, Volume 56, Issue 1, pp 196–204 | Cite as

Bone turnover response is linked to both acute and established metabolic changes in ultra-marathon runners

  • Veronica Sansoni
  • Gianluca Vernillo
  • Silvia Perego
  • Andrea Barbuti
  • Giampiero Merati
  • Federico Schena
  • Antonio La Torre
  • Giuseppe Banfi
  • Giovanni LombardiEmail author
Original Article


Bone and energy metabolisms regulation depends on a two-way street aimed at regulating energy utilization. Mountain ultra-marathons are highly demanding aerobic performances that deeply affect the whole body homeostasis. In this study we aimed to investigate and characterize the metabolic profile (in terms of hormones involved in energy metabolism), the inflammatory adipokines, and the bone turnover; in particular the osteocalcin-mediated response has been compared in experienced mountain ultra-marathons runners versus control subjects. Serum concentrations of specific markers of bone turnover (pro-collagen type I N-terminal propeptide, carboxylated/undercarboxylated osteocalcin), measured by enzyme-linked immunosorbent assay, and metabolic hormones (C-peptide, insulin, glucagon, glucagon-like peptide, gastric-inhibitory peptide, ghrelin, leptin, resistin, and visfatin), measured by fluorescent-based multiplex assay, were compared before and after a 65 km mountain ultra-marathons in 17 trained runners and 12 age-matched controls characterized by a low physical activity profile. After the mountain ultra-marathons, runners experienced a reduction in pro-collagen type I N-terminal propeptide, though it remained higher than in controls; while carboxylated osteocalcin remained unchanged. Among the metabolic hormones, only glucagon and leptin were different between runners and controls at rest. C-peptide and leptin decreased after the mountain ultra-marathons in runners; while glucagon, glucagon-like peptide 1, resistin, and visfatin were all increased. Uncarboxylated osteocalcin (and uncarboxylated/carboxylated osteocalcin ratio) was decreased and this highly correlated with insulin and C-peptide levels. In conditions of high energy expenditure, homeostasis is maintained at expenses of bone metabolism. Changes in the uncarboxylated osteocalcin clearly mark the global energy needs of the body.


Fatigue Osteocalcin Bone turnover Energy metabolism Mountain ultra-marathon 



This work has been funded by the Italian Ministry of Health and the Italian Ministry of Education, University, and Research. The authors are indebted to Jincheng Xu, PhD, and Spyros Skafidas, MD, for their invaluable aid in performing and managing blood samplings. The authors would like to express their gratitude to Alberto Fondriest, Herbert Lorenzoni, Roberta Casagranda, and the Vigolana Trail® Organizing Committee. Finally, special thanks to the participants.

Compliance with ethical standards

Conflict of interest

The authors declare that they have conflict of interest. The results of the present study do not constitute endorsement by ACSM.

