Comprehensive assessment of tissue and serum parameters of bone metabolism in a series of orthopaedic patients

Autoři: Jan Gunsser aff001;  Regina Hermann aff002;  Andreas Roth aff003;  Amelie Lupp aff001
Působiště autorů: Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany aff001;  Department of Internal Medicine 2, HELIOS Hospital Erfurt, Erfurt, Germany aff002;  Orthopaedic Professorship of the University Hospital Jena, Orthopaedic Department of the Waldkliniken, former Rudolf Elle Hospital, Eisenberg, Germany aff003;  Department of Orthopaedics, Traumatology and Plastic Surgery, Division of Endoprosthetics/Orthopaedics, University Hospital Leipzig, Leipzig, Germany aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


Bone diseases represent an increasing health burden worldwide, and basic research remains necessary to better understand the complexity of these pathologies and to improve and expand existing prevention and treatment approaches. In the present study, 216 bone samples from the caput femoris and collum femoris of 108 patients with degenerative or dysplastic coxarthrosis, hip fracture, or osteonecrosis were evaluated for the proportion of trabecular bone (TB) and expression of parathyroid hormone (PTH) type 1 receptor (PTH1R), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL). Serum levels of PTH, OPG, soluble RANKL (sRANKL), alkaline phosphatase (AP), osteocalcin, total procollagen type-1 intact N-terminal propeptide (TP1NP), tartrate-resistant acid phosphatase type 5b (TRAP5b), sclerostin, and C-telopeptide of type-1 collagen (ICTP) were also determined. Age was positively correlated with serum levels of PTH, OPG, and sclerostin but negatively associated with TB and sRANKL. Women exhibited less TB, lower sclerostin and ICTP, and higher TRAP5b. Impaired kidney function was associated with shorter bone decalcification time, less TB, lower sRANKL, and higher serum PTH, OPG, and sclerostin. Furthermore, correlations were observed between bone PTH1R and OPG expression and between serum PTH, OPG, and AP. There were also positive correlations between serum OPG and TP1NP; serum OPG and sclerostin; serum AP, osteocalcin, and TRAP5b; and serum sclerostin and ICTP. Serum OPG was negatively associated with sRANKL. In summary, clear relationships between specific bone metabolism markers were observed, and distinct influences of age, sex, and kidney function, thus underscoring their suitability as diagnostic or prognostic markers.

Klíčová slova:

Bone fracture – Bone remodeling – Creatinine – Glomerular filtration rate – Osteoblasts – Osteocalcin – Osteocytes – Parathyroid hormone


1. U.S. Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Office of the Surgeon General. 2004.

2. Lupsa BC, Insogna K. Bone Health and osteoporosis. Endocinol Metab Clin N Am. 2015;44:517–530.

3. Pisani P, Renna MD, Conversano F, Casciaro E, Di Paola M, Quarta E, et al. Major osteoporotic fragility fractures: risk factor updates and social impact. World J Orthop. 2016;7:171–181. doi: 10.5312/wjo.v7.i3.171 27004165

4. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinol. 2001;142:5050–5055.

5. Ma YL, Cain RL, Halladay DL, Yang X, Zeng Q, Miles RR, et al. Catabolic effects of continuous human PTH (1–38) in vivo is associated with sustained stimulation of RANKL and inhibition of OPG and gene-associated bone formation. Endocrinology. 2001;142:4047–4054. doi: 10.1210/endo.142.9.8356 11517184

6. Kostenuik PJ, Shalhoub V. Osteoprotegerin: a physiological and pharmacological inhibitor of bone resorption. Curr Pharm Des. 2001;7:613–635. doi: 10.2174/1381612013397807 11375772

7. Huang JC, Sakata T, Pfleger LL, Bencsik M, Halloran BP, Bikle DD, et al. PTH differentially regulates expression of RANKL and OPG. J Bone Miner Res. 2004;19:235–244. doi: 10.1359/JBMR.0301226 14969393

8. Kaemmerer D, Sänger J, Arsenic R, D’Haese JG, Neumann J, Schmitt-Graeff A, et al. Evaluation of somatostatin, CXCR4 chemokine and endothelin A receptor expression in a large set of paragangliomas. Oncotarget. 2017;8:89958–89969. doi: 10.18632/oncotarget.21194 29163802

9. Lupp A, Klenk C, Röcken C, Evert M, Mawrin C, Schulz S. Immunohistochemical identification of the PTHR1 in normal and neoplastic human tissues. Mol Endocrinol. 2010;162:979–986.

