C-reactive protein: a biomarker of secondary osteoporosis and fractures in chronic inflammatory diseases

Authors: J. Štěpán
Authors‘ workplace: Revmatologický ústav Praha ;  Revmatologická klinika 1. LF UK Praha
Published in: Čes. Revmatol., 24, 2016, No. 3, p. 70-77.
Category: Review Article


High sensitivity C-reactive protein (hsCRP), an acute phase serum component involved in inflammation, is associated with factors critical for physiology of musculoskeletal system. An association between circulating hsCRP level and bone mineral density, biochemical bone turnover markers and increased risk of fracture has been observed in rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and other inflammatory diseases. Moreover, subclinical low-grade systemic inflammation may be an important factor in bone turnover rate and bone mass. In healthy individuals, serum hsCRP concentrations greater than upper limit of reference range are associated with higher bone turnover rate and osteoporosis and/or osteopenia, and affect the risk of low impact fractures. CRP is negatively associated with appendicular lean mass

Key words:
High sensitivity C-reactive protein, osteoporosis, sarcopenia, fracture


1. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999; 340(6): 448–54.

2. Weinhold B, Ruther U. Interleukin-6-dependent and -independent regulation of the human C-reactive protein gene. Biochem J 1997; 327 (Pt 2): 425–9.

3. Yoshida N, Ikemoto S, Narita K, et al. Interleukin–6, tumour necrosis factor alpha and interleukin-1beta in patients with renal cell carcinoma. Br J Cancer 2002; 86(9): 1396–400.

4. Jain S, Gautam V, Naseem S. Acute–phase proteins: As diagnostic tool. Journal of pharmacy & bioallied sciences 2011; 3(1): 118–27.

5. Watson J, Round A, Hamilton W. Raised inflammatory markers. BMJ 2012; 344: e454.

6. Chenillot O, Henny J, Steinmetz J, et al. High sensitivity C-reactive protein: biological variations and reference limits. Clin Chem Lab Med 2000; 38(10): 1003–11.

7. Herbeth B, Siest G, Henny J. High sensitivity C-reactive protein (CRP) reference intervals in the elderly. Clin Chem Lab Med 2001; 39(11): 1169–70.

8. Nakamura K, Saito T, Kobayashi R, et al. C-reactive protein predicts incident fracture in community–dwelling elderly Japanese women: the Muramatsu study. Osteoporos Int 2011; 22(7): 2145–50.

9. Harris TB, Ferrucci L, Tracy RP, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 1999; 106(5): 506–12.

10. Ferrucci L, Guralnik JM. Inflammation, hormones, and body composition at a crossroad. Am J Med 2003; 115(6): 501–2.

11. Weaver JD, Huang MH, Albert M, et al. Interleukin–6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology 2002; 59(3): 371–8.

12. McGeer PL, McGeer EG. Inflammation, autotoxicity and Alzheimer disease. Neurobiol Aging 2001; 22(6): 799–809.

13. Kritchevsky SB, Cesari M, Pahor M. Inflammatory markers and cardiovascular health in older adults. Cardiovasc Res 2005; 66(2): 265–75.

14. Giovannini S, Onder G, Liperoti R, et al. Interleukin-6, C-reactive protein, and tumor necrosis factor–alpha as predictors of mortality in frail, community-living elderly individuals. J Am Geriatr Soc 2011; 59(9): 1679–85.

15. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107(3): 499–511.

16. Hradec J. Farmakologické ovlivnění hladiny C-reaktivního proteinu a jeho souvislost s kardiovaskulárním rizikem. Remedia 2009; 19(2): 158–62.

17. Calder PC. n-3 polyunsaturated fatty acids and cytokine production in health and disease. Ann Nutr Metab 1997; 41(4): 203–34.

18. Heller A, Koch T, Schmeck J, et al. Lipid mediators in inflammatory disorders. Drugs 1998; 55(4): 487–96.

19. Stephensen CB. Burden of infection on growth failure. J Nutr 1999; 129(2S Suppl): 534S–8S.

20. Orstavik RE, Haugeberg G, Uhlig T, et al. Incidence of vertebral deformities in 255 female rheumatoid arthritis patients measured by morphometric X-ray absorptiometry. Osteoporos Int 2005; 16(1): 35–42.

21. Huusko TM, Korpela M, Karppi P, et al. Threefold increased risk of hip fractures with rheumatoid arthritis in Central Finland. Ann Rheum Dis 2001; 60(5): 521–2.

22. Walsh NC, Crotti TN, Goldring SR, et al. Rheumatic diseases: the effects of inflammation on bone. Immunol Rev 2005; 208: 228–51.

23. Spector TD, Hall GM, McCloskey EV, et al. Risk of vertebral fracture in women with rheumatoid arthritis. BMJ 1993; 306(6877): 558.

