#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#
preLekára.sk / Journals / Clinical Osteology / 2021 - 2

Pathophysiology of bone quality changes in obese diabetics

Česká verzia

Authors: Fröhlich Mária;  Jackuliak Peter;  Smaha Juraj;  Payer Juraj
Authors place of work: V. interná klinika LF UK a UNB, Nemocnica Ružinov, Bratislava
Published in the journal: Clinical Osteology 2021; 26(2): 80-88
Category:

Summary

Diabetes mellitus (DM) and osteoporosis are the predominant diseases worldwide and are associated with significant prevalence, morbidity and mortality. The main goal of this work is to determine the importance of the association between type 2 diabetes mellitus (T2DM) and osteoporosis, as well as to confirm the possible negative effect on bone tissue and at the same time to prove changes in bone microarchitecture. Complications associated with diabetes may increase the risk of falls and thus adversely affect bone tissue, as well as DM treatment with antidiabetics and insulin alone may contribute to the alteration of bone material by either a direct or indirect mechanism. T2DM is often accompanied by obesity, which mediates its negative effect through inflammation and the release of adipokines. Early detection of the disease is key in the prevention and treatment of potential complications of bone changes. This article is divided into 8 sections, which deal with the diseases of diabetes mellitus and osteoporosis, their classification, etiopathogenesis, diagnosis and treatment. In the next part, we tried to evaluate the mechanism of action of T2DM on bone tissue.

Keywords:

bone tissue – diabetes mellitus – Osteoblasts – Osteocytes – Osteoclasts – osteoporosis – age

Zdroje
  1. Paschou SΑ, Dede AD, Anagnostis PG et al. Type 2 Diabetes and Osteoporosis: A Guide to Optimal Management. J Clin Endocrinol Metab 2017; 102(10): 3621–3634. Dostupné z DOI: <http://dx.doi.org/10.1210/jc.2017–00042>.
  2. Picke A-K, Campbell G, Napoli N et al. Update on the impact of type 2 diabetes mellitus on bone metabolism and material properties. Endocr Connect 2019; 8(3): R55-R70. Dostupné z DOI: <http://dx.doi. org/10.1530/EC-18–0456>.
  3. Savvidis C, Tournis S, Dede AD. Obesity and bone metabolism. Hormones ( Athens) 2 018; 1 7(2): 2 05–217. D ostupné z DOI: < http:// dx.doi.org/10.1007/s42000–018–0018–4>.                                      Shapses SA, Pop LC, Wang Y. Obesity is a concern for bone health with aging. Nutr Res 2017; 39: 1–13. Dostupné z DOI: <http://dx.doi.org/ 10.1016/j.nutres.2016.12.010>.
  4. Karim L, Rezaee T, Vaidya R. The Effect of Type 2 Diabetes on Bone Biomechanics. Curr Osteoporos Rep 2019; 17(5): 291–300. Dostupné z DOI: <http://dx.doi.org/10.1007/s11914–019–00526-w>.
  5. Dirkes RK, Ortinau LC, Scott Rector R et al. Insulin-Stimulated Bone Blood Flow and Bone Biomechanical Properties Are Compromised in Obese, Type 2 Diabetic OLETF Rats. JBMR Plus 2017; 1(2): 116– 126. Dostupné z DOI: <http://dx.doi.org/10.1002/jbm4.10007>.
  6. Karim L, Moulton J, Van Vliet M et al. Bone microarchitecture, biomechanical properties, and advanced glycation end-products in the proximal femur of adults with type 2 diabetes. Bone 2018; 114: 32–39. Dostupné z DOI: <http://dx.doi.org/10.1016/j.bone.2018.05.030>.
  7. Samelson EJ, Demissie S, Cupples LA et al. Diabetes and Deficits in Cortical Bone Density, Microarchitecture, and Bone Size: Framingham HR-pQCT Study. J Bone Miner Res 2018; 33(1): 54–62. Dostupné z DOI: <http://dx.doi.org/10.1002/jbmr.3240>.
