Osteoporosis International

, Volume 16, Issue 10, pp 1263–1271 | Cite as

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

  • Jung-Min Koh
  • Young-Ho Khang
  • Chang-Hee Jung
  • Sungjin Bae
  • Duk Jae Kim
  • Yun-Ey Chung
  • Ghi Su Kim
Original Article

Abstract

Factors involved in inflammation are linked with those critical for bone remodeling. We examined the association between serum high sensitivity C-reactive protein (hsCRP) levels and bone mineral density (BMD) in healthy women. Serum concentrations of hsCRP and total alkaline phosphatase (ALP) were measured in premenopausal ( n =3,662) and postmenopausal ( n =1,031) women aged 30 years or older. BMD was measured at the femoral neck and lumbar spine using dual energy X-ray absorptiometry. According to the WHO definition, osteopenia was diagnosed at –2.5< T -score <–1.0 SD, and osteoporosis was diagnosed at T -score ≤–2.5 SD at any sites. Compared with normal subjects, log-transformed serum hsCRP levels were higher in osteopenic and osteoporotic subjects (all, P <0.001) with linearity ( P for trend <0.001), after adjustment for age, BMI and menopausal status. Menopausal status did not have a significant interaction on the association ( P =0.457). In both premenopausal and postmenopausal women, serum total ALP levels were higher in the subjects with higher hsCRP quintiles than those with the lowest quintile (all, P for trend <0.001). Multivariate-adjusted odds ratio (OR) for osteoporosis and osteopenia were 1.35 (95% CI, 1.08 to 1.68) in the highest hsCRP quintile of premenopausal women, and OR for osteoporosis was 1.54 (95% CI, 1.10 to 2.53) in the highest hsCRP quintile of postmenopausal women. These findings suggest that subclinical systemic inflammation may be associated with bone turnover rate and bone mass in healthy women.