24. van Staa TP, Geusens P, Bijlsma JW, et al. Clinical assessment of the long–term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54(10): 3104–12.

25. Ghozlani I, Ghazi M, Nouijai A, et al. Prevalence and risk factors of osteoporosis and vertebral fractures in patients with ankylosing spondylitis. Bone 2009; 44(5): 772–6.

26. Lange U, Kluge A, Strunk J, et al. Ankylosing spondylitis and bone mineral density––what is the ideal tool for measurement? Rheumatol Int 2005; 26(2): 115–20.

27. Feldtkeller E, Vosse D, Geusens P, et al. Prevalence and annual incidence of vertebral fractures in patients with ankylosing spondylitis. Rheumatol Int 2006; 26(3): 234–9.

28. Vosse D, Landewe R, van der Heijde D, et al. Ankylosing spondylitis and the risk of fracture: results from a large primary care–based nested case–control study. Ann Rheum Dis 2009; 68(12): 1839–42.

29. Gilboe IM, Kvien TK, Haugeberg G, et al. Bone mineral density in systemic lupus erythematosus: comparison with rheumatoid arthritis and healthy controls. Ann Rheum Dis 2000; 59(2): 110–5.

30. Vrieze A, de Greef MH, Wijkstra PJ, et al. Low bone mineral density in COPD patients related to worse lung function, low weight and decreased fat-free mass. Osteoporos Int 2007; 18(9): 1197–202.

31. Graat–Verboom L, van den Borne BE, Smeenk FW, et al. Osteoporosis in COPD outpatients based on bone mineral density and vertebral fractures. J Bone Miner Res 2011; 26(3): 561–8.

32. Biskobing DM. COPD and osteoporosis. Chest 2002; 121(2): 609–20.

33. Jaramillo JD, Wilson C, Stinson DS, et al. Reduced bone density and vertebral fractures in smokers. Men and COPD patients at increased risk. Ann Am Thorac Soc 2015; 12(5): 648–56.

34. Romme EA, Murchison JT, Edwards LD, et al. CT–measured bone attenuation in patients with chronic obstructive pulmonary disease: relation to clinical features and outcomes. J Bone Miner Res 2013; 28(6):1369–77.

35. Larussa T, Suraci E, Nazionale I, et al. Bone mineralization in celiac disease. Gastroenterol Res Pract 2012; 2012: 198025.

36. Zanchetta MB, Longobardi V, Bai JC. Bone and celiac disease. Curr Osteoporos Rep 2016; 14(2): 43–8.

37. Bernstein CN, Blanchard JF, Leslie W, et al. The incidence of fracture among patients with inflammatory bowel disease. A population-based cohort study. Ann Intern Med 2000; 133(10): 795–9.

38. Haugeberg G, Conaghan PG, Quinn M, et al. Bone loss in patients with active early rheumatoid arthritis: infliximab and methotrexate compared with methotrexate treatment alone. Explorative analysis from a 12-month randomised, double-blind, placebo–controlled study. Ann Rheum Dis 2009; 68(12): 1898–901.

39. Schett G, Kiechl S, Weger S, et al. High–sensitivity C-reactive protein and risk of nontraumatic fractures in the Bruneck study. Arch Intern Med 2006; 166(22): 2495–501.

40. Eriksson AL, Moverare–Skrtic S, Ljunggren O, et al. High-sensitivity CRP is an independent risk factor for all fractures and vertebral fractures in elderly men: the MrOS Sweden study. J Bone Miner Res 2014; 29(2): 418–23.

41. Berglundh S, Malmgren L, Luthman H, et al. C–reactive protein, bone loss, fracture, and mortality in elderly women: a longitudinal study in the OPRA cohort. Osteoporos Int 2015; 26(2): 727–35.

42. Pasco JA, Kotowicz MA, Henry MJ, et al. High–sensitivity C–reactive protein and fracture risk in elderly women. JAMA 2006; 296(11): 1353–5.

43. Ahmadi–Abhari S, Luben RN, Wareham NJ, et al. C-reactive protein and fracture risk: European prospective investigation into Cancer Norfolk Study. Bone 2013; 56(1): 67–72.

44. Ishii S, Cauley JA, Greendale GA, et al. C-reactive protein, bone strength, and nine–year fracture risk: data from the Study of Women’s Health Across the Nation (SWAN). J Bone Miner Res 2013; 28(7): 1688–98.

45. Cauley JA, Danielson ME, Boudreau RM, et al. Inflammatory markers and incident fracture risk in older men and women: the health aging and body composition study. J Bone Miner Res 2007; 22(7): 1088–95.

46. Barbour KE, Boudreau R, Danielson ME, et al. Inflammatory markers and the risk of hip fracture: the Women’s Health Initiative. J Bone Miner Res 2012; 27(5): 1167–76.