  8. Seeman E, Delmas PD. Bone quality--the material and structural basis of bone strength and fragility. N Engl J Med 2006; 354(21): 2250– 2261. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMra053077>.
  9. Sanguineti R, Puddu A, Mach F et al. Advanced Glycation End Products Play Adverse Proinflammatory Activities in Osteoporosis. Mediators Inflamm 2 014; 2 014: 975872. D ostupné z DOI: <http://dx.doi. org/10.1155/2014/975872>.
  10. Nakano M, Nakamura Y, Takako Suzuki T et al. Pentosidine and carboxymethyl-lysine associate differently with prevalent osteoporotic vertebral fracture and various bone markers. Sci Rep 2020; 10(1): 22090. Dostupné z DOI: <http://dx.doi.org/10.1038/s41598–020– 78993-w>.
  11. Torres-Costoso A, Pozuelo-Carrascosa DP, Álvarez-Bueno C et al. Insulin and bone health in young adults: The mediator role of lean mass. PloS One 2017; 12(3): e0173874. Dostupné z DOI: <http://dx.doi. org/10.1371/journal.pone.0173874>.
  12. Fowlkes JL, Bunn RC, Thrailkill KM. Contributions of the Insulin/ Insulin-Like Growth Factor-1 Axis to Diabetic Osteopathy. J Diabetes Metab 2 011; 1(3). D ostupné z DOI: <http://dx.doi.org/10.4172/2155– 6156.S1–003>.
  13. Palui R, Pramanik S, Mondal S et al. Critical review of bone health, fracture risk and management of bone fragility in diabetes mellitus. World J Diabetes 2021; 12(6): 706–729. Dostupné z DOI: <http://dx.doi. oeg/10.4239/wjd.v12.i6.706>.
  14. Ferron M, Wei J, Yoshizawa T et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 2010; 142(2): 296–308. Dostupné z DOI: <http://dx.doi.org/10.1016/j.cell.2010.06.003>.
  15. Yousefi F, Shabaninejad Z, Vakili S et al. TGF-β and WNT signaling pathways in cardiac fibrosis: non-coding RNAs come into focus. Cell Communication and Signaling 2020; 18(1): 87. Dostupné z DOI: <http:// dx.doi.org/10.1186/s12964–020–00555–4>.
  16. Napoli N, Pannacciulli N, Vittinghoff E et al. Effect of denosumab on fasting glucose in women with diabetes or prediabetes from the FREEDOM trial. Diabetes Metab Res Rev 2018; 34(4): e2991. Dostupné z DOI: <http://dx.doi.org/10.1002/dmrr.2991>.
  17. Picke A-K, Campbell G, Napoli N et al. Update on the impact of type 2 diabetes mellitus on bone metabolism and material properties. Endocr Connect 2019; 8(3): R55-R70. Dostupné z DOI: <http://dx.doi. org/10.1530/EC-18–0456>.
  18. Jackuliak P, Payer J. Osteoporosis, fractures, and diabetes. Int J Endocrinol 2014; 2014: 820615. Dostupné z DOI: <http://dx.doi. org/10.1155/2014/820615>.
  19. Dallas SL, Prideaux M, Bonewald LF. The osteocyte: an endocrine cell ... and more. Endocr Rev 2013; 34(5): 658–690. Dostupné z DOI: <http://dx.doi.org/10.1210/er.2012–1026>.
  20. Nan S, Yang J, Xie Y et al. Bone function, dysfunction and its role in diseases including critical illness. Int J Biol Sci 2019; 15(4): 776–787. Dostupné z DOI: <http://dx.doi.org/10.7150/ijbs.27063>.
  21. Corrado A, Cici D, Rotondo C et al. Molecular Basis of Bone Aging. Int J Mol S ci 2 020; 2 1(10): 3 679. D ostupné z DOI: < http://dx.doi. org/10.3390/ijms21103679>.
  22. Villarino ME, Sánchez LM, Bozal CB et al. Influence of short-term diabetes on osteocytic lacunae of alveolar bone. A histomorphometric study. Acta Odontol Latinoam 2006; 19(1): 23–28.
