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Homocysteine – a newly recognised risk factor for osteoporosis

  • Markus Herrmann , Thomas Widmann and Wolfgang Herrmann
Published/Copyright: September 21, 2011
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 43 Issue 10

Abstract

Osteoporosis is a widespread problem, which frequently has devastating health consequences through its association with fragility fractures. The total number of fractures, and hence the cost to society, will increase dramatically over the next 50years as a result of demographic changes in the number of elderly people. Thus, prevention of osteoporosis by identifying risk factors or risk indicators, as well as the development of new treatment strategies, are major issues. Recent data suggest that homocysteine (Hcy), folate, vitamin B6 and vitamin B12 affect bone metabolism, bone quality and fracture risk in humans. Since circulating Hcy depends on folate, vitamin B6 and vitamin B12, Hcy could be suitable as a risk indicator for micronutrient-deficiency-related osteoporosis. Initial experimental results indicate that Hcy is not only a risk indicator, but also a player in bone metabolism. Moreover, existing data open speculation that folate, vitamin B6 and vitamin B12 act not only via Hcy-dependent pathways, but also via Hcy-independent pathways. However, more studies are needed to clarify the mechanistic role of Hcy, folate, vitamin B6 and vitamin B12 in bone metabolism.

Keywords: bone mineral density; bone turnover markers; homocysteine
Corresponding author: Dr. med. Markus Herrmann, Institut für Klinische Chemie und Laboratoriumsmedizin/Zentrallabor, Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany Phone: +49-6841-163-0707, Fax: +49-6841-163-0703,

References

1. Walker-Bone K, Walter G, Cooper C. Recent developments in the epidemiology of osteoporosis. Curr Opin Rheumatol 2002; 14:411–5.10.1097/00002281-200207000-00014Search in Google Scholar

2. Melton LJ III. Adverse outcomes of osteoporotic fractures in the general population. J Bone Miner Res 2003; 18:1139–41.10.1359/jbmr.2003.18.6.1139Search in Google Scholar

3. Chrischilles E, Shireman T, Wallace R. Costs and health effects of osteoporotic fractures. Bone 1994; 15:377–86.10.1016/8756-3282(94)90813-3Search in Google Scholar

4. Kanis JA, Jonsson B. Economic evaluation of interventions for osteoporosis. Osteoporos Int 2002; 13:765–7.10.1007/s001980200106Search in Google Scholar

5. McKusick VA. Heritable disorders of connective tissue. St. Louis: C.V. Mosby, 1966:155 pp.Search in Google Scholar

6. Kraus JP, Janosik M, Kozich V, Mandell R, Shih V, Sperandeo MP, et al. Cystathionine beta-synthase mutations in homocystinuria. Hum Mutat 1999; 13:362–75.10.1002/(SICI)1098-1004(1999)13:5<362::AID-HUMU4>3.0.CO;2-KSearch in Google Scholar

7. Schedewie H, Willich E, Grobe H, Schmidt H, Muller KM. Skeletal findings in homocystinuria: a collaborative study. Pediatr Radiol 1973; 1:12–23.10.1007/BF00972819Search in Google Scholar

8. Brenton DP. Skeletal abnormalities in homocystinuria. Postgrad Med J 1977; 53:488–96.10.1136/pgmj.53.622.488Search in Google Scholar

9. Parrot F, Redonnet-Vernhet I, Lacombe D, Gin H. Osteoporosis in late-diagnosed adult homocystinuric patients. J Inherit Metab Dis 2000; 23:338–40.10.1023/A:1005618927729Search in Google Scholar

10. Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985; 37:1–31.Search in Google Scholar

11. Lees S, Eyre DR, Barnard SM. BAPN dose dependence of mature crosslinking in bone matrix collagen of rabbit compact bone: corresponding variation of sonic velocity and equatorial diffraction spacing. Connect Tissue Res 1990; 24:95–105.10.3109/03008209009152426Search in Google Scholar

