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High Circulating Sphingosine 1-Phosphate is a Risk Factor for Osteoporotic Fracture Independent of Fracture Risk Assessment Tool

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Abstract

Circulating sphingosine 1-phosphate (S1P) levels may be a biomarker for osteoporotic fracture (OF). This study assessed whether the addition of S1P levels to the fracture risk assessment tool (FRAX) could improve predictability of OF risk. Plasma S1P concentrations and FRAX variables were measured in 81 subjects with and 341 subjects without OF. S1P levels were higher in subjects with than those without OF (3.11 ± 0.13 μmol/L vs. 2.65 ± 0.61 μmol/L, P = 0.001). Higher S1P levels were associated with a higher likelihood of OF (odds ratio [OR] = 1.33, 95% confidence interval [CI] = 1.05–1.68), even after adjusting for FRAX probabilities. Compared with the lowest S1P tertile, subjects in the middle (OR = 3.37, 95% CI = 1.58–7.22) and highest (OR = 3.65, 95% CI = 1.66–8.03) S1P tertiles had higher rates of OF after adjustment. The addition of S1P levels to FRAX probabilities improved the area under the receiver-operating characteristics curve (AUC) for OF, from 0.708 to 0.769 (P = 0.013), as well as enhancing category-free net reclassification improvement (NRI = 0.504, 95% CI = 0.271–0.737, P < 0.001) and integrated discrimination improvement (IDI = 0.044, 95% CI = 0.022–0.065, P < 0.001). Adding S1P levels to FRAX probabilities especially in 222 subjects with osteopenia having a FRAX probability of 3.66–20.0% markedly improved the AUC for OF from 0.630 to 0.741 (P = 0.012), as well as significantly enhancing category-free NRI (0.571, 95% CI = 0.221–0.922, P = 0.001) and IDI (0.060, 95% CI = 0.023–0.097, P = 0.002). S1P is a consistent and significant risk factor of OF independent of FRAX, especially in subjects with osteopenia and low FRAX probability.

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Data Availability

Restrictions apply to the availability of data generated or analyzed during this study because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.

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Funding

This study was supported by grants from the Asan Institute for Life Sciences, Seoul, Republic of Korea (Project No. 2019IP0862) and from the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Project No. HI15C2792). The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea

    Seung Hun Lee, Jee Yang Lee, Kyeong-Hye Lim & Jung-Min Koh

  2. Asan Institute for Life Sciences, Seoul, 05505, Republic of Korea

    Young-Sun Lee

  3. Sejong Biomed Co., Ltd., Paju, 10880, Republic of Korea

    Seong-Hee Kim, Sooyoung Choi & Seong-Hwan Cho

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  1. Seung Hun Lee
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Contributions

SHL and J-MK contributed to the conception and design of study. Material preparation and data collection were performed by SHL, JYL, K-HL, Y-SL, S-HK, SC, S-HC, and J-MK. Analysis and interpretation of data were performed by SHL and J-MK. The first draft of the manuscript was written by SHL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jung-Min Koh.

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Conflict of Interest

Seong-Hee Kim, Sooyoung Choi, and Seong-Hwan Cho have patents registered in Korea (KR 10-1486368) and patent applications in the USA (US 15/927,459) for sphingosine-1-phosphate. They provided the S1P ELISA kits, but were not involved in the design and conduct of the study (i.e. the management, analysis, and interpretation of the data). Seung Hun Lee, Jee Yang Lee, Kyeong-Hye Lim, Young-Sun Lee, and Jung-Min Koh state that they have no conflicts of interest.

Ethics Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Asan Medical Center Ethics Review Committee (2018–0556).

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Written informed consent was obtained from all study subjects.

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Lee, S.H., Lee, J.Y., Lim, KH. et al. High Circulating Sphingosine 1-Phosphate is a Risk Factor for Osteoporotic Fracture Independent of Fracture Risk Assessment Tool. Calcif Tissue Int 107, 362–370 (2020). https://doi.org/10.1007/s00223-020-00731-1

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