  23. Yeung SM, Stephan J, Bakker L et al. Fibroblast Growth Factor 23 and Adverse Clinical Outcomes in Type 2 Diabetes: a Bitter-Sweet Symphony. Curr Diab Rep 2020; 20(10): 5 0. D ostupné z DOI: <http:// dx.doi.org/10.1007/s11892–020–01335–7>.
  24. Hu Z, Liang Y, Zou S et al. Osteoclasts in bone regeneration under type 2 diabetes mellitus. Acta Biomater 2019; 84: 402–413. Dostupné z DOI: <http://dx.doi.org/10.1016/j.actbio.2018.11.052>.
  25. Picke AK, Salbach-Hirsch J, Hintze V et al. Sulfated hyaluronan improves bone regeneration of diabetic rats by binding sclerostin and enhancing osteoblast function. Biomaterials 2016; 96: 11–23. Dostupné z DOI: <http://dx.doi.org/10.1016/j.biomaterials.2016.04.013>.
  26. Xu F, Ye Y-P, Dong Y-H et al. Inhibitory effects of high glucose/ insulin environment on osteoclast formation and resorption in vitro. J Huazhong U niv S ci Technolog M ed S ci 2 013; 3 3(2): 2 44–249. Dostupné z DOI: <http://dx.doi.org/10.1007/s11596–013–1105-z>.
  27. Kim H, Oh B, Park-Min KH. Regulation of Osteoclast Differentiation and Activity by Lipid Metabolism. Cells 2021; 10(1): 89. Dostupné z DOI: <http://dx.doi.org/10.3390/cells10010089>.
  28. Scheller EL, Cawthorn WP, Burr AA et al. Marrow Adipose Tissue: Trimming the Fat. Trends Endocrinol Metab 2016; 27(6): 392–403. <http://dx.doi.org/10.1016/j.tem.2016.03.016>.
  29. Sheu Y, Amati F, Schwartz AV et al. Vertebral bone marrow fat, bone mineral density and diabetes: The Osteoporotic Fractures in Men (MrOS) study. Bone 2017; 97: 299–305. Dostupné z DOI: <http://dx.doi. org/10.1016/j.bone.2017.02.001>.
  30. de Araújo IM, Salmon CE, Nahas AK et al. Marrow adipose tissue spectrum in obesity and type 2 diabetes mellitus. Eur J Endocrinol 2017; 176(1): 21–30. Dostupné z DOI: <http://dx.doi.org/10.1530/EJE- 16–0448>.
  31. Patsch JM, Li X, Baumet T et al. Bone marrow fat composition as a novel imaging biomarker in postmenopausal women with prevalent fragility fractures. J Bone Miner Res 2013; 28(8): 1721–1728. Dostupné z DOI: <http://dx.doi.org/10.1002/jbmr.1950>.
  32. Piccinin MA, Khan ZA. Pathophysiological role of enhanced bone marrow adipogenesis in diabetic complications. Adipocyte 2014; 3(4): 263–272. Dostupné z DOI: <http://dx.doi.org/10.4161/adip.32215>.
  33. Keats EC, Dominguez JM, Grant MB et al. Switch from canonical to noncanonical Wnt signaling mediates high glucose-induced adipogenesis. Stem Cells 2014; 32(6): 1649–1660. Dostupné z DOI: <http:// dx.doi.org/10.1002/stem.1659>.
  34. Okamoto M, Udagawa N, Uehara S et al. Noncanonical Wnt5a enhances Wnt/β-catenin signaling during osteoblastogenesis. Sci Rep 2014; 4: 4493. Dostupné z DOI: <http://dx.doi.org/10.1038/srep04493>.
  35. Cawthorn WP, Adam J Bree AJ, Y Y et al. Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism. B one 2012; 5 0(2): 477–489. Dostupné z DOI: <http://dx.doi.org/10.1016/j.bone.2011.08.010>.
  36. Singh VP, Bali A, Singh N et al. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol 2014; 18(1): 1–14. Dostupné z DOI: <http://dx.doi.org/10.4196/kjpp.2014.18.1.1>.
