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Osteologie 2022; 31(03): 146-152
DOI: 10.1055/a-1909-0144
Review

Osteoporose bei/durch Adipositas – Schutz oder Risiko?

Osteoporosis and Obesity – Risk or Benefit?
Hans-Christof Schober
1   Klinik für Innere Medizin, Klinikum Südstadt Rostock, Rostock, Germany
,
Katharina Kasch
2   Klinik für Innere Medizin IV, Klinikum Südstadt Rostock, Rostock, Germany
,
Guido Schröder
3   Klinik für Orthopädie und Unfallchirurgie, Warnow-Klinik Bützow, Bützow, Germany
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Zusammenfassung

Adipositas und Osteoporose sind häufige Erkrankungen, ein Zusammenhang zwischen beiden wird kontrovers beschrieben. Zum einen geht Adipositas mit einer Vielzahl von Komorbiditäten einher die den Knochenstoffwechsel beeinflussen und das Frakturrisiko erhöhen, zum anderen können die höhere Last auf den Knochen und der Weichteilmantel protektiv bei Stürzen wirken. Komorbiditäten der Adipositas fördern eine eingeschränkte Beweglichkeit und Stürze. Bei Adipositas findet sich daher eine Kombination aus peripheren Frakturen und Osteoporose-assoziierten Brüchen. Knochendichtemessungen und Bestimmungen der Knochenumbaumarker sind zur Abschätzung des Frakturrisikos bei dieser Klientel nur bedingt geeignet.

Abstract

Obesity and osteoporosis are common conditions, the relationship between the two is complex. On the one hand, obesity is associated with a variety of comorbidities that affect bone metabolism and increase fracture risk; on the other hand, the high mechanical loading and the larger soft tissue “envelope” maybe protective in falls. The increasing number of people in older age with obesity requires a differentiated view. Motion-associated peripheral fractures are most likely to be more common in obese people, especially ankle fractures, Osteoporotic fractures seem to be associated with increased frailty in obesity. Bone density measurements and determinations of bone remodeling markers are of limited use in estimating fracture risk in these patients.

