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24-hour profile of serum sclerostin and its association with bone biomarkers in men

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Abstract

Summary

The osteocyte’s role in orchestrating diurnal variations in bone turnover markers (BTMs) is unclear. We identified no rhythm in serum sclerostin (osteocyte protein). These results suggest that serum sclerostin can be measured at any time of day and the osteocyte does not direct the rhythmicity of other BTMs in men.

Introduction

The osteocyte exerts important effects on bone remodeling, but its rhythmicity and effect on the rhythms of other bone cells are not fully characterized. The purpose of this study was to determine if serum sclerostin displays rhythmicity over a 24-h interval, similar to that of other bone biomarkers.

Methods

Serum sclerostin, FGF-23, CTX, and P1NP were measured every 2 h over a 24-h interval in ten healthy men aged 20–65 years. Maximum likelihood estimates of the parameters in a repeated measures model were used to determine if these biomarkers displayed a diurnal, sinusoidal rhythm.

Results

No discernible 24-h rhythm was identified for sclerostin (p = 0.99) or P1NP (p = 0.65). CTX rhythmicity was confirmed (p < 0.001), peaking at 05:30 (range 01:30–07:30). FGF-23 levels were also rhythmic (p < 0.001), but time of peak was variable (range 02:30–11:30). The only significant association identified between these four bone biomarkers was for CTX and P1NP mean 24-h metabolite levels (r = 0.65, p = 0.04).

Conclusions

Sclerostin levels do not appear to be rhythmic in men. This suggests that in contrast to CTX, serum sclerostin could be measured at any time of day. The 24-h profiles of FGF-23 suggest that a component of osteocyte function is rhythmic, but its timing is variable. Our results do not support the hypothesis that osteocytes direct the rhythmicity of other bone turnover markers (CTX), at least not via a sclerostin-mediated mechanism.

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Abbreviations

CTX:

C-terminal cross-linked telopeptide of type I collagen

P1NP:

N-terminal propeptide of type I collagen

FGF-23:

Fibroblast growth factor 23

BTM:

Bone turnover marker

h:

hour

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Acknowledgements

Complimentary graphic design consultation for figures was provided by Brian D. Swanson. Assistance with acquisition of study documentation was provided by Nina Vujovic.

Research reported in this manuscript was supported by grants from the Medical Research Foundation of Oregon Early Clinical Investigator Grant MRF515 and the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR000128.  Research reported in this publication was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR070275) and the National Institute on Aging (P01 AG009975). The studies were carried out in the Intensive Physiological Monitoring Unit of the Brigham and Women’s Hospital Center for Clinical Investigation, part of the Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciencies (UL1 TR0001102 and UL1 RR025758) and financial contributions from Harvard University and its affiliated academic health care centers.  The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Author notes

  1. O.M.B. and E.S.O. are co-senior authors—they contributed equally to this work.

Authors and Affiliations

  1. Division of Endocrinology and Bone and Mineral Unit, Oregon Health & Science University, Portland, OR, USA

    C. Swanson & E. S. Orwoll

  2. Division of Endocrinology, University of Colorado, 12801 E. 17th Ave. Mail Stop 8106, Aurora, CO, 80045, USA

    C. Swanson

  3. Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USA

    S. A. Shea

  4. Sleep Health Institute, Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital, Boston, MA, USA

    S. A. Shea, S. W. Cain, C. A. Czeisler & O. M. Buxton

  5. OHSU–PSU School of Public Health, Portland, OR, USA

    S. A. Shea & S. Markwardt

  6. Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    P. Wolfe

  7. Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA

    S. W. Cain, C. A. Czeisler & O. M. Buxton

  8. Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Clayton, VIC, 3800, Australia

    S. W. Cain

  9. Charité University Medicine Berlin, Institute of Physiology, Berlin, Germany

    M. Munch

  10. Department of Biobehavioral Health, Pennsylvania State University, University Park, PA, USA

    O. M. Buxton

  11. Department of Social and Behavioral Sciences, Harvard Chan School of Public Health, Boston, MA, USA

    O. M. Buxton

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  1. C. Swanson
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Corresponding author

Correspondence to C. Swanson.