  37. Kay AM, Simpson CL, Stewart JA. The Role of AGE/RAGE Signaling in Diabetes-Mediated Vascular Calcification. J Diabetes R es 2 016; 2 016: 6 809703. D ostupné z DOI: <http://dx.doi.org/10.1155/2016/6809703>.
  38. Karim L, Bouxsein ML. Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties. Bone 2016; 8 2: 2 1–27. D ostupné z DOI: < http://dx.doi.org/10.1016/j.bone.2015.07.028>.
  39. Asadipooya K, Uy EM. Advanced Glycation End Products (AGEs), Receptor for AGEs, Diabetes, and Bone: Review of the Literature. J Endocr Soc 2019; 3(10): 1799–1818. Dostupné z DOI: <http://dx.doi.org/10.1210/js.2019–00160>.
  40. Furst JR, Bandeira LC, Fan W-W et al. Advanced Glycation Endproducts and Bone Material Strength in Type 2 Diabetes. J Clin Endocrinol M etab 2016; 1 01(6): 2502–2510. Dostupné z DOI: <http://dx.doi. org/10.1210/jc.2016–1437>.                                                                                                                                                                                                                                              Notsu M, Kanazawa I, Takeno A et al. Advanced Glycation End Product 3 (AGE3) Increases Apoptosis and the Expression of Sclerostin by Stimulating TGF-β Expression and Secretion in Osteocyte-Like MLO-Y4-A2 Cells. Calcif Tissue Int 2017; 100(4): 402–411. Dostupné z DOI: <http://dx.doi.org/10.1007/s00223–017–0243-x>.
  41. Sanguineti R, Storace D, Monacelli F et al. Pentosidine effects on human osteoblasts in vitro. Ann N Y Acad Sci 2008; 1126: 166–172. Dostupné z DOI: <http://dx.doi.org/10.1196/annals.1433.044>.
  42. Acevedo C, Sylvia M, Schaible E et al. Contributions of Material Properties and Structure to Increased Bone Fragility for a Given Bone Mass in the UCD-T2DM Rat Model of Type 2 Diabetes. J Bone
  43. Miner R es 2 018; 3 3(6): 1 066–1075. D ostupné z DOI: < http://dx.doi. org/10.1002/jbmr.3393>.
  44. Dong XN, An Qin A, Xu J et al. In situ accumulation of advanced glycation endproducts (AGEs) in bone matrix and its correlation with osteoclastic bone resorption. Bone 2011; 49(2): 174–183. Dostupné z DOI: <http://dx.doi.org/10.1016/j.bone.2011.04.009>.
  45. Tanaka K, Yamaguchi T, Kanazawa I et al. Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells. Biochem Biophys Res Commun 2015; 461(2): 193–199. Dostupné z DOI: <http://dx.doi.org/10.1016/j.bbrc.2015.02.091>.
  46. Litwinoff E, Del Pozo CH, Ramasamy R et al. Emerging Targets for Therapeutic Development in Diabetes and Its Complications: The RAGE Signaling Pathway. Clin Pharmacol Ther 2015; 98(2): 135–144. Dostupné z DOI: <http://dx.doi.org/10.1002/cpt.148>.
  47. Franke S, Siggelkow H, Wolf G et al. Advanced glycation endproducts influence the mRNA expression of RAGE, RANKL and various osteoblastic genes in human osteoblasts. Arch Physiol
  48. Biochem 2007; 113(3): 154–161. Dostupné z DOI: <http://dx.doi. org/10.1080/13813450701602523>.
  49. Zhou Z, Han J-Y, Xi C-X et al. HMGB1 regulates RANKL-induced osteoclastogenesis in a manner dependent on RAGE. J Bone Miner Res 2008; 23(7): 1084–1096. Dostupné z DOI: <http://dx.doi.org/10.1359/ jbmr.080234>.
  50. Philip BK, Childress PJ, Robling AG et al. RAGE supports parathyroid hormone-induced gains in femoral trabecular bone. Am J Physiol Endocrinol Metab 2010; 298(3): E 714-E725. Dostupné z DOI: <http:// dx.doi.org/10.1152/ajpendo.00564.2009>.