Schlüsselwörter

Adipositas - Osteoporose - Frakturrisiko - Adipositas - 3

Key words

obesity - osteoporosis - fracture risk - obesity - 3


Publication History

Received: 15 May 2022
Received: 24 July 2022

Accepted: 20 July 2022

Article published online:
08 September 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 Bonewald L. Use it or lose it to age: A review of bone and muscle communication. Bone 2019; 120: 212-218 DOI: 10.1016/j.bone.2018.11.002.
    CrossrefPubMedGoogle Scholar
  • 2 Feng JQ, Ward LM, Liu S. et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006; 38: 1310-1315 DOI: 10.1038/ng1905.
    CrossrefPubMedGoogle Scholar
  • 3 Dallas SL, Prideaux M, Bonewald LF. The osteocyte: an endocrine cell … and more. Endocr Rev 2013; 34: 658-690 DOI: 10.1210/er.2012-1026.
    CrossrefPubMedGoogle Scholar
  • 4 Manolagas SC. Birth and death of bone cells: Basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000; 21: 115-137
    PubMedGoogle Scholar
  • 5 Hernlund E, Svedbom A, Ivergård M. et al. Osteoporosis in the European Union: Medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 2013; 8: 136
    CrossrefPubMedGoogle Scholar
  • 6 NIH Consensus Development Panel on Osteoporosis Prevention. Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001; 285: 785-795
    CrossrefPubMedGoogle Scholar
  • 7 Kanis JA, McCloskey EV, Johansson H. et al. A reference standard for the description of osteoporosis. Bone 2008; 42: 467-475
    CrossrefPubMedGoogle Scholar
  • 8 Centre for Metabolic Bone Diseases, University of Sheffield, UK. FRAX® Fracture Risk Assessment Tool. Im Internet:. https://www.sheffield.ac.uk/FRAX/ Stand: 20.06.2022
    Google Scholar
  • 9 Hadji P, Klein S, Gothe H. et al. The epidemiology of osteoporosis –Bone Evaluation Study (BEST): An analysis of routine health insurance data. Dtsch Arztebl Int 2013; 110: 52-57
    CrossrefPubMedGoogle Scholar
  • 10 Svedbom A, Hernlund E, Ivergård M. et al. Osteoporosis in the European Union: A compendium of country-specific reports. Arch Osteoporos 2013; 8: 137
    CrossrefPubMedGoogle Scholar
  • 11 Bässgen K, Westphal T, Haar P. et al. Population-based prospective study on the incidence of osteoporosis-associated fractures in a German population of 200,413 inhabitants. J Public Health (Oxf) 2013; 35: 255-261
    CrossrefPubMedGoogle Scholar
  • 12 Veronese N, Reginster J-Y. The effects of calorie restriction, intermittent fasting and vegetarian diets on bone health. Aging Clin Exp Res 2019; 31: 753-758
    CrossrefPubMedGoogle Scholar
  • 13 Karsenty G, Olson EN. Bone and Muscle Endocrine Functions. Unexpected Paradigms of Inter-organ Communication. Cell 2016; 164: 1248-1256
    CrossrefPubMedGoogle Scholar
  • 14 Khosla S, Atkinson EJ, Dunstan CR. et al. Effect of estrogen versus testosterone on circulating osteoprotegerin and other cytokine levels in normal elderly men. J Clin Endocrinol Metab 2002; 87: 1550-1554
    CrossrefPubMedGoogle Scholar
  • 15 Slemenda C, Hui SL, Longcope C. et al. Sex steroids and bone mass. A study of changes about the time of menopause. J Clin Invest 1987; 80: 1261-1269
    CrossrefPubMedGoogle Scholar
  • 16 Frost HM. Bone “mass” and the “mechanostat”: A proposal. Anat Rec 1987; 219: 1-9
    CrossrefPubMedGoogle Scholar
  • 17 World Health Organization. Obesity: Preventing and managing the global epidemic ; report of a WHO Consultation ; [1999, Geneva]. Vol. 894. WHO technical report series. Geneva: World Health Organization; 2000
    Google Scholar
  • 18 Dachverbandes Osteologie e.V. Prophylaxe, Diagnostik und Therapie der OSTEOPOROSE bei postmenopausalen Frauen und bei Männern. Leitlinie des Dachverbands der Deutschsprachigen Wissenschaftlichen Osteologischen Gesellschaften e.V.; 2017