12. Lubec B, Fang-Kircher S, Lubec T, Blom HJ, Boers GH. Evidence for McKusick's hypothesis of deficient collagen cross-linking in patients with homocystinuria. Biochim Biophys Acta 1996; 1315:159–62.10.1016/0925-4439(95)00119-0Search in Google Scholar

13. van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, van der Klift M, de Jonge R, Lindemans J, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 2004; 350:2033–41.10.1056/NEJMoa032546Search in Google Scholar

14. McLean RR, Jacques PF, Selhub J, Tucker KL, Samelson EJ, Broe KE, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 2004; 350:2042–9.10.1056/NEJMoa032739Search in Google Scholar

15. Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. J Am Med Assoc 2005; 293:1082–8.10.1001/jama.293.9.1082Search in Google Scholar

16. Herrmann M, Kraenzlin M, Pape G, Sand-Hill M, Herrmann W. Relation between homocysteine and biochemical bone turnover markers and bone mineral density in peri- and postmenopausal women. Clin Chem Lab Med 2005; 43:1118–23.10.1515/CCLM.2005.195Search in Google Scholar

17. Cagnacci A, Baldassari F, Rivolta G, Arangino S, Volpe A. Relation of homocysteine, folate, and vitamin B12 to bone mineral density of postmenopausal women. Bone 2003; 33:956–9.10.1016/j.bone.2003.07.001Search in Google Scholar

18. Golbahar J, Hamidi A, Aminzadeh MA, Omrani GR. Association of plasma folate, plasma total homocysteine, but not methylenetetrahydrofolate reductase C667T polymorphism, with bone mineral density in postmenopausal Iranian women: a cross-sectional study. Bone 2004; 35:760–5.10.1016/j.bone.2004.04.018Search in Google Scholar

19. Miyao M, Morita H, Hosoi T, Kurihara H, Inoue S, Hoshino S, et al. Association of methylenetetrahydrofolate reductase (MTHFR) polymorphism with bone mineral density in postmenopausal Japanese women. Calcif Tissue Int 2000; 66:190–4.10.1007/s002230010038Search in Google Scholar

20. Bode MK, Laitinen P, Risteli J, Uusimaa P, Juvonen T. Atherosclerosis, type 1 collagen cross-linking and homocysteine. Atherosclerosis 2000; 152:531–2.10.1016/S0021-9150(00)00548-7Search in Google Scholar

21. Masse PG, Boskey AL, Ziv I, Hauschka P, Donovan SM, Howell DS, et al. Chemical and biomechanical characterization of hyperhomocysteinemic bone disease in an animal model. BMC Musculoskelet Disord 2003; 4:2.10.1186/1471-2474-4-2Search in Google Scholar PubMed PubMed Central

22. Herrmann M, Widmann T, Colaianni G, Colucci S, Zallone A, Herrmann W. Increased osteoclast activity in the presence of elevated homocysteine levels. Clin Chem 2005. In press.10.1373/clinchem.2005.053363Search in Google Scholar PubMed

23. Itzstein C, Cheynel H, Burt-Pichat B, Merle B, Espinosa L, Delmas PD, et al. Molecular identification of NMDA glutamate receptors expressed in bone cells. J Cell Biochem 2001; 82:134–44.10.1002/jcb.1114Search in Google Scholar

24. Merle B, Itzstein C, Delmas PD, Chenu C. NMDA glutamate receptors are expressed by osteoclast precursors and involved in the regulation of osteoclastogenesis. J Cell Biochem 2003; 90:424–36.10.1002/jcb.10625Search in Google Scholar

25. Espinosa L, Itzstein C, Cheynel H, Delmas PD, Chenu C. Active NMDA glutamate receptors are expressed by mammalian osteoclasts. J Physiol 1999; 518:47–53.10.1111/j.1469-7793.1999.0047r.xSearch in Google Scholar

26. Itzstein C, Espinosa L, Delmas PD, Chenu C. Specific antagonists of NMDA receptors prevent osteoclast sealing zone formation required for bone resorption. Biochem Biophys Res Commun 2000; 268:201–9.10.1006/bbrc.2000.2097Search in Google Scholar