Supplementary material

12020_2016_1012_MOESM1_ESM.pdf (304 kb)
Supplementary Table 1


  1. 1.
    D.M. Bramble, D.E. Lieberman, Endurance running and the evolution of Homo. Nature 432(7015), 345–352 (2004)CrossRefPubMedGoogle Scholar
  2. 2.
    World Health Organization. Global Database on Blood Safety: Report 2004–2005. World Health Organization, Geneva (2008)Google Scholar
  3. 3.
    Z.C. Thent, S. Das, L.J. Henry, Role of exercise in the management of diabetes mellitus: the global scenario. PLoS One 8(11), e80436 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    G. Lombardi, F. Sanchis-Gomar, S. Perego, V. Sansoni, G. Banfi, Implications of exercise-induced adipo-myokines in bone metabolism. Endocrine (2015). [Epub ahead of print]. doi: 10.1007/s12020-015-0834-0
  5. 5.
    H. Wallberg-Henriksson, J.R. Zierath, Metabolism. Exercise remodels subcutaneous fat tissue and improves metabolism. Nat. Rev. Endocrinol. 11(4), 198–200 (2015)CrossRefPubMedGoogle Scholar
  6. 6.
    M. Gleeson, N.C. Bishop, D.J. Stensel, M.R. Lindley, S.S. Mastana, M.A. Nimmo, The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat. Rev. Immunol. 11(9), 607–615 (2011)CrossRefPubMedGoogle Scholar
  7. 7.
    A. Sahin-Efe, F. Katsikeris, C.S. Mantzoros, Advances in adipokines. Metabolism 61(12), 1659–1665 (2012)CrossRefPubMedGoogle Scholar
  8. 8.
    M.A. Nimmo, M. Leggate, J.L. Viana, J.A. King, The effect of physical activity on mediators of inflammation. Diabetes Obes. Metab. 15(Suppl 3), 51–60 (2013)CrossRefPubMedGoogle Scholar
  9. 9.
    G. Banfi, G. Lombardi, A. Colombini, G. Lippi, Bone metabolism markers in sports medicine. Sports Med. 40, 697–714 (2010)CrossRefPubMedGoogle Scholar
  10. 10.
    J. Xu, G. Lombardi, W. Jiao, G. Banfi, Effects of exercise on bone status in female subjects, from young girls to postmenopausal women: an overview of systematic reviews and meta-analyses. Sports Med. (2016). [Epub ahead of print]. doi: 10.1007/s40279-016-0494-0
  11. 11.
    G. Lombardi, P. Lanteri, G. Graziani, A. Colombini, G. Banfi, R. Corsetti, Bone and energy metabolism parameters in professional cyclists during the Giro d’Italia 3-weeks stage race. PLoS One 7(7), e42077 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    D. Grasso, R. Corsetti, P. Lanteri, C. Di Bernardo, A. Colombini, R. Graziani, G. Banfi, G. Lombardi, Bone-muscle unit activity, salivary steroid hormones profile, and physical effort over a 3-week stage race. Scand. J. Med. Sci. Sports 25(1), 70–80 (2015)CrossRefPubMedGoogle Scholar
  13. 13.
    G. Lombardi, P. Lanteri, A. Colombini, M. Mariotti, G. Banfi, Sclerostin concentrations in athletes: role of load and gender. J. Biol. Regul. Homeost. Agents 26(1), 157–163 (2012)PubMedGoogle Scholar
  14. 14.
    K.J. Motyl, L.R. McCabe, A.V. Schwartz, Bone and glucose metabolism: a two-way street. Arch. Biochem. Biophys. 503(1), 2–10 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    T. Otani, A. Mizokami, Y. Hayashi, J. Gao, Y. Mori, S. Nakamura, H. Takeuchi, M. Hirata, Signaling pathway for adiponectin expression in adipocytes by osteocalcin. Cell. Signal. 27(3), 532–544 (2015)CrossRefPubMedGoogle Scholar
  16. 16.
    G. Lombardi, S. Perego, L. Luzi, G. Banfi, A four-season molecule: osteocalcin. Updates in its physiological roles. Endocrine 48, 394–404 (2015)CrossRefPubMedGoogle Scholar
  17. 17.
    G. Vernillo, A. Savoldelli, A. Zignoli, P. Trabucchi, B. Pellegrini, G.P. Millet, F. Schena, Influence of the world’s most challenging mountain ultra-marathon on energy cost and running mechanics. Eur. J. Appl. Physiol. 114(5), 929–939 (2014)CrossRefPubMedGoogle Scholar
  18. 18.
    G. Vernillo, N. Rinaldo, A. Giorgi, F. Esposito, P. Trabucchi, G.P. Millet, F. Schena, Changes in lung function during an extreme mountain ultramarathon. Scand. J. Med. Sci. Sports 25(4), e374–e380 (2015)CrossRefPubMedGoogle Scholar
  19. 19.
