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Rapid suppression of bone formation marker in response to sleep restriction and circadian disruption in men

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Abstract

Summary

We describe the time course of bone formation marker (P1NP) decline in men exposed to ~ 3 weeks of sleep restriction with concurrent circadian disruption. P1NP declined within 10 days and remained lower with ongoing exposure. These data suggest even brief exposure to sleep and circadian disruptions may disrupt bone metabolism.

Introduction

A serum bone formation marker (procollagen type 1 N-terminal, P1NP) was lower after ~ 3 weeks of sleep restriction combined with circadian disruption. We now describe the time course of decline.

Methods

The ~ 3-week protocol included two segments: “baseline,” ≥ 10-h sleep opportunity/day × 5 days; “forced desynchrony” (FD), recurring 28 h day (circadian disruption) with sleep restriction (~ 5.6-h sleep per 24 h). Fasted plasma P1NP was measured throughout the protocol in nine men (20–59 years old). We tested the hypothesis that PINP would steadily decline across the FD intervention because the magnitude of sleep loss and circadian misalignment accrued as the protocol progressed. A piecewise linear regression model was used to estimate the slope (β) as ΔP1NP per 24 h with a change point mid-protocol to estimate the initial vs. prolonged effects of FD exposure.

Results

Plasma P1NP levels declined significantly within the first 10 days of FD (\( \hat{\beta} \) = − 1.33 μg/L per 24 h, p < 0.0001) and remained lower than baseline with prolonged exposure out to 3 weeks (\( \hat{\beta} \) = − 0.18 μg/L per 24 h, p = 0.67). As previously reported, levels of a bone resorption marker (C-telopeptide (CTX)) were unchanged.

Conclusion

Sleep restriction with concurrent circadian disruption induced a relatively rapid decline in P1NP (despite no change in CTX) and levels remained lower with ongoing exposure. These data suggest (1) even brief sleep restriction and circadian disruption can adversely affect bone metabolism, and (2) there is no P1NP recovery with ongoing exposure that, taken together, could lead to lower bone density over time.

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Abbreviations

BMD:

Bone mineral density

P1NP:

N-terminal propeptide of type 1 procollagen

CTX:

C-terminal telopeptide of type 1 collagen

FD:

Forced desynchrony

BTM:

Bone turnover markers

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Authors’ Roles

Study concept and design: CMS, ESO, OMB

Data collection and study performance: SWC, MM, NV

Data analysis: PW, CMS

Data interpretation: CMS, WMK, PW, KPW, SAS, ESO, OMB

Drafting manuscript: CMS

Manuscript revisions and approval of final manuscript: CMS, WMK, PW, KPW, SAS, SWC, MM, NV, CAC, ESO, OMB

Responsibility for integrity of data analysis: PW, CMS

Funding

Data collection was supported by NIA (P01 AG009975), NHLBI (K24 HL76446), and NSBRI through NASA NCC 9-58 (HFP01601), and was conducted in the BWH’s General Clinical Research Center supported by the NCRR (M01 RR02635), and the CCI of the Harvard Clinical and Translational Science Center (1 UL1 RR025758-01).

This work was further supported by K23AR070275 (Swanson), P50 HD073063 (Kohrt), and the National Center for Advancing Translational Sciences of the NIH under award number UL1TR000128.

CMS is supported by K23AR070275.

SAS received support from The Oregon Institute of Occupational Health Sciences at Oregon Health & Science University via funds from the Division of Consumer and Business Services of the State of Oregon, and NIH grants R01 HL142064, R01 HL125893, HL125893-03A1, and R01 HL140577 (to SA Shea); DoD grant PT150133 (to L Hammer); and CDC grant U19 OH010154 (To WK Anger).

NV was supported by the following NIH grants: F32AG051325, R01DK099512, R01HL118601, and R01DK105072.

OMB was supported in part by the NHLBI (R01HL107240).

ESO as overall PI for the Osteoporotic Fractures in Men (MrOS) Study is supported by NIH funding via the following institutes: the National Institute on Aging, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Center for Advancing Translational Sciences, and NIH Roadmap for Medical Research, under the following grant numbers: U01AG027810, U01AG042124, U01AG042139, U01AG042140, U01 AG042143, U01 AG042145, U01 AG042168, and U01 AR066160.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author information

Author notes

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

Authors and Affiliations

  1. Division of Endocrinology, Metabolism and Diabetes, University of Colorado, 12801 E. 17th Ave. Mail Stop 8106, Aurora, CO, 80045, USA

    C.M. Swanson & K.P. Wright Jr.

  2. Division of Geriatric Medicine, University of Colorado Anschutz Medical Campus, and Eastern Colorado VA Geriatric, Research, Education, and Clinical Center, Aurora, CO, USA

    W.M. Kohrt

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

    P. Wolfe

  4. Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA

    K.P. Wright Jr.