  51. Bidwell JP, Yang J, Robling AG. Is HMGB1 an osteocyte alarmin? J Cell Biochem 2008; 103(6): 1671–1680. Dostupné z DOI: <http://dx.doi.org/10.1002/jcb.21572>.
  52. Ida T, Kaku M, Kitami M et al. Extracellular matrix with defective collagen cross-linking affects the differentiation of bone cells. PLoS One 2018; 1 3(9): e 0204306. D ostupné z DOI: <http://dx.doi.org/10.1371/ journal.pone.0204306>.
  53. Birben E, Sahiner UM, Sackesen C et al. Oxidative stress and antioxidant defense. World Allergy Organ J 2012; 5(1): 9–19. Dostupné z DOI: <http://dx.doi.org/10.1097/WOX.0b013e3182439613>.
  54. Shahen VA, Gerbaix M, Koeppenkastrop S et al. Multifactorial effects of hyperglycaemia, hyperinsulinemia and inflammation on bone remodelling in type 2 diabetes mellitus. Cytokine Growth FactorRev 2020; 55: 109–118. Dostupné z DOI: <http://dx.doi.org/10.1016/j. cytogfr.2020.04.001>.
  55. Sarkar PD, Choudhury AB. Relationships between serum osteocalcin levels versus blood glucose, insulin resistance and markers of systemic inflammation in central Indian type 2 diabetic patients. Eur Rev Med Pharmacol Sci 2013; 17(12): 1631–1635.
  56. Frommer K, Andreas Schäffler A, Uwe Lange U et al. 02.03 Influence of free fatty acids on osteoblasts and osteoclasts in rheumatic diseases. Ann Rheum Dis 2017; 76(Suppl 1): A9. Dostupné z DOI: <http://dx.doi.org/10.1136/annrheumdis-2016–211050.3
  57. Kraakman MJ, Murphy AJ, Jandeleit-Dahm K et al., Macrophage Polarization in Obesity and Type 2 Diabetes: Weighing Down Our Understanding of Macrophage Function? Front Immunol 2014; 5: 470. Dostupné z DOI: <http://dx.doi.org/10.3389/fimmu.2014.00470>.
  58. Lee YM, Fujikado N, Manaka H et al. IL-1 plays an important role in the bone metabolism under physiological conditions. Int Immunol 2010; 2 2(10): 8 05–816. D ostupné z DOI: <http://dx.doi.org/10.1093/intimm/dxq431>.
  59. Polzer K, Joosten L, Gasser J et al. Interleukin-1 is essential for systemic inflammatory bone loss. Ann Rheum Dis 2010; 69(01): 284. Dostupné z DOI: <http://dx.doi.org/10.1136/ard.2008.104786>.
  60. Harmer D, Falank C, Reagan MR. Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma. Front Endocrinol (Lausanne) 2019; 9:788. Dostupné z DOI: <http://dx.doi.org/10.3389/fendo.2018.00788>.
  61. Kaneshiro S, Ebina K, Shi K et al. IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro. J Bone Miner Metab 2014; 32(4): 378–392. Dostupné z DOI: <http://dx.doi.org/10.1007/s00774–013–0514–1>.
  62. Spindler MP, Ho AM, Tridgell D et al. Acute hyperglycemia impairs IL-6 expression in humans. Immun Inflamm Dis 2016; 4(1): 91–97. Dostupné z DOI: <http://dx.doi.org/10.1002/iid3.97>.
  63. Idriss HT, Naismith JH. TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech 2000; 5 0(3): 1 84–195. D ostupné z DOI: < http://dx.doi.org/10.1002/1097–0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H>.
  64. Lam J, Takeshita S, Barker JE et al. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000; 106(12): 1481–1488. Dostupné z DOI: <http://dx.doi.org/10.1172/JCI11176>.
  65. Abu-Amer Y, Erdmann J, Alexopoulou L et al. Tumor necrosis factor receptors types 1 and 2 differentially regulate osteoclastogenesis. J Biol Chem 2000; 275(35): 27307–2710. Dostupné z DOI: <http://dx.doi.org/10.1074/jbc.M003886200>.
