential confounders (odds ratio = 2.05; 95 % confidence interval [CI] = 1.03–4.00). Incident fractures occurred more frequently in the highest S1P tertile (T3) than in the lower two tertiles (T1–2) after adjusting for confounders, including baseline FN BMD, prevalent fracture, antiosteoporotic medication, annualized changes in FN BMD, BRM, and potential confounders (hazard ratio = 5.52; 95 % CI = 1.04–56.54). Insufficient response to bisphosphonate therapy occurred more frequently in T3 than T1–2 (odds ratio = 4.43; 95 % CI = 1.02–21.25).

Conclusions

The plasma S1P level may be a potential predictor of fracture occurrence and an insufficient response to bisphosphonate therapy in postmenopausal women.
Appendix
Available only for authorised users
Literature
1.
go back to reference Lee YK, Yoon BH, Koo KH (2013) Epidemiology of osteoporosis and osteoporotic fractures in South Korea. Endocrinol Metab (Seoul) 28:90–93CrossRef Lee YK, Yoon BH, Koo KH (2013) Epidemiology of osteoporosis and osteoporotic fractures in South Korea. Endocrinol Metab (Seoul) 28:90–93CrossRef
2.
go back to reference Sattui SE, Saag KG (2014) Fracture mortality: associations with epidemiology and osteoporosis treatment. Nat Rev Endocrinol 10:592–602CrossRefPubMed Sattui SE, Saag KG (2014) Fracture mortality: associations with epidemiology and osteoporosis treatment. Nat Rev Endocrinol 10:592–602CrossRefPubMed
3.
go back to reference National Osteoporosis Foundation (2014) The clinician’s guide to prevention and treatment of osteoporosis version 1. National osteoporosis foundation, Washington National Osteoporosis Foundation (2014) The clinician’s guide to prevention and treatment of osteoporosis version 1. National osteoporosis foundation, Washington
4.
go back to reference Orimo H, Nakamura T, Hosoi T et al (2012) Japanese 2011 guidelines for prevention and treatment of osteoporosis—executive summary. Arch Osteoporos 7:3–20CrossRefPubMedPubMedCentral Orimo H, Nakamura T, Hosoi T et al (2012) Japanese 2011 guidelines for prevention and treatment of osteoporosis—executive summary. Arch Osteoporos 7:3–20CrossRefPubMedPubMedCentral
5.
go back to reference Watts NB, Bilezikian JP, Camacho PM et al (2010) American association of clinical endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract 16(Suppl 3):1–37CrossRefPubMedPubMedCentral Watts NB, Bilezikian JP, Camacho PM et al (2010) American association of clinical endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract 16(Suppl 3):1–37CrossRefPubMedPubMedCentral
6.
go back to reference Sanders KM, Nicholson GC, Watts JJ, Pasco JA, Henry MJ, Kotowicz MA, Seeman E (2006) Half the burden of fragility fractures in the community occur in women without osteoporosis. When is fracture prevention cost-effective? Bone 38:694–700CrossRefPubMed Sanders KM, Nicholson GC, Watts JJ, Pasco JA, Henry MJ, Kotowicz MA, Seeman E (2006) Half the burden of fragility fractures in the community occur in women without osteoporosis. When is fracture prevention cost-effective? Bone 38:694–700CrossRefPubMed
7.
go back to reference Siris ES, Chen YT, Abbott TA, Barrett-Connor E, Miller PD, Wehren LE, Berger ML (2004) Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 164:1108–1112CrossRefPubMed Siris ES, Chen YT, Abbott TA, Barrett-Connor E, Miller PD, Wehren LE, Berger ML (2004) Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 164:1108–1112CrossRefPubMed
8.
go back to reference Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9:1137–1141CrossRefPubMed Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9:1137–1141CrossRefPubMed
9.
go back to reference Bolland MJ, Siu AT, Mason BH, Horne AM, Ames RW, Grey AB, Gamble GD, Reid IR (2011) Evaluation of the FRAX and Garvan fracture risk calculators in older women. J Bone Miner Res 26:420–427CrossRefPubMed Bolland MJ, Siu AT, Mason BH, Horne AM, Ames RW, Grey AB, Gamble GD, Reid IR (2011) Evaluation of the FRAX and Garvan fracture risk calculators in older women. J Bone Miner Res 26:420–427CrossRefPubMed
10.