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

    S.A. Shea

  6. OHSU-PSU School of Public Health, Portland, OR, USA

    S.A. Shea

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

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

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

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

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

    S.W. Cain

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

    M. Munch

  11. Sleep/Wake Research Centre, Massey University Wellington Campus, Wellington, New Zealand

    M. Munch

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

    E.S. Orwoll

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

    O.M. Buxton

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  1. C.M. Swanson
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  8. N. Vujović
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  9. C.A. Czeisler
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  10. E.S. Orwoll
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  11. O.M. Buxton
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Corresponding author

Correspondence to C.M. Swanson.

Ethics declarations

All participants provided written informed consent [17]. All procedures were approved by the Partners Human Research Committee and were conducted in accordance with the Declaration of Helsinki. The current analysis used de-identified samples, was deemed nonhuman subjects research by The University of Colorado Institutional Review Board, and was approved by Brigham and Women’s Hospital institutional review board.

Conflicts of interest

WMK, PW, SWC, MM, and NV have nothing to disclose.

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

CMS consulting for Radius Health, Inc.

SAS received support from The Oregon Institute of Occupational Health Sciences at Oregon Health & Science University via funds from the Division of Consumer and Business Services of the State of Oregon, and NIH grants R01 HL142064, R01 HL125893, HL125893-03A1, and R01 HL140577 (to SA Shea); DoD grant PT150133 (to L Hammer); and CDC grant U19 OH010154 (to WK Anger).

KPW reports research support from the NIH, Office of Naval Research, Pac-12, Philips Inc., CurAegis Technologies (formerly known as Torvec Inc.), Somalogics; Financial relationships: consulting fees from or served as a paid member of scientific advisory boards for NIH (Sleep Disorders Research Advisory Board - National Heart, Lung and Blood Institute), CurAegis Technologies, Circadian Therapeutics, LTD, Kellogg Company; Board of Directors: Sleep Research Society; Speaker/educational consultant honorarium fees: American Academy of Sleep Medicine, American College of Chest Physicians, American Diabetes Association.

CAC has received consulting fees from or served as a paid member of scientific advisory boards for: Ganésco Inc.; Institute of Digital Media and Child Development; Klarman Family Foundation; Vanda Pharmaceuticals and Washington State Board of Pilotage Commissioners. Dr. Czeisler has also received education/research support from Jazz Pharmaceuticals Plc., Inc., Optum, Philips Respironics, Inc., Regeneron Pharmaceuticals, San Francisco Bar Pilots, Sanofi S.A., Schneider Inc., Sysco, and Vanda Pharmaceuticals. He has received lecture fees from the American Academy of Dental Sleep Medicine and the University of Michigan. The Sleep and Health Education Program of the Harvard Medical School Division of Sleep Medicine, and the Sleep Matters Initiative (which Dr. Czeisler directs) have received funding for educational activities from Cephalon, Inc.; Jazz Pharmaceuticals; ResMed; Takeda Pharmaceuticals; Sanofi-Aventis, Inc.; Sepracor, Inc.; Teva Pharmaceuticals Industries Ltd.; Wake Up Narcolepsy; and Mary Ann & Stanley Snider via Combined Jewish Philanthropies. Dr. Czeisler is the incumbent of an endowed professorship provided to Harvard University by Cephalon, Inc. and holds a number of process patents in the field of sleep/circadian rhythms (e.g., photic resetting of the human circadian pacemaker). Since 1985, Dr. Czeisler has also served as an expert on various legal and technical cases related to sleep and/or circadian rhythms including those involving the following commercial entities: Casper Sleep Inc., Complete General Construction Company, Dreamcloud Holdings LLC, FedEx, Greyhound, HG Energy LLC, Level Sleep LLC, Palomar Health District, South Carolina Central Railroad Co., Steel Warehouse Inc., Stric-Lan Companies LLC, Texas Premier Resource LLC, and United Parcel Service (UPS). Dr. Czeisler owns or owned an equity interest in Vanda Pharmaceuticals. He received royalties from McGraw Hill, New England Journal of Medicine and Koninklijke Philips Electronics, N.V. for the Actiwatch-2 and Actiwatch-Spectrum devices. Dr. Czeisler’s interests were reviewed and managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies.

ESO has received research support from or consulting for Radius, Mereo, Amgen, and Bayer.

OMB previously served as a 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, prior investigator-initiated research grant support from Sepracor (now Sunovion) and Cephalon (now Teva). Outside of the current work, OMB received two subcontract grants to Pennsylvania State University from Mobile Sleep Technologies (NSF/STTR #1622766, NIH/NIA SBIR R43AG056250).

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Swanson, C., Kohrt, W., Wolfe, P. et al. Rapid suppression of bone formation marker in response to sleep restriction and circadian disruption in men. Osteoporos Int 30, 2485–2493 (2019). https://doi.org/10.1007/s00198-019-05135-y

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