  • 19 Haftenberger M, Mensink GBM, Vogt S. et al. Changes in Waist Circumference among German Adults over Time – Compiling Results of Seven Prospective Cohort Studies. Obes Facts 2016; 9: 332-343
    CrossrefPubMedGoogle Scholar
  • 20 Stang A, Döring A, Völzke H. et al. Regional differences in body fat distributions among people with comparable body mass index: A comparison across six German population-based surveys. Eur J Cardiovasc Prev Rehabil 2011; 18: 106-114
    CrossrefPubMedGoogle Scholar
  • 21 De Laet C, Kanis JA, Odén A. et al. Body mass index as a predictor of fracture risk: A meta-analysis. Osteoporos Int 2005; 16: 1330-1338
    CrossrefPubMedGoogle Scholar
  • 22 Lacombe J, Cairns BJ, Green J. et al. The Effects of Age, Adiposity, and Physical Activity on the Risk of Seven Site-Specific Fractures in Postmenopausal Women. J Bone Miner Res 2016; 31: 1559-1568
    CrossrefPubMedGoogle Scholar
  • 23 Premaor MO, Pilbrow L, Tonkin C. et al. Obesity and fractures in postmenopausal women. J Bone Miner Res 2010; 25: 292-297
    CrossrefPubMedGoogle Scholar
  • 24 Malkov S, Cawthon PM, Peters KW. et al. Hip Fractures Risk in Older Men and Women Associated With DXA-Derived Measures of Thigh Subcutaneous Fat Thickness, Cross-Sectional Muscle Area, and Muscle Density. J Bone Miner Res 2015; 30: 1414-1421
    CrossrefPubMedGoogle Scholar
  • 25 Xiang B-Y, Huang W, Zhou G-Q. et al. Body mass index and the risk of low bone mass-related fractures in women compared with men: A PRISMA-compliant meta-analysis of prospective cohort studies. Medicine (Baltimore) 2017; 96: e5290
    CrossrefPubMedGoogle Scholar
  • 26 Shuhart CR, Yeap SS, Anderson PA. et al. Executive Summary of the 2019 ISCD Position Development Conference on Monitoring Treatment, DXA Cross-calibration and Least Significant Change, Spinal Cord Injury, Peri-prosthetic and Orthopedic Bone Health, Transgender Medicine, and Pediatrics. J Clin Densitom 2019; 22: 453-471
    CrossrefPubMedGoogle Scholar
  • 27 Ma M, Feng Z, Liu X. et al. The Saturation Effect of Body Mass Index on Bone Mineral Density for People Over 50 Years Old: A Cross-Sectional Study of the US Population. Front Nutr 2021; 8: 763677 DOI: 10.3389/fnut.2021.763677.
    CrossrefPubMedGoogle Scholar
  • 28 Ouyang Y, Quan Y, Guo C. et al. Saturation Effect of Body Mass Index on Bone Mineral Density in Adolescents of Different Ages: A Population-Based Study. Front. Endocrinol. 2022; 13 DOI: 10.3389/fendo.2022.922903.
    CrossrefPubMedGoogle Scholar
  • 29 Kojta I, Chacińska M, Błachnio-Zabielska A. Obesity, Bioactive Lipids, and Adipose Tissue Inflammation in Insulin Resistance. Nutrients 2020 12.
    PubMedGoogle Scholar
  • 30 Apovian CM. Obesity: Definition, comorbidities, causes, and burden. Am J Manag Care 2016; 22: s176-s185
    PubMedGoogle Scholar
  • 31 Ensrud KE, Lipschutz RC, Cauley JA. et al. Body Size and Hip Fracture Risk in Older Women. The American Journal of Medicine 1997; 103: 274-280
    CrossrefPubMedGoogle Scholar
  • 32 Prieto-Alhambra D, Premaor MO, Fina Avilés F. et al. The association between fracture and obesity is site-dependent: A population-based study in postmenopausal women. J Bone Miner Res 2012; 27: 294-300
    CrossrefPubMedGoogle Scholar
  • 33 Mpalaris V, Anagnostis P, Goulis DG. et al. Complex association between body weight and fracture risk in postmenopausal women. Obes Rev 2015; 16: 225-233
    CrossrefPubMedGoogle Scholar
  • 34 Kanis JA, Harvey NC, McCloskey E. et al. Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures. Osteoporos Int 2020; 31: 1-12
