Osteoporosis International

, Volume 18, Issue 3, pp 251–259

Vascular calcification and osteoporosis—from clinical observation towards molecular understanding

  • L. C. Hofbauer
  • C. C. Brueck
  • C. M. Shanahan
  • M. Schoppet
  • H. Dobnig
Review

Abstract

Patients with osteoporosis frequently suffer from vascular calcification, which was shown to predict both cardiovascular morbidity/mortality and osteoporotic fractures. Various common risk factors and mechanisms have been suggested to cause both bone loss and vascular calcification, including aging, estrogen deficiency, vitamin D and K abnormalities, chronic inflammation and oxidative stress. Major breakthroughs in molecular and cellular biology of bone metabolism and the characterization of knockout animals with deletion of bone-related genes have led to the concept that common signaling pathways, transcription factors and extracellular matrix interactions may account for both skeletal and vascular abnormalities. For example, mice that lack the cytokine decoy receptor osteoprotegerin or the hormone Klotho display a combined osteoporosis-arterial calcification phenotype. In this review, we summarize the current data and evaluate potential mechanisms of the osteoporosis-arterial calcification syndrome. We propose a unifying hypothesis of vascular calcification that combines both active and passive mechanisms of vascular mineralization with aspects of bone resorption and age-related changes.

Keywords

Fetuin-A Klotho Matrix Gla protein Osteoporosis Osteoprotegerin Vascular calcification 