10. Bressot C, Meunier PJ, Chapuy MC, Lejeune E, Edouard C, Darby AJ. Histomorphometric profile, pathophysiology and reversibility of cortico-steroid-induced osteoporosis. Metab Bone Dis Rel Res. 1979;1:303–311.

11. Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987;8:138–140. 3303008

12. Bellido T. Osteocyte-driven bone remodeling. Calcif Tissue Int. 2014;94:25–34. doi: 10.1007/s00223-013-9774-y 24002178

13. Goldring SR. The osteocyte: key player in regulating bone turnover. RMD Open. 2014;1:e000049.

14. Schaffler MB, Cheung WY, Majeska R, Kennedy O. Osteocytes: master orchestrators of bone. Calcif Tissue Int. 2014;94:5–24. doi: 10.1007/s00223-013-9790-y 24042263

15. Rao LG, Murray TM, Heersche J. Immunohistochemical demonstration of parathyroid hormone binding to specific cell types in fixed rat bone tissue. Endocrinology. 1983;113:805–810. doi: 10.1210/endo-113-2-805 6307656

16. Rouleau MF, Mitchell J, Goltzman D. In vivo distribution of parathyroid hormone receptors in bone: evidence that a predominant osseous target cell is not the mature osteoblast. Endocrinol. 1988;123:187–191.

17. Lee K, Deeds JD, Chiba S, Un-No M, Bond AT, Segre GV. Parathyroid hormone induces sequential c-fos expression in bone cells in vivo: in situ localisation of its receptor and c-fos messenger ribonucleic acids. Endocrinol. 1994;134:441–450.

18. Fermor B, Skerry TM. PTH/PTHrP receptor expression on osteoblasts and osteocytes but not resorbing bone surfaces in growing rats. J Bone Miner Res. 1995;10:1935–1943. doi: 10.1002/jbmr.5650101213 8619374

19. Picton ML, Moore PR, Mawer EB, Houghton D, Freemont AJ, Hutchinson AJ, et al. Down-regulation of human osteoblast PTH/PTHrP receptor mRNA in end-stage renal failure. Kidney Int. 2000;58:1440–1449. doi: 10.1046/j.1523-1755.2000.00306.x 11012879

20. Ikeda T, Utsuyama M, Hirokawa K. Expression profiles of receptor activator of nuclear factor κB ligand, receptor activator of nuclear factor κB, and osteoprotegerin messenger RNA in aged and ovariectomized rat bones. J Bone Miner Res. 2001;16:1416–1425. doi: 10.1359/jbmr.2001.16.8.1416 11499864

21. Langub MC, Monier-Faugere MC, Qi Q, Geng Z, Koszewski NJ, Malluche HH. Parathyroid hormone/parathyroid hormone-related peptide type 1 receptor in human bone. J Bone Miner Res. 2001;16:448–456. doi: 10.1359/jbmr.2001.16.3.448 11277262

22. Silvestrini G, Ballanti P, Patacchioli F, Leopizzi M, Gualtieri N, Monnazzi P, et al. Detection of osteoprotegerin (OPG) and its ligand (RANKL) mRNA and protein in femur and tibia of the rat. J Mol Hist. 2004;36:59–67.

23. Carda C, Silvestrini G, Gomez de Ferraris ME, Peydró A, Bonucci E. Osteoprotegerin (OPG) and RANKL expression and distribution in developing human craniomandibular joint. Tissue & Cell. 2005;37:247–255.