    CrossrefPubMedGoogle Scholar
  • 35 Ferrari S, Lippuner K, Lamy O. et al. 2020 recommendations for osteoporosis treatment according to fracture risk from the Swiss Association against Osteoporosis (SVGO). Swiss Med Wkly. 2020 150. w20352
    PubMedGoogle Scholar
  • 36 Lee NK, Sowa H, Hinoi E. et al. Endocrine regulation of energy metabolism by the skeleton. Cell 2007; 130: 456-469
    CrossrefPubMedGoogle Scholar
  • 37 Oury F, Ferron M, Huizhen W. et al. Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. J Clin Invest 2013; 123: 2421-2433
    CrossrefPubMedGoogle Scholar
  • 38 Komori T. Functions of Osteocalcin in Bone, Pancreas, Testis, and Muscle. Int J Mol Sci 2020; 21 DOI: 10.3390/ijms21207513.
    CrossrefPubMedGoogle Scholar
  • 39 Hamann C, Kirschner S, Günther K-P. et al. Bone, sweet bone--osteoporotic fractures in diabetes mellitus. Nat Rev Endocrinol 2012; 8: 297-305
    CrossrefPubMedGoogle Scholar
  • 40 Moon JS, Jin MH, Koh HM. Association between Serum Osteocalcin Levels and Metabolic Syndrome according to the Menopausal Status of Korean Women. J Korean Med Sci 2021; 36: e56 DOI: 10.3346/jkms.2021.36.e56.
    CrossrefPubMedGoogle Scholar
  • 41 Kahn CR, Wang G, Lee KY. Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. J Clin Invest 2019; 129: 3990-4000 DOI: 10.1172/JCI129187.
    CrossrefPubMedGoogle Scholar
  • 42 Krishnan A, Muthusami S. Hormonal alterations in PCOS and its influence on bone metabolism. J Endocrinol 2017; 232: R99-R113
    CrossrefPubMedGoogle Scholar
  • 43 Di Bari F, Catalano A, Bellone F. et al. Vitamin D, Bone Metabolism, and Fracture Risk in Polycystic Ovary Syndrome. Metabolites 2021; 11 DOI: 10.3390/metabo11020116.
    CrossrefPubMedGoogle Scholar
  • 44 Rubin KH, Glintborg D, Nybo M. et al. Fracture Risk Is Decreased in Women With Polycystic Ovary Syndrome: A Register-Based and Population-Based Cohort Study. J Bone Miner Res 2016; 31: 709-717 DOI: 10.1002/jbmr.2737.
    CrossrefPubMedGoogle Scholar
  • 45 Yang H-Y, Lee H-S, Huang W-T. et al. Increased risk of fractures in patients with polycystic ovary syndrome: a nationwide population-based retrospective cohort study. J Bone Miner Metab 2018; 36: 741-748 DOI: 10.1007/s00774-017-0894-8.
    CrossrefPubMedGoogle Scholar
  • 46 Garnero P, Sornay-Rendu E, Claustrat B. et al. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: The OFELY study. J Bone Miner Res 2000; 15: 1526-1536
    CrossrefPubMedGoogle Scholar
  • 47 Evans AL, Paggiosi MA, Eastell R. et al. Bone density, microstructure and strength in obese and normal weight men and women in younger and older adulthood. J Bone Miner Res 2015; 30: 920-928
    CrossrefPubMedGoogle Scholar
  • 48 Leeners B, Geary N, Tobler PN. et al. Ovarian hormones and obesity. Hum Reprod Update 2017; 23: 300-321
    CrossrefPubMedGoogle Scholar
  • 49 Stout MB, Justice JN, Nicklas BJ. et al. Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty. Physiology (Bethesda) 2017; 32: 9-19
    PubMedGoogle Scholar
  • 50 Walsh JS, Bowles S, Evans AL. Vitamin D in obesity. Curr Opin Endocrinol Diabetes Obes 2017; 24: 389-394
    CrossrefPubMedGoogle Scholar
  • 51 Reid IR. Fat and bone. Arch Biochem Biophys 2010; 503: 20-27
    CrossrefPubMedGoogle Scholar
  • 52 Walsh JS, Evans AL, Bowles S. et al. Free 25-hydroxyvitamin D is low in obesity, but there are no adverse associations with bone health. Am J Clin Nutr 2016; 103: 1465-1471
    CrossrefPubMedGoogle Scholar
  • 53 Roy B, Curtis ME, Fears LS. et al. Molecular Mechanisms of Obesity-Induced Osteoporosis and Muscle Atrophy. Front Physiol 2016; 7: 439
    CrossrefPubMedGoogle Scholar
