Skip to main content

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

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

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

References

  1. Buxton OM, Pavlova M, Reid EW, Wang W, Simonson DC, Adler GK (2010) Sleep restriction for 1 week reduces insulin sensitivity in healthy men. Diabetes 59(9):2126–2133. https://doi.org/10.2337/db09-0699

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Knutsson A, Kempe A (2014) Shift work and diabetes--a systematic review. Chronobiol Int 31(10):1146–1151. https://doi.org/10.3109/07420528.2014.957308

    Article  PubMed  Google Scholar 

  3. McHill AW, Wright KP Jr (2017) Role of sleep and circadian disruption on energy expenditure and in metabolic predisposition to human obesity and metabolic disease. Obesity reviews : an official journal of the International Association for the Study of Obesity 18(Suppl 1):15–24. https://doi.org/10.1111/obr.12503

    Article  Google Scholar 

  4. Buxton OM, Marcelli E (2010) Short and long sleep are positively associated with obesity, diabetes, hypertension, and cardiovascular disease among adults in the United States. Soc Sci Med 71(5):1027–1036. https://doi.org/10.1016/j.socscimed.2010.05.041

    Article  PubMed  Google Scholar 

  5. Scheer FA, Hilton MF, Mantzoros CS, Shea SA (2009) Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A 106(11):4453–4458. https://doi.org/10.1073/pnas.0808180106

    Article  PubMed  PubMed Central  Google Scholar 

  6. Goel N, Rao H, Durmer JS, Dinges DF (2009) Neurocognitive consequences of sleep deprivation. Semin Neurol 29(4):320–339. https://doi.org/10.1055/s-0029-1237117

    Article  PubMed  PubMed Central  Google Scholar 

  7. Swanson CM, Kohrt WM, Buxton OM, Everson CA, Wright KP Jr, Orwoll ES, Shea SA (2018) The importance of the circadian system & sleep for bone health. Metabolism 84:28–43. https://doi.org/10.1016/j.metabol.2017.12.002

    CAS  Article  PubMed  Google Scholar 

  8. Swanson CM, Shea SA, Stone KL, Cauley JA, Rosen CJ, Redline S, Karsenty G, Orwoll ES (2015) Obstructive sleep apnea and metabolic bone disease: insights into the relationship between bone and sleep. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 30(2):199–211. https://doi.org/10.1002/jbmr.2446

    Article  Google Scholar 

  9. Feskanich D, Hankinson SE, Schernhammer ES (2009) Nightshift work and fracture risk: the Nurses’ health study. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 20(4):537–542. https://doi.org/10.1007/s00198-008-0729-5

    CAS  Article  Google Scholar 

  10. Quevedo I, Zuniga AM (2010) Low bone mineral density in rotating-shift workers. J Clin Densitom 13(4):467–469. https://doi.org/10.1016/j.jocd.2010.07.004

    Article  PubMed  Google Scholar 

  11. Kim BK, Choi YJ, Chung YS (2013) Other than daytime working is associated with lower bone mineral density: the Korea National Health and Nutrition Examination Survey 2009. Calcif Tissue Int 93(6):495–501. https://doi.org/10.1007/s00223-013-9779-6

    CAS  Article  PubMed  Google Scholar 

  12. Santhanam P, Khthir R, Dial L, Driscoll HK, Gress TW (2016) Femoral neck bone mineral density in persons over 50 years performing shiftwork: an epidemiological study. J Occup Environ Med 58(3):e63–e65. https://doi.org/10.1097/JOM.0000000000000662

    Article  PubMed  Google Scholar 

  13. Everson CA, Folley AE, Toth JM (2012) Chronically inadequate sleep results in abnormal bone formation and abnormal bone marrow in rats. Exp Biol Med 237(9):1101–1109. https://doi.org/10.1258/ebm.2012.012043

    CAS  Article  Google Scholar 

  14. Xu X, Wang L, Chen L, Su T, Zhang Y, Wang T, Ma W, Yang F, Zhai W, Xie Y, Li D, Chen Q, Fu X, Ma Y, Zhang Y (2016) Effects of chronic sleep deprivation on bone mass and bone metabolism in rats. J Orthop Surg Res 11(1):87. https://doi.org/10.1186/s13018-016-0418-6

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lucassen EA, Coomans CP, van Putten M, de Kreij SR, van Genugten JH, Sutorius RP, de Rooij KE, van der Velde M, Verhoeve SL, Smit JW, Lowik CW, Smits HH, Guigas B, Aartsma-Rus AM, Meijer JH (2016) Environmental 24-hr cycles are essential for health. Curr Biol 26(14):1843–1853. https://doi.org/10.1016/j.cub.2016.05.038

    CAS  Article  PubMed  Google Scholar 

  16. Swanson C, Shea SA, Wolfe P, Cain SW, Munch M, Vujovic N, Czeisler CA, Buxton OM, Orwoll ES (2017) Bone turnover markers after sleep restriction and circadian disruption: a mechanism for sleep-related bone loss in humans. J Clin Endocrinol Metab 102:3722–3730. https://doi.org/10.1210/jc.2017-01147

    Article  PubMed  PubMed Central  Google Scholar 

  17. Buxton OM, Cain SW, O’Connor SP, Porter JH, Duffy JF, Wang W, Czeisler CA, Shea SA (2012) Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Science translational medicine 4(129):129ra143. https://doi.org/10.1126/scitranslmed.3003200