Keywords

Bone density Bone turnover C-reactive protein Inflammation Osteoporosis 

References

  1. 1.
    Arron JR, Choi Y (2000) Bone versus immune system. Nature 408:535–536CrossRefPubMedGoogle Scholar
  2. 2.
    Lorenzo J (2000) Interactions between immune and bone cells: new insights with many remaining questions. J Clin Invest 106:749–752Google Scholar
  3. 3.
    Muller B (2002) Cytokine imbalance in non-immunological chronic disease. Cytokine 18:334–339CrossRefGoogle Scholar
  4. 4.
    Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS, Boyce B, Broxmeyer H, Manolagas SC (1992) Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 257:88–91PubMedGoogle Scholar
  5. 5.
    Roodman GD, Kurihara N, Ohsaki Y, Kukita A, Hosking D, Demulder A, Smith JF, Singer FR (1992) Interleukin 6. A potential autocrine/paracrine factor in Paget’s disease of bone. J Clin Invest 89:46–52PubMedGoogle Scholar
  6. 6.
    Yamamoto T, Ozono K, Kasayama S, Yoh K, Hiroshima K, Takagi M, Matsumoto S, Michigami T, Yamaoka K, Kishimoto T, Okada S (1996) Increased IL-6-production by cells isolated from the fibrous bone dysplasia tissues in patients with McCune-Albright syndrome. J Clin Invest 98:30–35Google Scholar
  7. 7.
    Guise TA, Mundy GR (1998) Cancer and bone. Endocr Rev 19:18–54CrossRefGoogle Scholar
  8. 8.
    Devlin RD, Bone HG 3rd, Roodman GD (1996) Interleukin-6: a potential mediator of the massive osteolysis in patients with Gorham-Stout disease. J Clin Endocrinol Metab 81:1893–1897Google Scholar
  9. 9.
    Manolagas SC (2000) Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21:115–137CrossRefPubMedGoogle Scholar
  10. 10.
    Gowen M, Mundy GR (1986) Actions of recombinant interleukin 1, interleukin 2, and interferon-gamma on bone resorption in vitro. J Immunol 136:2478–2482Google Scholar
  11. 11.
    Pacifici R, Rifas L, Teitelbaum S, Slatopolsky E, McCracken R, Bergfeld M, Lee W, Avioli LV, Peck WA (1987) Spontaneous release of interleukin 1 from human blood monocytes reflects bone formation in idiopathic osteoporosis. Proc Natl Acad Sci USA 84:4616–4620Google Scholar
  12. 12.
    Pacifici R, Rifas L, McCracken R, Vered I, McMurtry C, Avioli LV, Peck WA (1989) Ovarian steroid treatment blocks a postmenopausal increase in blood monocyte interleukin 1 release. Proc Natl Acad Sci USA 86:2398–2402Google Scholar
  13. 13.
    Johnson RA, Boyce BF, Mundy GR, Roodman GD (1989) Tumors producing human tumor necrosis factor induced hypercalcemia and osteoclastic bone resorption in nude mice. Endocrinology 124:1424–1427Google Scholar
  14. 14.
    Bertolini DR, Nedwin GE, Bringman TS, Smith DD, Mundy GR (1986) Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature 319:516–518Google Scholar
  15. 15.
    Walsh MC, Choi Y (2003) Biology of the TRANCE axis. Cytokine Growth Factor Rev 14:251–263CrossRefGoogle Scholar
  16. 16.
    Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304–309CrossRefPubMedGoogle Scholar
  17. 17.
    Pepys MB, Baltz ML (1983) Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol 34:141–212PubMedGoogle Scholar
  18. 18.
    Weinhold B, Ruther U (1997) Interleukin-6-dependent and -independent regulation of the human C-reactive protein gene. Biochem J 327:425–429Google Scholar
  19. 19.
    Yoshida N, Ikemoto S, Narita K, Sugimura K, Wada S, Yasumoto R, Kishimoto T, Nakatani T (2002) Interleukin-6, tumour necrosis factor alpha and interleukin-1beta in patients with renal cell carcinoma. Br J Cancer 86:1396–1400CrossRefGoogle Scholar
  20. 20.
    Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, Rubin SM, Ding J, Simonsick EM, Harris TB, Pahor M (2003) Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation 108:2317–2322CrossRefGoogle Scholar
  21. 21.
    Yeh ET, Willerson JT (2003) Coming of age of C-reactive protein: using inflammation markers in cardiology. Circulation 107:370–371CrossRefGoogle Scholar
  22. 22.
    Spector TD, Hart DJ, Nandra D, Doyle DV, Mackillop N, Gallimore JR, Pepys MB (1997) Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum 40:723–727Google Scholar
  23. 23.
    Chang JW, Yang WS, Min WK, Lee SK, Park JS, Kim SB (2002) Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients. Am J Kidney Dis 39:1213–1217CrossRefGoogle Scholar
  24. 24.
    Orimo H, Sugioka Y, Fukunaga M, Muto Y, Hotokebuchi T, Gorai I, Nakamura T, Kushida K, Tanaka H, Ikai T, Oh-hashi Y (1998) Diagnostic criteria of primary osteoporosis. J Bone Miner Metab 16:139–150CrossRefGoogle Scholar
  25. 25.