24. O´Brien CA, Plotkin LI, Galli C, Goellner JJ, Gortazar AR, Allen MR, et al. Control of bone mass and remodeling by PTH receptor signaling in osteocytes. PLoS One. 2008;3:e2942. doi: 10.1371/journal.pone.0002942 18698360

25. Rhee Y, Allen MR, Condon K, Lezcano V, Ronda AC, Galli C, et al. PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling. J Bone Miner Res. 2011;26:1035–1046. doi: 10.1002/jbmr.304 21140374

26. Powell WF Jr, Barry KJ, Tulum I, Kobayashi T, Harris SE, Bringhurst FR, et al. Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. J Endocrinol. 2011;209:21–32. doi: 10.1530/JOE-10-0308 21220409

27. Honma M, Ikebuchi Y, Kariya Y, Hayashi M, Hayashi N, Aoki S, et al. RANKL subcellular trafficking and regulatory mechanisms in osteocytes. J Bone Miner Res. 2013;28:1936–1949. doi: 10.1002/jbmr.1941 23529793

28. Saini V, Marengi DA, Barry KJ, Fulzele KS, Heiden E, Liu X, et al. Parathyroid hormone (PTH)/PTH-related peptide type 1 receptor (PPR) signaling in osteocytes regulates anabolic and catabolic skeletal responses to PTH. J Biol Chem. 2013;288:20122–20134. doi: 10.1074/jbc.M112.441360 23729679

29. Kartsogiannis V, Zhou H, Horwood NJ, Thomas RJ, Hards DK, Quinn JM, et al. Localization of RANKL (receptor activator of NF kappa B ligand) mRNA and protein in skeletal and extraskeletal tissues. Bone. 1999;25:525–534. doi: 10.1016/s8756-3282(99)00214-8 10574572

30. Oshiro T, Shibasaki Y, Martin TJ, Sasaki T. Immunolocalization of vacuolar-type H+-ATPase, cathepsin K, matrix metalloproteinase-9, and receptor activator of NFkappaB ligand in odontoclasts during physiological root resorption of human deciduous teeth. Anat Rec. 2001;264:305–311. doi: 10.1002/ar.1127 11596012

31. Dempster DW, Hughes-Begos CE, Plavetic-Chee K, Brandao-Burch A, Cosman F, Nieves J, et al. Normal human osteoclasts formed from peripheral blood monocytes express PTH type 1 receptors and are stimulated by PTH in the absence of osteoblasts. J Cell Biochem. 2005;95:139–148. doi: 10.1002/jcb.20388 15723294

32. Silve CM, Hradek GT, Jones AL, Arnaud CD. Parathyroid hormone receptor in intact embryonic chicken bone: characterization and cellular localization. J Cell Biol. 1982;94:379–386. doi: 10.1083/jcb.94.2.379 6286691

33. Nakamura H, Tsuji T, Hirata A, Yamamoto T. Localization of osteoprotegerin (OPG) on bone surfaces and cement lines in rat tibia. J Histochem Cytochem. 2002;50:945–953. doi: 10.1177/002215540205000708 12070273

34. Burkhardt R, Kettner G, Böhm W, Schmidmeier M, Schlag R, Frisch B, et al. Changes in trabecular bone, hematopoieses and bone marrow vessels in aplastic anemia, primary osteoporosis, and old age: a comparative histomorphometric study. Pergamon J. 1987;8:157–164.

35. Seeman E. Pathogenesis of bone fragility in women and men. Lancet. 2002;359:1841–1850. doi: 10.1016/S0140-6736(02)08706-8 12044392

36. Seeman E. Invited Review: Pathogenesis of osteoporosis. J Appl Physiol. 2003;95:2142–2151. doi: 10.1152/japplphysiol.00564.2003 14555675

37. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12:1260–1268. doi: 10.1101/gad.12.9.1260 9573043

38. Carter JL O´Riordan SE, Eaglestone GL, Delaney MP, Lamb EJ. Bone mineral metabolism and its relationship to kidney disease in a residential care home population: a cross-sectional study. Nephro Dial Transplant. 2008;23:3554–3565.

39. Findlay D, Chehade M, Tsangari H, Neale S, Hay S, Hopwood B, et al. Circulating RANKL is inversely correlated to RANKL mRNA levels in bone in osteoarthritic males. Arth Res Ther. 2008;10:R2.