    G. Vernillo, A. Savoldelli, A. Zignoli, S. Skafidas, A. Fornasiero, A. La Torre, L. Bortolan, B. Pellegrini, F. Schena, Energy cost and kinematics of level, uphill and downhill running: fatigue-induced changes after a mountain ultramarathon. J. Sports Sci. 33(19), 1998–2005 (2015)CrossRefPubMedGoogle Scholar
  20. 20.
    G.P. Millet, G.Y. Millet, Ultramarathon is an outstanding model for the study of adaptive responses to extreme load and stress. BMC Med. 10, 77 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    I. Mujika, S. Padilla, Scientific bases for precompetition tapering strategies. Med. Sci. Sports Exerc. 35(7), 1182–1187 (2003)CrossRefPubMedGoogle Scholar
  22. 22.
    ACSM: American College of Sports Medicine. ACSM’s Guidelines for Exercise Testing and Prescription, 8th edn., Philadephia, PA (2010)Google Scholar
  23. 23.
    G. Lombardi, P. Lanteri, A. Colombini, G. Banfi, Blood biochemical markers of bone turnover: pre-analytical and technical aspects of sample collection and handling. Clin. Chem. Lab. Med. 50(5), 771–789 (2012)CrossRefPubMedGoogle Scholar
  24. 24.
    F. Curtin, P. Schulz, Multiple correlations and Bonferroni’s correction. Biol. Psychiatry 44(8), 775–777 (1998)CrossRefPubMedGoogle Scholar
  25. 25.
    C. Fiuza-Luces, J.R. Ruiz, G. Rodriguez-Romo, C. Santiago, F. Gomez-Gallego, T. Yvert, A. Cano-Nieto, N. Garatachea, M. Moran, A. Lucia, Are ‘endurance’ alleles ‘survival’ alleles? Insights from the ACTN3 R577X polymorphism. PLoS One 6(3), e17558 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    S.L. Booth, A. Centi, S.R. Smith, C. Gundberg, The role of osteocalcin in human glucose metabolism: marker or mediator? Nat. Rev. Endocrinol. 9(1), 43–55 (2013)CrossRefPubMedGoogle Scholar
  27. 27.
    K. Kerschan-Schindl, M.M. Thalmann, E. Weiss, M. Tsironi, U. Foger-Samwald, J. Meinhart, K. Skenderi, P. Pietschmann, Changes in serum levels of myokines and Wnt-Antagonists after an ultramarathon race. PLoS One 10(7), e0132478 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    K. Kerschan-Schindl, M. Thalmann, G.H. Sodeck, K. Skenderi, A.L. Matalas, S. Grampp, C. Ebner, P. Pietschmann, A 246-km continuous running race causes significant changes in bone metabolism. Bone 45(6), 1079–1083 (2009)CrossRefPubMedGoogle Scholar
  29. 29.
    G. Lombardi, R. Corsetti, P. Lanteri, D. Grasso, E. Vianello, M.G. Marazzi, R. Graziani, A. Colombini, E. Galliera, M.M. Corsi Romanelli, G. Banfi, Reciprocal regulation of calcium-/phosphate-regulating hormones in cyclists during the Giro d’Italia 3-week stage race. Scand. J. Med. Sci. Sports 24(5), 779–787 (2014)CrossRefPubMedGoogle Scholar
  30. 30.
    T. Hew-Butler, K.J. Stuempfle, M.D. Hoffman, Bone: an acute buffer of plasma sodium during exhaustive exercise? Horm. Metab. Res. 45(10), 697–700 (2013)CrossRefPubMedGoogle Scholar
  31. 31.
    T. Bobbert, K. Mai, L. Brechtel, H.M. Schulte, B. Weger, A.F. Pfeiffer, J. Spranger, S. Diederich, Leptin and endocrine parameters in marathon runners. Int. J. Sports Med. 33(3), 244–248 (2012)CrossRefPubMedGoogle Scholar
  32. 32.
    L.M. Burke, Nutrition strategies for the marathon: fuel for training and racing. Sports Med. 37(4-5), 344–347 (2007)CrossRefPubMedGoogle Scholar
  33. 33.
    T. Montalcini, P. Gallotti, A. Coppola, V. Zambianchi, M. Fodaro, E. Galliera, M.G. Marazzi, S. Romeo, S. Giannini, M.M. Corsi Romanelli, A. Pujia, C. Gazzaruso, Association between low C-peptide and low lumbar bone mineral density in postmenopausal women without diabetes. Osteoporos. Int. 26(5), 1639–1646 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    D. Hansen, R. Meeusen, A. Mullens, P. Dendale, Effect of acute endurance and resistance exercise on endocrine hormones directly related to lipolysis and skeletal muscle protein synthesis in adult individuals with obesity. Sports Med. 42(5), 415–431 (2012)CrossRefPubMedGoogle Scholar
  35. 35.
    G. Banfi, A. Colombini, G. Lombardi, A. Lubkowska, Metabolic markers in sports medicine. Adv. Clin. Chem. 56, 1–54 (2012)CrossRefPubMedGoogle Scholar
  36. 36.