References

  1. 1.
    Kiel DP, Kauppila LI, Cupples LA, Hannan MT, O’Donnell CJ, Wilson PW (2001) Bone loss and the progression of abdominal aortic calcification over a 25-year period: the Framingham heart study. Calcif Tissue Int 68:271–276. Erratum in: Calcif Tissue Int (2004) 74:208PubMedCrossRefGoogle Scholar
  2. 2.
    Schulz E, Arfai K, Liu X, Sayre J, Gilsanz V (2004) Aortic calcification and the risk of osteoporosis and fractures. J Clin Endocrinol Metab 89:4246–4253PubMedCrossRefGoogle Scholar
  3. 3.
    Bagger YZ, Tanko LB, Alexandersen P, Qin G, Christiansen C, Prospective Epidemiological Risk Factors Study Group (2006) Radiographic measure of aorta calcification is a site-specific predictor of bone loss and fracture risk at the hip. J Intern Med 259:598–605PubMedCrossRefGoogle Scholar
  4. 4.
    Tanko LB, Bagger YZ, Christiansen C (2003) Low bone mineral density in the hip as a marker of advanced atherosclerosis in elderly women. Calcif Tissue Int 73:15–20PubMedCrossRefGoogle Scholar
  5. 5.
    Pennisi P, Signorelli SS, Riccobene S, Celotta G, Di Pino L, La Malfa T, Fiore CE (2004) Low bone density and abnormal bone turnover in patients with atherosclerosis of peripheral vessels. Osteoporos Int 15:389–395PubMedCrossRefGoogle Scholar
  6. 6.
    Demer LL (2002) Vascular calcification and osteoporosis: inflammatory responses to oxidized lipids. Int J Epidemiol 31:737–741PubMedCrossRefGoogle Scholar
  7. 7.
    Watson KE, Abrolat ML, Malone LL, Hoeg JM, Doherty T, Detrano R, Demer LL (1997) Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation 96:1755–1760PubMedGoogle Scholar
  8. 8.
    Parhami F, Morrow AD, Balucan J, Leitinger N, Watson AD, Tintut Y, Berliner JA, Demer LL (1997) Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol 17:680–687PubMedGoogle Scholar
  9. 9.
    Jie KG, Bots ML, Vermeer C, Witteman JC, Grobbee DE (1996) Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study. Calcif Tissue Int 59:352–356PubMedCrossRefGoogle Scholar
  10. 10.
    Doherty TM, Fitzpatrick LA, Inoue D, Qiao JH, Fishbein MC, Detrano RC, Shah PK, Rajavashisth TB (2004) Molecular, endocrine, and genetic mechanisms of arterial calcification. Endocr Rev 25:629–672PubMedCrossRefGoogle Scholar
  11. 11.
    Shanahan CM (2005) Mechanisms of vascular calcification in renal disease. Clin Nephrol 63:146–157PubMedGoogle Scholar
  12. 12.
    Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL (1994) High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest 93:2393–2402PubMedCrossRefGoogle Scholar
  13. 13.
    Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51PubMedCrossRefGoogle Scholar
  14. 14.
    Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268PubMedCrossRefGoogle Scholar
  15. 15.
    Thompson GR, Partridge J (2004) Coronary calcification score: the coronary-risk impact factor. Lancet 363:557–559PubMedCrossRefGoogle Scholar
  16. 16.
    Schaefer S (2002) Will helical CT replace electron beam CT in the assessment of coronary calcium? Prev Cardiol 5:84–86PubMedCrossRefGoogle Scholar
  17. 17.
    Stanford W, Thompson BH, Burns TL, Heery SD, Burr MC (2004) Coronary artery calcium quantification at multi-detector row helical CT versus electron-beam CT. Radiology 230:397–402PubMedCrossRefGoogle Scholar
  18. 18.
    Schousboe JT, Wilson KE, Kiel DP (2006) Detection of abdominal aortic calcification with lateral spine imaging using DXA. J Clin Densitom 9:302–308PubMedCrossRefGoogle Scholar
  19. 19.
    Eisman JA (1999) Genetics of osteoporosis. Endocr Rev 20:788–804PubMedCrossRefGoogle Scholar
  20. 20.
    Kawano K, Ogata N, Chiano M, Molloy H, Kleyn P, Spector TD, Uchida M, Hosoi T, Suzuki T, Orimo H, Inoue S, Nabeshima Y, Nakamura K, Kuro-o M, Kawaguchi H (2002) Klotho gene polymorphisms associated with bone density of aged postmenopausal women. J Bone Miner Res 17:1744–1751PubMedCrossRefGoogle Scholar
  21. 21.
    Imamura A, Okumura K, Ogawa Y, Murakami R, Torigoe M, Numaguchi Y, Murohara T (2006) Klotho gene polymorphism may be a genetic risk factor for atherosclerotic coronary artery disease but not for vasospastic angina in Japanese. Clin Chim Acta 371:66–70PubMedCrossRefGoogle Scholar
  22. 22.
    Langdahl BL, Carstens M, Stenkjaer L, Eriksen EF (2002) Polymorphisms in the osteoprotegerin gene are associated with osteoporotic fractures. J Bone Miner Res 17:1245–1255PubMedCrossRefGoogle Scholar
  23. 23.
    Soufi M, Schoppet M, Sattler AM, Herzum M, Maisch B, Hofbauer LC, Schaefer JR (2004) Osteoprotegerin gene polymorphisms in men with coronary artery disease. J Clin Endocrinol Metab 89:3764–3768PubMedCrossRefGoogle Scholar
  24. 24.