40. Samelson EJ, Broe KE, Demissie S, Beck TJ, Karasik D, Kathiresan S, et al. Increased plasma osteoprotegerin concentrations are associated with indices of bone strength of the hip. J Clin Endocrinol Metab. 2008;93:1789–1795. doi: 10.1210/jc.2007-2492 18303076

41. Uemura H, Yasui T, Miyatani Y, Yamada M, Hiyoshi M, Arisawa K, et al. Circulating profiles of osteoprotegerin and soluble receptor activator of nuclear factor kappaB ligand in post-menopausal women. J Endocrinol Invest. 2008;31:163–168. doi: 10.1007/bf03345584 18362509

42. Zhao HY, Liu JM, Ning G, Zhao YJ, Chen Y, Sun LH, et al. Relationships between insulin-like growth factor-I (IGF-I) and OPG, RANKL, bone mineral density in healthy Chinese women. Osteoporos Int. 2008;19:221–226. doi: 10.1007/s00198-007-0440-y 17703270

43. Nabipour I, Larijani B, Vahdat K, Assadi M, Jafari SM, Ahmadi E, et al. Relationships among serum receptor of nuclear factor-kappaB ligand, osteoprotegerin, high-sensitivity C-reactive protein, and bone mineral density in postmenopausal women: osteoimmunity versus osteoinflammatory. Menopause. 2009;16:950–955. doi: 10.1097/gme.0b013e3181a181b8 19387415

44. LaCroix AZ, Jackson RD, Aragaki A, Kooperberg C, Cauley JA, Chen Z, et al. OPG and sRANKL serum levels and incident hip fracture in postmenopausal Caucasian women in the Women's Health Initiative Observational Study. Bone. 2013;56: doi: 10.1016/j.bone.2013.05.018 23735608

45. Piatek S, Adolf D, Wex T, Halangk W, Klose S, Westphal S, et al. Multiparameter analysis of serum levels of C-telopeptide crosslaps, bone-specific alkaline phosphatase, cathepsin K, osteoprotegerin and receptor activator of nuclear factor κB ligand in the diagnosis of osteoporosis. Maturitas. 2013;74:363–368. doi: 10.1016/j.maturitas.2013.01.005 23391500

46. Di Monaco M, Castiglioni C, Vallero F, Di Monaco R, Tappero R. Parathyroid-hormone variance is only marginally explained by a panel of determinants: a cross-sectional study of 909 hip-fracture patients. J Bone Miner Metab. 2014;32:573–579. doi: 10.1007/s00774-013-0532-z 24202062

47. Yano K, Tsuda E, Washida N, Kobayashi F, Goto M, Harada A, et al. Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis. J Bone Miner Res. 1999;14:518–527. doi: 10.1359/jbmr.1999.14.4.518 10234572

48. Fahrleitner-Pammer A, Dobnig H, Piswanger-Soelkner C, Bonelli C, Dimai HP, Leb G, et al. Osteoprotegerin serum levels in women: correlation with age, bone mass, bone turnover and fracture status. Wien Klin Wochenschr. 2003;115:291–297. doi: 10.1007/bf03040334 12793029

49. Liu JM, Zhao HY, Ning G, Zhao YJ, Chen Y, Zhang ZH, et al. Relationships between the changes of serum levels of OPG and RANKL with age, menopause, bone biochemical markers and bone mineral density in Chinese women aged 20–75. Calcif Tissue Int. 2005;76:1–6. doi: 10.1007/s00223-004-0007-2 15455183

50. Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res. 2004;95:1046–1057. doi: 10.1161/01.RES.0000149165.99974.12 15564564

51. Kiechl S, Schett G, Wenning G, Redlich K, Oberhollenzer M, Mayr A, et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation. 2004;109:2175–2180. doi: 10.1161/01.CIR.0000127957.43874.BB 15117849

52. Van Campenhout A, Golledge J. Osteoprotegerin, vascular calcification and atherosclerosis. Atherosclerosis. 2009;204:321–329. doi: 10.1016/j.atherosclerosis.2008.09.033 19007931

53. Venuraju SM, Yerramasu A, Corder R, Lahiri A. Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidity. J Am Coll Cardiol. 2010;55:2049–2061. doi: 10.1016/j.jacc.2010.03.013 20447527