go back to reference Hillier TA, Cauley JA, Rizzo JH et al (2011) WHO absolute fracture risk models (FRAX): do clinical risk factors improve fracture prediction in older women without osteoporosis? J Bone Miner Res 26:1774–1782CrossRefPubMedPubMedCentral Hillier TA, Cauley JA, Rizzo JH et al (2011) WHO absolute fracture risk models (FRAX): do clinical risk factors improve fracture prediction in older women without osteoporosis? J Bone Miner Res 26:1774–1782CrossRefPubMedPubMedCentral
12.
go back to reference Lotinun S, Kiviranta R, Matsubara T et al (2013) Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J Clin Invest 123:666–681PubMedPubMedCentral Lotinun S, Kiviranta R, Matsubara T et al (2013) Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J Clin Invest 123:666–681PubMedPubMedCentral
13.
go back to reference Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ (2008) Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci U S A 105:20764–20769CrossRefPubMedPubMedCentral Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ (2008) Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci U S A 105:20764–20769CrossRefPubMedPubMedCentral
14.
go back to reference Grey A, Chen Q, Callon K, Xu X, Reid IR, Cornish J (2002) The phospholipids sphingosine-1-phosphate and lysophosphatidic acid prevent apoptosis in osteoblastic cells via a signaling pathway involving G(i) proteins and phosphatidylinositol-3 kinase. Endocrinology 143:4755–4763CrossRefPubMed Grey A, Chen Q, Callon K, Xu X, Reid IR, Cornish J (2002) The phospholipids sphingosine-1-phosphate and lysophosphatidic acid prevent apoptosis in osteoblastic cells via a signaling pathway involving G(i) proteins and phosphatidylinositol-3 kinase. Endocrinology 143:4755–4763CrossRefPubMed
15.
go back to reference Grey A, Xu X, Hill B, Watson M, Callon K, Reid IR, Cornish J (2004) Osteoblastic cells express phospholipid receptors and phosphatases and proliferate in response to sphingosine-1-phosphate. Calcif Tissue Int 74:542–550CrossRefPubMed Grey A, Xu X, Hill B, Watson M, Callon K, Reid IR, Cornish J (2004) Osteoblastic cells express phospholipid receptors and phosphatases and proliferate in response to sphingosine-1-phosphate. Calcif Tissue Int 74:542–550CrossRefPubMed
16.
go back to reference Roelofsen T, Akkers R, Beumer W, Apotheker M, Steeghs I, van de Ven J, Gelderblom C, Garritsen A, Dechering K (2008) Sphingosine-1-phosphate acts as a developmental stage specific inhibitor of platelet-derived growth factor-induced chemotaxis of osteoblasts. J Cell Biochem 105:1128–1138CrossRefPubMed Roelofsen T, Akkers R, Beumer W, Apotheker M, Steeghs I, van de Ven J, Gelderblom C, Garritsen A, Dechering K (2008) Sphingosine-1-phosphate acts as a developmental stage specific inhibitor of platelet-derived growth factor-induced chemotaxis of osteoblasts. J Cell Biochem 105:1128–1138CrossRefPubMed
17.
go back to reference Ryu J, Kim HJ, Chang EJ, Huang H, Banno Y, Kim HH (2006) Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. EMBO J 25:5840–5851CrossRefPubMedPubMedCentral Ryu J, Kim HJ, Chang EJ, Huang H, Banno Y, Kim HH (2006) Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. EMBO J 25:5840–5851CrossRefPubMedPubMedCentral
18.
go back to reference Ishii M, Egen JG, Klauschen F, Meier-Schellersheim M, Saeki Y, Vacher J, Proia RL, Germain RN (2009) Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature 458:524–528CrossRefPubMedPubMedCentral Ishii M, Egen JG, Klauschen F, Meier-Schellersheim M, Saeki Y, Vacher J, Proia RL, Germain RN (2009) Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature 458:524–528CrossRefPubMedPubMedCentral
19.
go back to reference Ishii M, Kikuta J, Shimazu Y, Meier-Schellersheim M, Germain RN (2010) Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo. J Exp Med 207:2793–2798CrossRefPubMedPubMedCentral Ishii M, Kikuta J, Shimazu Y, Meier-Schellersheim M, Germain RN (2010) Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo. J Exp Med 207:2793–2798CrossRefPubMedPubMedCentral
20.