    J. Pettus, I. Hirsch, S. Edelman, GLP-1 agonists in type 1 diabetes. Clin. Immunol. 149(3), 317–323 (2013)CrossRefPubMedGoogle Scholar
  37. 37.
    T. Yada, B. Damdindorj, R.S. Rita, T. Kurashina, A. Ando, M. Taguchi, M. Koizumi, H. Sone, M. Nakata, M. Kakei, K. Dezaki, Ghrelin signalling in beta-cells regulates insulin secretion and blood glucose. Diabetes Obes. Metab. 16(Suppl 1), 111–117 (2014)CrossRefPubMedGoogle Scholar
  38. 38.
    G. Fernandez-Formoso, S. Perez-Sieira, D. Gonzalez-Touceda, C. Dieguez, S. Tovar, Leptin, 20 years of searching for glucose homeostasis. Life Sci. 140, 4–9 (2015)CrossRefPubMedGoogle Scholar
  39. 39.
    M. Zaccaria, A. Ermolao, E. Brugin, M. Bergamin, Plasma leptin and energy expenditure during prolonged, moderate intensity, treadmill exercise. J. Endocrinol. Invest. 36(6), 396–401 (2013)PubMedGoogle Scholar
  40. 40.
    N.D. Roupas, I. Mamali, S. Maragkos, L. Leonidou, A.K. Armeni, G.K. Markantes, A. Tsekouras, G.C. Sakellaropoulos, K.B. Markou, N.A. Georgopoulos, The effect of prolonged aerobic exercise on serum adipokine levels during an ultra-marathon endurance race. Hormones (Athens) 12(2), 275–282 (2013)CrossRefGoogle Scholar
  41. 41.
    G. Lombardi, A. Colombini, M. Freschi, R. Tavana, G. Banfi, Seasonal variation of bone turnover markers in top-level female skiers. Eur. J. Appl. Physiol. 111(3), 433–440 (2011)CrossRefPubMedGoogle Scholar
  42. 42.
    G. Lombardi, G. Banfi, Effects of sample matrix and storage conditions on full-length visfatin measurement in blood. Clin. Chim. Acta 440, 140–142 (2015)CrossRefPubMedGoogle Scholar
  43. 43.
    B. Lecka-Czernik, C.J. Rosen, Energy excess, glucose utilization and skeletal remodeling: new insights. J. Bone Miner. Res. 30(8), 1356–1361 (2015)CrossRefPubMedGoogle Scholar
  44. 44.
    J. Upadhyay, O.M. Farr, C.S. Mantzoros, The role of leptin in regulating bone metabolism. Metabolism 64(1), 105–113 (2015)CrossRefPubMedGoogle Scholar
  45. 45.
    P.J. Delhanty, B.C. van der Eerden, J.P. van Leeuwen, Ghrelin and bone. Biofactors 40(1), 41–48 (2014)CrossRefPubMedGoogle Scholar
  46. 46.
    R. Corsetti, G. Lombardi, P. Lanteri, A. Colombini, R. Graziani, G. Banfi, Haematological and iron metabolism parameters in professional cyclists during the Giro d’Italia 3-weeks stage race. Clin. Chem. Lab. Med. 50(5), 949–956 (2012)CrossRefPubMedGoogle Scholar
  47. 47.
    G. Banfi, G.S. Roi, A. Dolci, Erythrocytes, haemoglobin and packed cell volume in athletes performing races in altitude environment. Haematologica 85(E-letters), E12 (2000)PubMedGoogle Scholar
  48. 48.
    G. Banfi, G.S. Roi, A. Dolci, D. Susta, Behaviour of haematological parameters in athletes performing marathons and ultramarathons in altitude (‘skyrunners’). Clin. Lab. Haematol. 26(6), 373–377 (2004)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Veronica Sansoni
    • 1
  • Gianluca Vernillo
    • 2
    • 3
    • 4
  • Silvia Perego
    • 1
  • Andrea Barbuti
    • 5
    • 6
  • Giampiero Merati
    • 2
    • 7
  • Federico Schena
    • 3
    • 8
  • Antonio La Torre
    • 2
  • Giuseppe Banfi
    • 1
    • 9
  • Giovanni Lombardi
    • 1
    Email author
  1. 1.Laboratory of Experimental Biochemistry & Molecular BiologyIRCCS Istituto Ortopedico GaleazziMilanoItaly
  2. 2.Department of Biomedical Sciences for HealthUniversity of MilanoMilanoItaly
  3. 3.CeRiSM, Research Centre “Sport, Mountain and Health”University of VeronaRoveretoItaly
  4. 4.Human Performance Laboratory, Faculty of KinesiologyUniversity of CalgaryCalgaryCanada
  5. 5.Department of BiosciencesUniversità degli Studi di MilanoMilanoItaly
  6. 6.Interuniversity Centre for Molecular Medicine and Applied Biophysics (CIMMBA)Università degli Studi di MilanoMilanoItaly
  7. 7.IRCCS Fondazione Don Carlo GnocchiMilanoItaly
  8. 8.Department of Neurological and Movement SciencesUniversità degli Studi di VeronaVeronaItaly
  9. 9.Vita-Salute San Raffaele UniversityMilanoItaly

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