54. Augoulea A, Vrachnis N, Lambrinoudaki I, Dafopoulos K, Iliodromiti Z, Daniilidis A, et al. Osteoprotegerin as a marker of atherosclerosis in diabetic patients. Int J Endocrinol. 2013:182060. doi: 10.1155/2013/182060 23401681

55. Tschiederer L, Willeit J, Schett G, Kiechl S, Willeit P. Osteoprotegerin concentration and risk of cardiovascular outcomes in nine general population studies: Literature-based meta-analysis involving 26,442 participants. PLOS ONE. 2017;

56. Rochette L, Meloux A, Rigal E, Zeller M, Cottin Y, Vergely C. The role of osteoprotegerin and its ligands in vascular function. Int J Mol Sci. 2019;20:705. doi: 10.3390/ijms20030705 30736365

57. Ardawi MS, Al-Kadi HA, Rouzi AA, Qari MH. Determinants of serum sclerostin in healthy pre- and postmenopausal women. J Bone Miner Res. 2011;26: 2812–2822. doi: 10.1002/jbmr.479 21812027

58. Mödder UI, Hoey KA, Amin S, McCready LK, Achenbach SJ, Riggs BL et al. Relation of age, gender, and bone mass to circulating sclerostin levels in women and men. J Bone Miner Res. 2011;26:373–279. doi: 10.1002/jbmr.217 20721932

59. Roforth MM, Fujita K, McGregor UI, Kirmany S, McCready LK, Peterson JM, et al. Effects of age on bone mRNA levels of sclerostin and other genes relevant to bone metabolism in humans. Bone. 2013;59:1–6. doi: 10.1016/j.bone.2013.10.019 24184314

60. Schett G, Kiechl S, Redlich K, Oberhollenzer F, Weger S, Egger G, et al. Soluble RANKL and risk of nontraumatic fracture. JAMA. 2004;291:1108–1113. doi: 10.1001/jama.291.9.1108 14996780

61. Doumouchtsis KK, Kostakis AI, Doumouchtsis SK, Tziamalis MP, Tsigris C, Kostaki MA, et al. sRANKL/osteoprotegerin complex and biochemical markers in a cohort of male and female hemodialysis patients. J Endocrinol Invest. 2007;30:762. doi: 10.1007/BF03350814 17993768

62. Naumnik B, Klejna K, Koc-Zorawska E, Mysliwiec M. Age and gender predict OPG level and OPG/sRANKL ratio in maintenance hemodialysis patients. Adv Mol Sci. 2013;58:382–387.

63. Arrighi HM, Hsieh A, Wong H. Osteoprotegerin levels in healthy volunteers. Bone. 1998;23 (Suppl 1):T411.

64. Khosla S, Arrighi HM, Melton LJ, Atkinson EJ, O’Fallon WM, Dunstan C, et al. Correlates of osteoprotegerin levels in women and men. Osteoporos Int. 2002;13:394–399. doi: 10.1007/s001980200045 12086350

65. Bernstein CN, Sargent M, Leslie WD. Serum osteoprotegerin is increased in Crohn’s disease: a population-based case control study. Inflamm Bowel Dis. 2005;11:325–330. doi: 10.1097/ 15803021

66. Jørgensen L, Vik A, Emaus N, Brox J, Hansen JB, Mathiesen E, et al. Bone loss in relation to serum levels of osteoprotegerin and nuclear factor-κB ligand: The Tromsø Study. Osteoporos Int. 2010;21:931–938. doi: 10.1007/s00198-009-1035-6 19701599

67. Shaarawy M, Fathy SA, Mehany NL, Hindy OW. Circulating levels of osteoprotegerin and receptor actvator of NF-κB ligand in patients with chronic renal failure. Clin Chem Lab Med. 2007;45:1498–1503. doi: 10.1515/CCLM.2007.306 17970704

68. Osorio A, Ortega E, Torres JM, Sanchez P, Ruiz-Requena E. Mineral-bone metabolism markers in young hemodialysis patients. Clin Biochem. 2011;44:1425–1428. doi: 10.1016/j.clinbiochem.2011.08.1143 21933667