    Brandstrom H, Stiger F, Lind L, Kahan T, Melhus H, Kindmark A (2002) A single nucleotide polymorphism in the promoter region of the human gene for osteoprotegerin is related to vascular morphology and function. Biochem Biophys Res Commun 293:13–17PubMedCrossRefGoogle Scholar
  25. 25.
    Taylor BC, Schreiner PJ, Doherty TM, Fornage M, Carr JJ, Sidney S (2005) Matrix Gla protein and osteopontin genetic associations with coronary artery calcification and bone density: the CARDIA study. Hum Genet 116:525–528PubMedCrossRefGoogle Scholar
  26. 26.
    Osawa M, Tian W, Horiuchi H, Kaneko M, Umetsu K (2005) Association of alpha2-HS glycoprotein (AHSG, fetuin-A) polymorphism with AHSG and phosphate serum levels. Hum Genet 116:146–151PubMedCrossRefGoogle Scholar
  27. 27.
    Ross R (2004) Atherosclerosis-an inflammatory disease. N Engl J Med 340:115–126CrossRefGoogle Scholar
  28. 28.
    Hofbauer LC, Schrader J, Niebergall U, Viereck V, Burchert A, Hörsch D, Preissner KT, Schoppet M (2006) Interleukin-4 differentially regulates osteoprotegerin expression and induces calcification in vascular smooth muscle cells. Thromb Haemost 95:708–714PubMedGoogle Scholar
  29. 29.
    Abedin M, Tintut Y, Demer LL (2004) Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol 24:1161–1170PubMedCrossRefGoogle Scholar
  30. 30.
    Tintut Y, Alfonso Z, Saini T, Radcliff K, Watson K, Bostrom K, Demer LL (2003) Multilineage potential of cells from the artery wall. Circulation 108:2505–2510PubMedCrossRefGoogle Scholar
  31. 31.
    Schinke T, Karsenty G (2000) Vascular calcification-a passive process in need of inhibitors. Nephrol Dial Transplant 15:1272–1274PubMedCrossRefGoogle Scholar
  32. 32.
    Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, Schauer G, Lehmann M, Roscioli T, Schnabel D, Epplen JT, Knisely A, Superti-Furga A, McGill J, Filippone M, Sinaiko AR, Vallance H, Hinrichs B, Smith W, Ferre M, Terkeltaub R, Nurnberg P (2003) Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 34:379–381PubMedCrossRefGoogle Scholar
  33. 33.
    Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G (1997) Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386:78–81PubMedCrossRefGoogle Scholar
  34. 34.
    Gerstenfeld LC (1999) Osteopontin in skeletal tissue homeostasis: an emerging picture of the autocrine/paracrine functions of the extracellular matrix. J Bone Miner Res 14:850–855PubMedCrossRefGoogle Scholar
  35. 35.
    Gravallese EM (2003) Osteopontin: a bridge between bone and the immune system. J Clin Invest 112:147–149. Erratum in: J Clin Invest (2003) 112:627PubMedGoogle Scholar
  36. 36.
    Denhardt DT, Noda M, O’Regan AW, Pavlin D, Berman JS (2001) Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest 107:1055–1061PubMedCrossRefGoogle Scholar
  37. 37.
    Khan SA, Lopez-Chua CA, Zhang J, Fisher LW, Sorensen ES, Denhardt DT (2002) Soluble osteopontin inhibits apoptosis of adherent endothelial cells deprived of growth factors. J Cell Biochem 85:728–736PubMedCrossRefGoogle Scholar
  38. 38.
    Pritzker LB, Scatena M, Giachelli CM (2004) The role of osteoprotegerin and tumor necrosis factor-related apoptosis-inducing ligand in human microvascular endothelial cell survival. Mol Biol Cell 15:2834–2841PubMedCrossRefGoogle Scholar
  39. 39.
    Yoshitake H, Rittling SR, Denhardt DT, Noda M (1999) Osteopontin-deficient mice are resistant to ovariectomy-induced bone resorption. Proc Natl Acad Sci USA 96:8156–8160. Erratum in: Proc Natl Acad Sci USA 96:10944PubMedCrossRefGoogle Scholar
  40. 40.
    Ishijima M, Tsuji K, Rittling SR, Yamashita T, Kurosawa H, Denhardt DT, Nifuji A, Noda M (2002) Resistance to unloading-induced three-dimensional bone loss in osteopontin-deficient mice. J Bone Miner Res 4:661–667. Erratum in: J Bone Miner Res (2003) 18:1558CrossRefGoogle Scholar
  41. 41.
    Yumoto K, Ishijima M, Rittling SR, Tsuji K, Tsuchiya Y, Kon S, Nifuji A, Uede T, Denhardt DT, Noda M (2002) Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice. Proc Natl Acad Sci USA 99:4556–4561PubMedCrossRefGoogle Scholar
  42. 42.
    Nemoto H, Rittling SR, Yoshitake H, Furuya K, Amagasa T, Tsuji K, Nifuji A, Denhardt DT, Noda M (2001) Osteopontin deficiency reduces experimental tumor cell metastasis to bone and soft tissue. J Bone Miner Res 16:652–659PubMedCrossRefGoogle Scholar
  43. 43.
    Fitzpatrick LA, Severson A, Edwards WD, Ingram RT (1994) Diffuse calcification in human coronary arteries. Association of osteopontin with atherosclerosis. J Clin Invest 94:1597–1604PubMedCrossRefGoogle Scholar
  44. 44.
    Speer MY, McKee MD, Guldberg RE, Liaw L, Yang HY, Tung E, Karsenty G, Giachelli CM (2002) Inactivation of the osteopontin gene enhances vascular calcification of matrix Gla protein-deficient mice: evidence for osteopontin as an inducible inhibitor of vascular calcification in vivo. J Exp Med 196:1047–1055PubMedCrossRefGoogle Scholar