  66. Osta B, Benedetti G, Miossec P. Classical and Paradoxical Effects of TNF-α on Bone Homeostasis. Front Immunol 2014; 5: 48. Dostupné z DOI: <http://dx.doi.org/10.3389/fimmu.2014.00048>.
  67. Zheng L, Wang W, Ni J et al. Role of autophagy in tumor necrosis factor-α-induced apoptosis of osteoblast cells. J Investig Med 2017; 65(6): 1014– 1020. Dostupné z DOI: <http://dx.doi.org/10.1136/jim-2017–000426>.
  68. Jia Z.-K, Li H-Y, Liang Y-L et al. Monomeric C-Reactive Protein Binds and Neutralizes Receptor Activator of NF-κB Ligand-Induced Osteoclast Differentiation. Front Immunol 2018; 9: 234. <http://dx.doi.org/10.3389/fimmu.2018.00234>.
  69. Cho IJ, Kyoung Hee Choi KH, Chi Hyuk Oh CH et al. Effects of C-reactive protein on bone cells. Life Sci 2016; 145: 1–8. Dostupné z DOI: <http://dx.doi.org/10.1016/j.lfs.2015.12.021>.
  70.  Alonso-Pérez A, Franco-Trepat E, Guillán-Fresco M et al. Role of Toll-Like Receptor 4 on Osteoblast Metabolism and Function. Front Physiol 2018; 9:504. Dostupné z DOI: <http://dx.doi.org/10.3389/fphys.2018.00504>.
  71. Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 2014; 507(7492): 323–328.Dostupné z DOI: <http://dx.doi.org/10.1038/ nature13145>.
  72. Oikawa A, Siragusa M, Quaini F et al. Diabetes mellitus induces bone marrow microangiopathy. Arterioscler Thromb Vasc Biol 2010; 30(3): 498–508. Dostupné z DOI: <http://dx.doi.org/10.1161/ATVBAHA. 109.200154>.
  73. Mangialardi G, Katare R, Oikawa A et al. Diabetes Causes Bone Marrow Endothelial Barrier Dysfunction by Activation of the RhoA– Rho-Associated Kinase Signaling Pathway. Arterioscler Thromb Vasc Biol 2013; 33(3): 555–564. Dostupné z DOI: <http://dx.doi.org/10.1161/ ATVBAHA.112.300424>.
  74. Spinetti G, Cordella D, Fortunato O et al. Global remodeling of the vascular stem cell niche in bone marrow of diabetic patients: implication of the microRNA-155/FOXO3a signaling pathway. Circ Res 2013; 112(3): 510–522. Dostupné z DOI: <http://dx.doi.org/10.1161/CIRCRESAHA. 112.300598>.
  75. Lattanzio S, Francesca Santilli F, Rossella Liani R et al. Circulating dickkopf-1 in diabetes mellitus: association with platelet activation and effects of improved metabolic control and low-dose aspirin. J Am Heart Assoc 2014; 3(4): e001000. Dostupné z DOI: <http://dx.doi. org/10.1161/JAHA.114.001000>.
  76. Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005; 96(9): 939–949. Dostupné z DOI: <http:// dx.doi.org/10.1161/01.RES.0000163635.62927.34>.
Štítky
Clinical biochemistry Paediatric gynaecology Paediatric radiology Paediatric rheumatology Endocrinology Gynaecology and obstetrics Internal medicine Orthopaedics General practitioner for adults Radiodiagnostics Rehabilitation Rheumatology Traumatology Osteology
Článek Farewell to a scientist, physician, philanthropist, and friend Prof. Vladyslav Povoroznyuk
Článek Significance and characteristics of selected genes in the pathogenesis of osteoporosis
Článek Musculoskeletal changes in hypothyroidism
Článek Intramedullar reosteosynthesis of distal femoral periprosthetic fractures
Článek Atraumatic heterotopic ossification after pulmonary failure and prolonged mechanical ventilation: case report
Článek Latest research and news in osteology
Článok vyšiel v časopise

Clinical Osteology

Číslo 2
2021 Číslo 2
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#