69. Patel S, Barron JL, Mirzazedeh M, Gallagher H, Hyer S, Cantor T, et al. Changes in bone mineral parameters, vitamin D metabolites, and PTH measurements with varying chronic kidney disease stages. J Bone Miner Metab. 2011;29:71–79. doi: 10.1007/s00774-010-0192-1 20521154

70. Vikrant S, Parashar A. Prevalence and severity of disordered mineral metabolism in patients with chronic kidney disease: a study from a tertiary care hospital in India. Indian J Endocrinol Metab. 2016;20:460–467. doi: 10.4103/2230-8210.183457 27366711

71. Coen G, Ballanti P, Balducci A, Calabria S, Fischer MS, Jankovic L, et al. Serum osteoprotegerin and renal osteodystrophy. Nephrol Dial Transplant. 2002;17:233–238. doi: 10.1093/ndt/17.2.233 11812872

72. Mansour A, Aboeerad M, Qorbani M, Taheri APH, Pajouhi M, Keshtkar AA, et al. Association between low bone mass and the serum RANKL and OPG in patients with nephrolithiasis. BMC Nephrology. 2018;19:172. doi: 10.1186/s12882-018-0960-z 29996796

73. Silva BC, Bilezikian JP. Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol. 2015;22:41–50. doi: 10.1016/j.coph.2015.03.005 25854704

74. Mezquita-Raya P, de la Higuera M, García DF, Alonso G, Ruiz-Requena ME, de Dios Luna J, et al. The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women. Osteopros Int. 2005;16:1368–1374.

75. Garnero P, Sornay-Rendu E, Claustrat B, Delmas PD. 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. doi: 10.1359/jbmr.2000.15.8.1526 10934651

76. Szalay F, Hegedus D, Lakatos PL, Tornai I, Bajnok E, Dunkel K, et al. High serum osteoprotegerin and low RANKL in primary biliary cirrhosis. J Hepatol. 2003;38:395–400. doi: 10.1016/s0168-8278(02)00435-x 12663228

77. Kim JG, Kim JH, Lee DO, Kim H, Kim JY, Suh CS, et al. Changes in serum levels of osteoprotegerin and soluble receptor activator for nuclear factor kappaB ligand after estrogen-progestogen therapy and their relationships with changes in bone mass in postmenopausal women. Menopause. 2008;15:357–362. doi: 10.1097/gme.0b013e318133a153 17925661

78. Bauer DC, Garnero P, Harrison SL, Cauley JA, Eastell R, Ensrud KE, et al. Biochemical markers of bone turnover, hip bone loss, and fracture in older men: the MrOS study. J Bone Miner Res. 2009;24:2032–2038. doi: 10.1359/jbmr.090526 19453262

79. Rosen CJ, Chesnut CH III and Mallinak NJ. The predictive value of biochemical markers of bone turnover for bone mineral density in early postmenopausal women treated with hormone replacement or calcium supplementation. J Clin Endocrinol Metab. 1997;82:1904–1910. doi: 10.1210/jcem.82.6.4004 9177404

80. Sornay-Rendu E, Munoz F, Garnero P, Duboeuf F, Delmas PD. Identification of osteopenic women at high risk of fracture: the OFELY study. J Bone Miner Res. 2005;20:1813–1819. doi: 10.1359/JBMR.050609 16160738

81. Yoshimura N, Muraki S, Oka H, Kawaguchi H, Nakamura K, Akune KT. Biochemical markers of bone turnover as predictors of osteoporosis and osteoporotic fractures in men and women: 10-year follow-up of the Taiji cohort. Mod Rheumatol. 2011;21:608–620. doi: 10.1007/s10165-011-0455-2 21512822

82. Johansson H, Odén A, Kanis JA, McCloskey EV, Morris HA, Cooper C, et al. A meta-analysis of reference markers of bone turnover for prediction of fracture. Calcif Tissue Int. 2014;94:560–567. doi: 10.1007/s00223-014-9842-y 24590144

83. Findlay DM, Atkins GJ. Relationship between serum RANKL and RANKL in bone. Osteoporos Int. 2011;22:2597–2602. doi: 10.1007/s00198-011-1740-9 21850548

Článek vyšel v časopise


2019 Číslo 12
Nejčtenější tento týden