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Financial disclosures/conflict of interest

In the interest of full disclosure, we report the following; however, we do not believe any of these pertain to the current work.

C.M.S. received support from NIH grant T32 DK007674, NIH grant T32 DK007446, K23 AR070275, and the Medical Research Foundation of Oregon Early Clinical Investigator Grant MRF515.

S.A.S. received support from NASA grant NNX1OAR1OG, CDC grant U19 OH010154, and NIH grant R01 HL125893.

P.W., S.W.C., and M.M. have no disclosures.

S.M. received support from the Oregon Clinical and Translational Research Institute (OCTRI), grant number UL1TR000128 from the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH).

C.A.C. is consultant to Amazon.com, Inc., A2Z Development Center, Bose, Boston Celtics, Boston Red Sox, Cleveland Browns, Columbia River Bar Pilots, Institute of Digital Media and Child Development, Jazz Pharma, Merck, NBA Coaches Association, Purdue Pharma, Quest Diagnostics, Samsung, Teva, and Vanda Pharma. C.A.C. holds equity in Vanda Pharma; receives research/education support from Cephalon, Mary Ann & Stanley Snider via Combined Jewish Philanthropies, NFL Charities, Jazz Pharma, Optum, ResMed, San Francisco Bar Pilots, Schneider, Simmons, Sysco, Philips, and Vanda; is an expert witness in legal cases, including those involving Bombardier, Continental Airlines, Fedex, Greyhound, Purdue Pharma, and UPS; serves as the incumbent of a professorship endowed by Cephalon; and receives royalties from McGraw Hill, Houghton Miflin Harcourt, and Philips Respironics for the Actiwatch-2 and Actiwatch Spectrum devices. C.A.C.’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies.

O.M.B. previously served as consultant to Takeda Pharmaceuticals North America (speaker’s bureau), Dinsmore LLC (expert witness testimony), Matsutani America (scientific advisory board), and Chevron (speaking fees). Outside of the submitted work, investigator-initiated research grant support from Sepracor (now Sunovion) and Cephalon (now Teva). This work was supported by grants from the National Institute on Aging (NIA) (P01 AG009975) and was conducted in the Brigham and Women’s Hospital General Clinical Research Center supported by the National Center for Research Resources (NCRR) (M01 RR02635), the CCI of the Harvard Clinical and Translational Science Center (1 UL1 RR025758-01), and with support from the Joslin Diabetes and Endocrinology Research Center Service (5P30 DK 36836) Specialized Assay Core. O.M.B. was supported in part by the NHLBI (R01HL107240).

E.S.O. consults for and has received research support from Amgen, Lilly, and Merck.

E.S.O. for The Osteoporotic Fractures in Men (MrOS) Study, and the National Institutes of Health via the following institutes: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research, under the following grant numbers: U01AG027810, U01 AG042124, U01 AG042139, U01 AG042140,U01 AG042143, U01 AG042145, U01 AG042168, U01AR066160, and UL1 TR000128.

Additional information

Research reported in this manuscript was supported by National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR000128.

Electronic supplementary material

Online Resource Fig 1

24-h fitted serum profile of P1NP (magnified y-axis). P1NP individual (dotted) and group (solid) fitted cosinor curves are displayed for all ten men by age group (older = dark red; younger = light blue) with a smaller y-axis than used in Fig. 2c. When the y-axis is magnified (and meal bars are removed), a very small amplitude profile for P1NP can be appreciated visually. All clock times are presented as two-digit military time in hours relative to breakfast, which occurred, on average, at 09:27 (SD 3 min). Ten-hour sleep opportunity is represented as a horizontal black bar (GIF 29 kb)

High resolution image (TIFF 20663 kb)

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Swanson, C., Shea, S.A., Wolfe, P. et al. 24-hour profile of serum sclerostin and its association with bone biomarkers in men. Osteoporos Int 28, 3205–3213 (2017). https://doi.org/10.1007/s00198-017-4162-5

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