  45. 45.
    Heiss A, DuChesne A, Denecke B, Grotzinger J, Yamamoto K, Renne T, Jahnen-Dechent W (2003) Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J Biol Chem 278:13333–13341PubMedCrossRefGoogle Scholar
  46. 46.
    Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Bohm R, Metzger T, Wanner C, Jahnen-Dechent W, Floege J (2003) Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361:827–833PubMedCrossRefGoogle Scholar
  47. 47.
    Schäfer C, Heiss A, Schwarz A, Westenfeld R, Ketteler M, Floege J, Muller-Esterl W, Schinke T, Jahnen-Dechent WJ (2003) The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 112:357–366PubMedGoogle Scholar
  48. 48.
    Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700PubMedCrossRefGoogle Scholar
  49. 49.
    Hruska KA, Mathew S, Saab G (2005) Bone morphogenetic proteins in vascular calcification. Circ Res 97:105–114PubMedCrossRefGoogle Scholar
  50. 50.
    Galvin KM, Donovan MJ, Lynch CA, Meyer RI, Paul RJ, Lorenz JN, Fairchild-Huntress V, Dixon KL, Dunmore JH, Gimbrone MA Jr, Falb D, Huszar D (2000) A role for smad6 in development and homeostasis of the cardiovascular system. Nature Genetics 24:171–174PubMedCrossRefGoogle Scholar
  51. 51.
    Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M (2005) Suppression of aging in mice by the hormone Klotho. Science 309:1829–1833PubMedCrossRefGoogle Scholar
  52. 52.
    Ikushima M, Rakugi H, Ishikawa K, Maekawa Y, Yamamoto K, Ohta J, Chihara Y, Kida I, Ogihara T (2005) Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. Biochem Biophys Res Commun 339:827–832PubMedCrossRefGoogle Scholar
  53. 53.
    Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, Nabeshima Y, NabeshimaT (2003) Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J 17:50–52PubMedGoogle Scholar
  54. 54.
    Shimada T, Takeshita Y, Murohara T, Sasaki K, Egami K, Shintani S, KatsudaY, Ikeda H, Nabeshima Y, Imaizumi T (2004) Angiogenesis and vasculogenesis are impaired in the precocious-aging klotho mouse. Circulation 110:1148–1155PubMedCrossRefGoogle Scholar
  55. 55.
    Kawaguchi H, Manabe N, Miyaura C, Chikuda H, Nakamura K, Kuro-o M (1999) Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. J Clin Invest 104:229–237PubMedCrossRefGoogle Scholar
  56. 56.
    Raisz LG (2005) Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest 115:3318–3325PubMedCrossRefGoogle Scholar
  57. 57.
    Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC, Young PR (1998) Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 273:14363–14367PubMedCrossRefGoogle Scholar
  58. 58.
    Min H, Morony S, Sarosi I, Dunstan CR, Capparelli C, Scully S, Van G, Kaufman S, Kostenuik PJ, Lacey DL, Boyle WJ, Simonet WS (2000) Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med 192:463–474PubMedCrossRefGoogle Scholar
  59. 59.
    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang M-S, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Eliott R, Colombero A, Tan H-L, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ, Amgen EST Program (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:159–161CrossRefGoogle Scholar
  60. 60.
    Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323PubMedCrossRefGoogle Scholar
  61. 61.
    Price PA, June HH, Buckley JR, Williamson MK (2001) Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D. Arterioscler Thromb Vasc Biol 21:1610–1616PubMedCrossRefGoogle Scholar
  62. 62.
    Price PA, June HH, Buckley JR, Williamson MK (2002) SB 242784, a selective inhibitor of the osteoclastic V-H+ATPase, inhibits arterial calcification in the rat. Circ Res 91:547–552PubMedCrossRefGoogle Scholar
  63. 63.
    Price PA, Faus SA, Williamson MK (2001) Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arterioscler Thromb Vasc Biol 21:817–824PubMedCrossRefGoogle Scholar
  64. 64.
    Tanko LB, Qin G, Alexandersen P, Bagger YZ, Christiansen C (2005) Effective doses of ibandronate do not influence the 3-year progression of aortic calcification in elderly osteoporotic women. Osteoporos Int 16:184–190PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2006

Authors and Affiliations

  • L. C. Hofbauer
    • 1
    • 4
  • C. C. Brueck
    • 1
    • 3
  • C. M. Shanahan
    • 2
  • M. Schoppet
    • 1
    • 2
  • H. Dobnig
    • 3
  1. 1.Department of Internal Medicine (LCH, CCB, MS)Philipps-UniversityMarburgGermany
  2. 2.Division of Cardiovascular Medicine (CMS, MS)Addenbrooke’s HospitalCambridgeUK
  3. 3.Department of Internal Medicine (CCB, HD), Division of Endocrinology and Nuclear MedicineUniversity of GrazGrazAustria
  4. 4.Division of Gastroenterology and Endocrinology, Department of Internal MedicinePhilipps-UniversityMarburgGermany

Personalised recommendations