    Bermudez EA, Rifai N, Buring JE, Manson JE, Ridker PM (2002) Relation between markers of systemic vascular inflammation and smoking in women. Am J Cardiol 89:1117–1119CrossRefGoogle Scholar
  26. 26.
    Devlin J, Lilley J, Gough A, Huissoon A, Holder R, Reece R, Perkins P, Emery P (1996) Clinical associations of dual-energy X-ray absorptiometry measurement of hand bone mass in rheumatoid arthritis. Br J Rheumatol 35:1256–1262CrossRefGoogle Scholar
  27. 27.
    Oelzner P, Franke S, Muller A, Hein G, Stein G (1999) Relationship between soluble markers of immune activation and bone turnover in post-menopausal women with rheumatoid arthritis. Rheumatology (Oxford) 38:841–847Google Scholar
  28. 28.
    Marhoffer W, Stracke H, Masoud I, Scheja M, Graef V, Bolten W, Federlin K (1995) Evidence of impaired cartilage/bone turnover in patients with active ankylosing spondylitis. Ann Rheum Dis 54:556–559PubMedGoogle Scholar
  29. 29.
    MacDonald AG, Birkinshaw G, Durham B, Bucknall RC, Fraser WD (1997) Biochemical markers of bone turnover in seronegative spondylarthropathy: relationship to disease activity. Br J Rheumatol 36:50–53PubMedGoogle Scholar
  30. 30.
    Salamone LM, Whiteside T, Friberg D, Epstein RS, Kuller LH, Cauley JA (1998) Cytokine production and bone mineral density at the lumbar spine and femoral neck in premenopausal women. Calcif Tissue Int 63:466–470CrossRefPubMedGoogle Scholar
  31. 31.
    Cohen-Solal ME, Graulet AM, Denne MA, Gueris J, Baylink D, de Vernejoul MC (1993) Peripheral monocyte culture supernatants of menopausal women can induce bone resorption: involvement of cytokines. J Clin Endocrinol Metab 77:1648–1653Google Scholar
  32. 32.
    Scheidt-Nave C, Bismar H, Leidig-Bruckner G, Woitge H, Seibel MJ, Ziegler R, Pfeilschifter J (2001) Serum interleukin 6 is a major predictor of bone loss in women specific to the first decade past menopause. J Clin Endocrinol Metab 86:2032–2042Google Scholar
  33. 33.
    Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW (1999) C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 19:972–978PubMedGoogle Scholar
  34. 34.
    Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E (2000) Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation 101:2149–2153Google Scholar
  35. 35.
    Van den Berghe G, Van Roosbroeck D, Vanhove P, Wouters PJ, De Pourcq L, Bouillon R (2003) Bone turnover in prolonged critical illness: effect of vitamin D. J Clin Endocrinol Metab 88:4623–4632Google Scholar
  36. 36.
    Manolagas SC, Jilka RL (1995) Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med 332:305–311CrossRefGoogle Scholar
  37. 37.
    Burger H, van Daele PL, Odding E, Valkenburg HA, Hofman A, Grobbee DE, Schutte HE, Birkenhager JC, Pols HA (1996) Association of radiographically evident osteoarthritis with higher bone mineral density and increased bone loss with age. The Rotterdam Study. Arthritis Rheum 39:81–86Google Scholar
  38. 38.
    Hak AE, Pols HA, van Hemert AM, Hofman A, Witteman JC (2000) Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study. Arterioscler Thromb Vasc Biol 20:1926–1931PubMedGoogle Scholar
  39. 39.
    Kado DM, Browner WS, Blackwell T, Gore R, Cummings SR (2000) Rate of bone loss is associated with mortality in older women: a prospective study. J Bone Miner Res 15:1974–1980Google Scholar
  40. 40.
    Jorgensen L, Engstad T, Jacobsen BK (2001) Bone mineral density in acute stroke patients: low bone mineral density may predict first stroke in women. Stroke 32:47–51Google Scholar
  41. 41.
    Wallin R, Wajih N, Greenwood GT, Sane DC (2001) Arterial calcification: a review of mechanisms, animal models, and the prospects for therapy. Med Res Rev 21:274–301Google Scholar
  42. 42.
    Hirose K, Tomiyama H, Okazaki R, Arai T, Koji Y, Zaydun G, Hori S, Yamashina A (2003) Increased pulse wave velocity associated with reduced calcaneal quantitative osteo-sono index: possible relationship between atherosclerosis and osteopenia. J Clin Endocrinol Metab 88:2573–2578CrossRefPubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2005

Authors and Affiliations

  • Jung-Min Koh
    • 1
  • Young-Ho Khang
    • 2
  • Chang-Hee Jung
    • 1
  • Sungjin Bae
    • 1
  • Duk Jae Kim
    • 1
  • Yun-Ey Chung
    • 3
  • Ghi Su Kim
    • 1
  1. 1.Division of Endocrinology and Metabolism, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
  2. 2.Department of Preventive Medicine, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
  3. 3.Department of Internal MedicineSeoul Veterans HospitalSeoulRepublic of Korea

Personalised recommendations