    Article  Google Scholar 

  18. Czeisler CA, Buxton OM (2015) Chapter 35: human circadian timing system and sleep-wake regulation. In: Kryger M, Roth T, Dement WC (eds) Principles and practice of sleep medicine sixth edition, 6th edn. Elsevier, Philadelphia, pp 362–376

    Google Scholar 

  19. Swanson C, Shea SA, Wolfe P, Markwardt S, Cain SW, Munch M, Czeisler CA, Orwoll ES, Buxton OM (2017) 24-hour profile of serum sclerostin and its association with bone biomarkers in men. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 28:3205–3213. https://doi.org/10.1007/s00198-017-4162-5

    CAS  Article  Google Scholar 

  20. Qvist P, Christgau S, Pedersen BJ, Schlemmer A, Christiansen C (2002) Circadian variation in the serum concentration of C-terminal telopeptide of type I collagen (serum CTx): effects of gender, age, menopausal status, posture, daylight, serum cortisol, and fasting. Bone 31(1):57–61

    CAS  Article  PubMed  Google Scholar 

  21. Redmond J, Fulford AJ, Jarjou L, Zhou B, Prentice A, Schoenmakers I (2016) Diurnal rhythms of bone turnover markers in three ethnic groups. The Journal of clinical endocrinology and metabolism:jc20161183. doi:https://doi.org/10.1210/jc.2016-1183

  22. Maronde E, Schilling AF, Seitz S, Schinke T, Schmutz I, van der Horst G, Amling M, Albrecht U (2010) The clock genes period 2 and cryptochrome 2 differentially balance bone formation. PLoS One 5(7):e11527. https://doi.org/10.1371/journal.pone.0011527

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Samsa WE, Vasanji A, Midura RJ, Kondratov RV (2016) Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype. Bone 84:194–203. https://doi.org/10.1016/j.bone.2016.01.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Takarada T, Xu C, Ochi H, Nakazato R, Yamada D, Nakamura S, Kodama A, Shimba S, Mieda M, Fukasawa K, Ozaki K, Iezaki T, Fujikawa K, Yoneda Y, Numano R, Hida A, Tei H, Takeda S, Hinoi E (2017) Bone resorption is regulated by circadian clock in osteoblasts. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 32(4):872–881. https://doi.org/10.1002/jbmr.3053

    CAS  Article  Google Scholar 

  25. Xu C, Ochi H, Fukuda T, Sato S, Sunamura S, Takarada T, Hinoi E, Okawa A, Takeda S (2016) Circadian clock regulates bone resorption in mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 31(7):1344–1355. https://doi.org/10.1002/jbmr.2803

    CAS  Article  Google Scholar 

  26. Fu L, Patel MS, Bradley A, Wagner EF, Karsenty G (2005) The molecular clock mediates leptin-regulated bone formation. Cell 122(5):803–815. https://doi.org/10.1016/j.cell.2005.06.028

    CAS  Article  PubMed  Google Scholar 

  27. Meier-Ewert HK, Ridker PM, Rifai N, Regan MM, Price NJ, Dinges DF, Mullington JM (2004) Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol 43(4):678–683. https://doi.org/10.1016/j.jacc.2003.07.050

    CAS  Article  PubMed  Google Scholar 

  28. Chen YM, Chen HH, Huang WN, Liao TL, Chen JP, Chao WC, Lin CT, Hung WT, Hsieh CW, Hsieh TY, Chen YH, Chen DY (2017) Tocilizumab potentially prevents bone loss in patients with anticitrullinated protein antibody-positive rheumatoid arthritis. PLoS One 12(11):e0188454. https://doi.org/10.1371/journal.pone.0188454

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Edwards CJ, Williams E (2010) The role of interleukin-6 in rheumatoid arthritis-associated osteoporosis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 21(8):1287–1293. https://doi.org/10.1007/s00198-010-1192-7

    CAS  Article  Google Scholar 

  30. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100(2):197–207

    CAS  Article  PubMed  Google Scholar 

  31. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G (2002) Leptin regulates bone formation via the sympathetic nervous system. Cell 111(3):305–317

    CAS  Article  PubMed  Google Scholar 

  32. Dimitri P, Rosen C (2017) The central nervous system and bone metabolism: an evolving story. Calcif Tissue Int 100(5):476–485. https://doi.org/10.1007/s00223-016-0179-6

    CAS  Article  PubMed  Google Scholar 

  33. Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C, Karsenty G (2005) Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434(7032):514–520. https://doi.org/10.1038/nature03398

    CAS  Article  PubMed  Google Scholar 

  34. Chavassieux P, Portero-Muzy N, Roux JP, Garnero P, Chapurlat R (2015) Are biochemical markers of bone turnover representative of bone Histomorphometry in 370 postmenopausal women? J Clin Endocrinol Metab 100(12):4662–4668. https://doi.org/10.1210/jc.2015-2957

    CAS  Article  PubMed  Google Scholar 

Download references

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

Authors and Affiliations

Authors

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).

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-019-05135-y

Keywords

  • Bone formation
  • Bone loss
  • Circadian disruption
  • P1NP
  • Sleep restriction