47. Barbour KE, Lui LY, Ensrud KE, et al. Inflammatory markers and risk of hip fracture in older white women: the study of osteoporotic fractures. J Bone Miner Res 2014; 29(9): 2057–64.

48. Agrawal M, Arora S, Li J, et al. Bone, inflammation, and inflammatory bowel disease. Curr Osteoporos Rep 2011; 9(4): 251–7.

49. Hardy R, Cooper MS. Bone loss in inflammatory disorders. J Endocrinol 2009; 201(3): 309–20.

50. Pacifici R. The immune system and bone. Arch Biochem Biophys 2010; 503(1): 41–53.

51. Li JY, Tawfeek H, Bedi B, et al. Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand. Proc Natl Acad Sci U S A 2011; 108(2): 768–73.

52. Rolland T, Boutroy S, Vilayphiou N, et al. Poor trabecular microarchitecture at the distal radius in older men with increased concentration of high–sensitivity C-reactive protein- the STRAMBO study. Calcif Tissue Int 2012; 90(6): 496–506.

53. Koh JM, Khang YH, Jung CH, et al. Higher circulating hsCRP levels are associated with lower bone mineral density in healthy pre– and postmenopausal women: evidence for a link between systemic inflammation and osteoporosis. Osteoporos Int 2005; 16(10):1263–71.

54. Ding C, Parameswaran V, Udayan R, et al. Circulating levels of inflammatory markers predict change in bone mineral density and resorption in older adults: a longitudinal study. J Clin Endocrinol Metab 2008; 93(5): 1952–8.

55. de Pablo P, Cooper MS, Buckley CD. Association between bone mineral density and C-reactive protein in a large population–based sample. Arthritis Rheum 2012; 64(8): 2624–31.

56. Kim BJ, Yu YM, Kim EN, et al. Relationship between serum hsCRP concentration and biochemical bone turnover markers in healthy pre- and postmenopausal women. Clin Endocrinol (Oxf) 2007; 67(1): 152–8.

57. Ganesan K, Teklehaimanot S, Tran TH, et al. Relationship of C-reactive protein and bone mineral density in community–dwelling elderly females. J Natl Med Assoc 2005; 97(3): 329–33.

58. Wu ZJ, He JL, Wei RQ, et al. C-reactive protein and risk of fracture: a systematic review and dose–response meta–analysis of prospective cohort studies. Osteoporos Int 2015; 26(1): 49–57.

59. Oei L, Campos-Obando N, Dehghan A, et al. Dissecting the relationship between high–sensitivity serum C-reactive protein and increased fracture risk: the Rotterdam Study. Osteoporos Int 2014; 25(4): 1247–54.

60. Ferretti JL, Capozza RF, Cointry GR, et al. Gender-related differences in the relationship between densitometric values of whole-body bone mineral content and lean body mass in humans between 2 and 87 years of age. Bone 1998; 22(6): 683–90.

61. Edwards MH, Dennison EM, Aihie Sayer A, et al. Osteoporosis and sarcopenia in older age. Bone 2015; 80: 126–30.

62. Madeira E, Mafort TT, Madeira M, et al. Lean mass as a predictor of bone density and microarchitecture in adult obese individuals with metabolic syndrome. Bone 2013; 59: 89–92.

63. Novotny SA, Warren GL, Hamrick MW. Aging and the muscle–bone relationship. Physiology (Bethesda) 2015; 30(1): 8–16.

64. Frost M, Nielsen TL, Brixen K, et al. Peak muscle mass in young men and sarcopenia in the ageing male. Osteoporos Int 2015; 26(2): 749–56.

65. Rezaei A, Dragomir–Daescu D. Femoral strength changes faster with age than BMD in both women and Men: A biomechanical study. J Bone Miner Res 2015; 30(12): 2200–6.

66. Morley JE. Sarcopenia: diagnosis and treatment. J Nutr Health Aging 2008; 12(7): 452–6.

67. Cruz–Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010; 39(4): 412–23.

68. Moreland JD, Richardson JA, Goldsmith CH, et al. Muscle weakness and falls in older adults: a systematic review and meta–analysis. J Am Geriatr Soc 2004; 52(7): 1121–9.

69. Pham HM, Nguyen ND, Center JR, et al. Contribution of quadriceps weakness to fragility fracture: A prospective study. J Bone Miner Res 2016; 31(1): 208–14.

70. Franceschi C, Bonafe M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000; 908: 244–54.

71. Giunta S. Exploring the complex relations between inflammation and aging (inflammaging): anti-inflamm-aging remodelling of inflamm- aging, from robustness to frailty. Inflamm Res 2008; 57(12): 558–63.