  • 54 Cohen A, Dempster DW, Recker RR. et al. Abdominal fat is associated with lower bone formation and inferior bone quality in healthy premenopausal women: a transiliac bone biopsy study. J Clin Endocrinol Metab 2013; 98: 2562-2572 DOI: 10.1210/jc.2013-1047.
    CrossrefPubMedGoogle Scholar
  • 55 Bredella MA, Torriani M, Ghomi RH. et al. Vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 in obese women. Obesity (Silver Spring) 2011; 19: 49-53 DOI: 10.1038/oby.2010.106.
    CrossrefPubMedGoogle Scholar
  • 56 de Araújo IM, Salmon CEG, Nahas AK. et al. Marrow adipose tissue spectrum in obesity and type 2 diabetes mellitus. Eur J Endocrinol 2017; 176: 21-30 DOI: 10.1530/EJE-16-0448.
    CrossrefPubMedGoogle Scholar
  • 57 Cao Y, Zhang S, Zou S. et al. The relationship between endogenous androgens and body fat distribution in early and late postmenopausal women. PLoS One 2013; 8: e58448
    CrossrefPubMedGoogle Scholar
  • 58 Abu EO, Horner A, Kusec V. et al. The localization of androgen receptors in human bone. J Clin Endocrinol Metab 1997; 82: 3493-3497
    CrossrefPubMedGoogle Scholar
  • 59 Hofbauer LC, Khosla S. Androgen effects on bone metabolism: Recent progress and controversies. Eur J Endocrinol 1999; 140: 271-286
    CrossrefPubMedGoogle Scholar
  • 60 Kasperk CH, Wergedal JE, Farley JR. et al. Androgens directly stimulate proliferation of bone cells in vitro. Endocrinology 1989; 124: 1576-1578
    CrossrefPubMedGoogle Scholar
  • 61 Schiessl H, Frost H, Jee W. Estrogen and Bone-Muscle Strength and Mass Relationships. Bone 1998; 22: 1-6
    CrossrefPubMedGoogle Scholar
  • 62 Liu C-T, Broe KE, Zhou Y. et al. Visceral Adipose Tissue Is Associated With Bone Microarchitecture in the Framingham Osteoporosis Study. J Bone Miner Res 2017; 32: 143-150
    CrossrefPubMedGoogle Scholar
  • 63 Schafer AL, Vittinghoff E, Lang TF. et al. Fat infiltration of muscle, diabetes, and clinical fracture risk in older adults. J Clin Endocrinol Metab 2010; 95: E368-E372
    CrossrefPubMedGoogle Scholar
  • 64 Friedmann JM, Elasy T, Jensen GL. The relationship between body mass index and self-reported functional limitation among older adults: A gender difference. J Am Geriatr Soc 2001; 49: 398-403
    CrossrefPubMedGoogle Scholar
  • 65 Beavers KM, Greene KA, Yu EW. MANAGEMENT OF ENDOCRINE DISEASE. Bone complications of bariatric surgery: updates on sleeve gastrectomy, fractures, and interventions. Eur J Endocrinol 2020; 183: R119-R132
    CrossrefPubMedGoogle Scholar
  • 66 Melton LJ, Crowson CS, O’Fallon WM. Fracture incidence in Olmsted County, Minnesota: Comparison of urban with rural rates and changes in urban rates over time. Osteoporos Int 1999; 9: 29-37
    CrossrefPubMedGoogle Scholar
  • 67 Gajic-Veljanoski O, Papaioannou A, Kennedy C. et al. Osteoporotic fractures and obesity affect frailty progression: A longitudinal analysis of the Canadian multicentre osteoporosis study. BMC Geriatr 2018; 18: 4
    CrossrefPubMedGoogle Scholar
  • 68 Mahgoub MO, D’Souza C, Al Darmaki RSMH. et al. An update on the role of irisin in the regulation of endocrine and metabolic functions. Peptides 2018; 104: 15-23
    CrossrefPubMedGoogle Scholar
  • 69 Polyzos SA, Anastasilakis AD, Efstathiadou ZA. et al. Irisin in metabolic diseases. Endocrine 2018; 59: 260-274 DOI: 10.1007/s12020-017-1476-1.
    CrossrefPubMedGoogle Scholar
  • 70 Neri SGR, Harvey LA, Tiedemann A. et al. Obesity and falls in older women: Mediating effects of muscle quality, foot loads and postural control. Gait Posture 2020; 77: 138-143
    CrossrefPubMedGoogle Scholar
  • 71 Gadelha AB, Neri SGR, Vainshelboim B. et al. Dynapenic abdominal obesity and the incidence of falls in older women: A prospective study. Aging Clin Exp Res 2020; 32: 1263-1270