go back to reference Lee SH, Lee SY, Lee YS, Kim BJ, Lim KH, Cho EH, Kim SW, Koh JM, Kim GS (2012) Higher circulating sphingosine 1-phosphate levels are associated with lower bone mineral density and higher bone resorption marker in humans. J Clin Endocrinol Metab 97:E1421–1428CrossRefPubMed Lee SH, Lee SY, Lee YS, Kim BJ, Lim KH, Cho EH, Kim SW, Koh JM, Kim GS (2012) Higher circulating sphingosine 1-phosphate levels are associated with lower bone mineral density and higher bone resorption marker in humans. J Clin Endocrinol Metab 97:E1421–1428CrossRefPubMed
21.
go back to reference Kim BJ, Koh JM, Lee SY et al (2012) Plasma sphingosine 1-phosphate levels and the risk of vertebral fracture in postmenopausal women. J Clin Endocrinol Metab 97:3807–3814CrossRefPubMed Kim BJ, Koh JM, Lee SY et al (2012) Plasma sphingosine 1-phosphate levels and the risk of vertebral fracture in postmenopausal women. J Clin Endocrinol Metab 97:3807–3814CrossRefPubMed
22.
go back to reference Kiel D (1995) Assessing vertebral fractures. National Osteoporosis Foundation Working Group on Vertebral Fractures. J Bone Miner Res 10:518–523PubMed Kiel D (1995) Assessing vertebral fractures. National Osteoporosis Foundation Working Group on Vertebral Fractures. J Bone Miner Res 10:518–523PubMed
23.
go back to reference Genant HK, Wu CY, van Kuijk C, Nevitt MC (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148CrossRefPubMed Genant HK, Wu CY, van Kuijk C, Nevitt MC (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148CrossRefPubMed
24.
go back to reference Eastell R, Hannon RA, Garnero P, Campbell MJ, Delmas PD (2007) Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate: review of statistical analysis. J Bone Miner Res 22:1656–1660CrossRefPubMed Eastell R, Hannon RA, Garnero P, Campbell MJ, Delmas PD (2007) Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate: review of statistical analysis. J Bone Miner Res 22:1656–1660CrossRefPubMed
25.
go back to reference Bae SJ, Kim BJ, Lim KH, Lee SH, Kim HK, Kim GS, Koh JM (2012) Efficacy of intravenously administered ibandronate in postmenopausal Korean women with insufficient response to orally administered bisphosphonates. J Bone Miner Metab 30:588–595CrossRefPubMed Bae SJ, Kim BJ, Lim KH, Lee SH, Kim HK, Kim GS, Koh JM (2012) Efficacy of intravenously administered ibandronate in postmenopausal Korean women with insufficient response to orally administered bisphosphonates. J Bone Miner Metab 30:588–595CrossRefPubMed
26.
27.
go back to reference Sebba AI (2008) Significance of a decline in bone mineral density while receiving oral bisphosphonate treatment. Clin Ther 30:443–452CrossRefPubMed Sebba AI (2008) Significance of a decline in bone mineral density while receiving oral bisphosphonate treatment. Clin Ther 30:443–452CrossRefPubMed
28.
go back to reference Parfitt AM, Mathews CH, Villanueva AR, Kleerekoper M, Frame B, Rao DS (1983) Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the microanatomic and cellular mechanisms of bone loss. J Clin Invest 72:1396–1409CrossRefPubMedPubMedCentral Parfitt AM, Mathews CH, Villanueva AR, Kleerekoper M, Frame B, Rao DS (1983) Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the microanatomic and cellular mechanisms of bone loss. J Clin Invest 72:1396–1409CrossRefPubMedPubMedCentral
29.
Metadata
Title
The circulating sphingosine-1-phosphate level predicts incident fracture in postmenopausal women: a 3.5-year follow-up observation study
Authors
S. J. Bae
S. H. Lee
S. H. Ahn
H.-M. Kim
B.-J. Kim
J.-M. Koh
Publication date
01-08-2016
Publisher
Springer London
Published in
Osteoporosis International / Issue 8/2016
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-016-3565-z

Other articles of this Issue 8/2016

Osteoporosis International 8/2016 Go to the issue