72. Cesari M, Kritchevsky SB, Baumgartner RN, et al. Sarcopenia, obesity, and inflammation––results from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors study. Am J Clin Nutr 2005; 82(2): 428–34.

73. Hamer M, Molloy GJ. Association of C-reactive protein and muscle strength in the English Longitudinal Study of Ageing. Age (Dordr) 2009; 31(3): 171–7.

74. Schaap LA, Pluijm SM, Deeg DJ, et al. Higher inflammatory marker levels in older persons: associations with 5-year change in muscle mass and muscle strength. J Gerontol A Biol Sci Med Sci 2009; 64(11): 1183–9.

75. Visser M, Pahor M, Taaffe DR, et al. Relationship of interleukin–6 and tumor necrosis factor–alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study. J Gerontol A Biol Sci Med Sci 2002; 57(5): M326–32.

76. Geffken DF, Cushman M, Burke GL, et al. Association between physical activity and markers of inflammation in a healthy elderly population. Am J Epidemiol 2001; 153(3): 242–50.

77. Shanely RA, Nieman DC, Henson DA, et al. Inflammation and oxidative stress are lower in physically fit and active adults. Scand J Med Sci Sports 2013; 23(2): 215–23.

78. Wahlin-Larsson B, Carnac G, Kadi F. The influence of systemic inflammation on skeletal muscle in physically active elderly women. Age (Dordr) 2014; 36(5): 9718.

79. Colbert LH, Visser M, Simonsick EM, et al. Physical activity, exercise, and inflammatory markers in older adults: findings from the Health, Aging and Body Composition Study. J Am Geriatr Soc 2004; 52(7): 1098–104.

80. Alsharidah M, Lazarus NR, George TE, et al. Primary human muscle precursor cells obtained from young and old donors produce similar proliferative, differentiation and senescent profiles in culture. Aging Cell 2013; 12(3): 333–44.

81. George T, Velloso CP, Alsharidah M, et al. Sera from young and older humans equally sustain proliferation and differentiation of human myoblasts. Exp Gerontol 2010; 45(11): 875–81.

82. Zhong W, Zen Q, Tebo J, et al. Effect of human C-reactive protein on chemokine and chemotactic factor–induced neutrophil chemotaxis and signaling. J Immunol 1998; 161(5): 2533–40.

83. Rodriguez W, Mold C, Kataranovski M, et al. C-reactive protein–mediated suppression of nephrotoxic nephritis: role of macrophages, complement, and Fcgamma receptors. J Immunol 2007; 178(1): 530–8.

84. Gershov D, Kim S, Brot N, et al. C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity. J Exp Med 2000; 192(9): 1353–64.

85. Liang YJ, Shyu KG, Wang BW, et al. C-reactive protein activates the nuclear factor-kappaB pathway and induces vascular cell adhesion molecule-1 expression through CD32 in human umbilical vein endothelial cells and aortic endothelial cells. J Mol Cell Cardiol 2006; 40(3): 412–20.

86. Svedbom A, Hernlund E, Ivergård M, et al. Osteoporosis in the European Union: a compendium of country-specific reports. Arch Osteoporos 2013; 8(137): 35–42.

87. Wilkinson CW, Petrie EC, Murray SR, et al. Human glucocorticoid feedback inhibition is reduced in older individuals: evening study. J Clin Endocrinol Metab 2001; 86(2): 545–50.

88. Reynolds RM, Dennison EM, Walker BR, et al. Cortisol secretion and rate of bone loss in a population-based cohort of elderly men and women. Calcif Tissue Int 2005; 77(3): 134–8.

89. Almeida M, Han L, Ambrogini E, et al. Glucocorticoids and tumor necrosis factor alpha increase oxidative stress and suppress Wnt protein signaling in osteoblasts. J Biol Chem 2011; 286(52): 44326–35.

90. Pathak JL, Bakker AD, Luyten FP, et al. Systemic inflammation affects human osteocyte–specific protein and cytokine expression. Calcif Tissue Int 2016; 98(6): 596–608.

91. Bertolini DR, Nedwin GE, Bringman TS, et al. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature 1986; 319(6053): 516–8.

92. Orsolini G, Adami G, Adami S, et al. Short-term effects of TNF inhibitors on bone turnover markers and bone mineral density in rheumatoid arthritis. Calcif Tissue Int 2016; 98(6): 580–5.

93. Shea B, Bonaiuti D, Iovine R, et al. Cochrane Review on exercise for preventing and treating osteoporosis in postmenopausal women. Eura Medicophys 2004; 40(3): 199–209.

94. Kim SY, Schneeweiss S, Liu J, et al. Risk of osteoporotic fracture in a large population-based cohort of patients with rheumatoid arthritis. Arthritis Res Ther 2010; 12(4): R154.

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