    CrossrefPubMedGoogle Scholar
  • 72 Gonzalez M, Gates DH, Rosenblatt NJ. The impact of obesity on gait stability in older adults. J Biomech 2020; 100: 109585
    CrossrefPubMedGoogle Scholar
  • 73 Compston JE, Watts NB, Chapurlat R. et al. Obesity is not protective against fracture in postmenopausal women: GLOW. The American Journal of Medicine 2011; 124: 1043-1050
    CrossrefPubMedGoogle Scholar
  • 74 Nielson CM, Marshall LM, Adams AL. et al. BMI and fracture risk in older men: The osteoporotic fractures in men study (MrOS). J Bone Miner Res 2011; 26: 496-502
    CrossrefPubMedGoogle Scholar
  • 75 Kim K-C, Shin D-H, Lee S-Y. et al. Relation between obesity and bone mineral density and vertebral fractures in Korean postmenopausal women. Yonsei Med J 2010; 51: 857-863
    CrossrefPubMedGoogle Scholar
  • 76 Gonnelli S, Caffarelli C, Nuti R. Obesity and fracture risk. Clin Cases Miner Bone Metab 2014; 11: 9-14
    PubMedGoogle Scholar
  • 77 Ong T, Sahota O, Tan W. et al. A United Kingdom perspective on the relationship between body mass index (BMI) and bone health: A cross sectional analysis of data from the Nottingham Fracture Liaison Service. Bone 2014; 59: 207-210
    CrossrefPubMedGoogle Scholar
  • 78 Johansson H, Kanis JA, Odén A. et al. A meta-analysis of the association of fracture risk and body mass index in women. J Bone Miner Res 2014; 29: 223-233
    CrossrefPubMedGoogle Scholar
  • 79 Sadeghi O, Saneei P, Nasiri M. et al. Abdominal Obesity and Risk of Hip Fracture: A Systematic Review and Meta-Analysis of Prospective Studies. Adv Nutr 2017; 8: 728-738 DOI: 10.3945/an.117.015545.
    CrossrefPubMedGoogle Scholar
  • 80 Li G, Compston JE, Leslie WD. et al. Relationship Between Obesity and Risk of Major Osteoporotic Fracture in Postmenopausal Women: Taking Frailty Into Consideration. J Bone Miner Res 2020; 35: 2355-2362
    CrossrefPubMedGoogle Scholar
  • 81 Calvani R, Martone AM, Marzetti E. et al. Pre-hospital dietary intake correlates with muscle mass at the time of fracture in older hip-fractured patients. Front Aging Neurosci 2014; 6: 269
    CrossrefPubMedGoogle Scholar
  • 82 Marques NR, LaRoche DP, Hallal CZ. et al. Association between energy cost of walking, muscle activation, and biomechanical parameters in older female fallers and non-fallers. Clin Biomech (Bristol, Avon) 2013; 28: 330-336
    CrossrefPubMedGoogle Scholar
  • 83 Daguet E, Jolivet E, Bousson V. et al. Fat content of hip muscles: An anteroposterior gradient. J Bone Joint Surg Am 2011; 93: 1897-1905
    CrossrefPubMedGoogle Scholar
  • 84 Roubenoff R. Sarcopenic obesity: the confluence of two epidemics. Obes Res 2004; 12: 887-888 DOI: 10.1038/oby.2004.107.
    CrossrefPubMedGoogle Scholar
  • 85 Chalhoub D, Boudreau R, Greenspan S. et al. Associations Between Lean Mass, Muscle Strength and Power, and Skeletal Size, Density and Strength in Older Men. J Bone Miner Res 2018; 33: 1612-1621
    CrossrefPubMedGoogle Scholar
  • 86 Li G, Ioannidis G, Pickard L. et al. Frailty index of deficit accumulation and falls: Data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) Hamilton cohort. BMC Musculoskelet Disord 2014; 15: 185
    CrossrefPubMedGoogle Scholar
  • 87 Caffarelli C, Alessi C, Nuti R. et al. Divergent effects of obesity on fragility fractures. Clin Interv Aging 2014; 9: 1629-1636
    PubMedGoogle Scholar
  • 88 Mignardot J-B, Olivier I, Promayon E. et al. Obesity impact on the attentional cost for controlling posture. PLoS One 2010; 5: e14387 DOI: 10.1371/journal.pone.0014387.
    CrossrefPubMedGoogle Scholar