27. Chenu C, Serre CM, Raynal C, Burt-Pichat B, Delmas PD. Glutamate receptors are expressed by bone cells and are involved in bone resorption. Bone 1998; 22:295–9.10.1016/S8756-3282(97)00295-0Search in Google Scholar

28. Brown AT, Chen H, Zhang X, Moursi MM. Homocysteine induces NADPH oxidase expression in rat vascular smooth muscle cells: role of NMDA receptor and PKC-epsilon. Clin Chem Lab Med 2005; 43:A27.Search in Google Scholar

29. Goerss JB, Kim CH, Atkinson EJ, Eastell R, O'Fallon WM, Melton LJ, III. Risk of fractures in patients with pernicious anemia. J Bone Miner Res 1992; 7:573–9.10.1002/jbmr.5650070514Search in Google Scholar PubMed

30. Reynolds TM, Marshall PD, Brain AM. Hip fracture patients may be vitamin B6 deficient. Controlled study of serum pyridoxal-5'-phosphate. Acta Orthop Scand 1992; 63:635–8.Search in Google Scholar

31. Melhus H, Michaelsson K, Holmberg L, Wolk A, Ljunghall S. Smoking, antioxidant vitamins, and the risk of hip fracture. J Bone Miner Res 1999; 14:129–35.10.1359/jbmr.1999.14.1.129Search in Google Scholar PubMed

32. Lumbers M, New SA, Gibson S, Murphy MC. Nutritional status in elderly female hip fracture patients: comparison with an age-matched home living group attending day centres. Br J Nutr 2001; 85:733–40.10.1079/BJN2001350Search in Google Scholar

33. Stanger O, Herrmann W, Pietrzik K, Fowler B, Geisel J, Dierkes J, et al. DACH-LIGA Homocystein (German, Austrian and Swiss Homocysteine Society): consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations. Clin Chem Lab Med 2003; 41:1392–403.10.1515/CCLM.2003.214Search in Google Scholar PubMed

34. Bathum L, von Bornemann HJ, Christiansen L, Madsen JS, Skytthe A, Christensen K. Evidence for an association of methylene tetrahydrofolate reductase polymorphism C677T and an increased risk of fractures: results from a population-based Danish twin study. Osteoporos Int 2004; 15:659–64.10.1007/s00198-003-1584-zSearch in Google Scholar PubMed

35. Abrahamsen B, Madsen JS, Tofteng CL, Stilgren L, Blad-bjerg EM, Kristensen SR, et al. A common methylene-tetra hydrofolate reductase (C677T) polymorphism is associated with low bone mineral density and increased fracture incidence after menopause: longitudinal data from the Danish osteoporosis prevention study. J Bone Miner Res 2003; 18:723–9.10.1359/jbmr.2003.18.4.723Search in Google Scholar PubMed

36. Villadsen MM, Bunger MH, Carstens M, Stenkjaer L, Langdahl BL. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a weak predictor of BMD. Osteoporos Int 2005; 16:411–6.10.1007/s00198-004-1704-4Search in Google Scholar PubMed

37. Jorgensen HL, Madsen JS, Madsen B, Saleh MM, Abrahamsen B, Fenger M, et al. Association of a commonallelic polymorphism (C677T) in the methylene tetrahydrofolate reductase gene with a reduced risk of osteoporotic fractures. A case control study in Danish postmenopausal women. Calcif Tissue Int 2002; 71:386–92.Search in Google Scholar

38. Dhonukshe-Rutten RA, Lips M, de JN, Chin APM, Hiddink GJ, Van DM, et al. Vitamin B-12 status is associated with bone mineral content and bone mineral density in frail elderly women but not in men. J Nutr 2003; 133:801–7.10.1093/jn/133.3.801Search in Google Scholar PubMed

39. Dhonukshe-Rutten RA, Van Dusseldorp M, Schneede J, de Groot LC, van Staveren WA. Low bone mineral density and bone mineral content are associated with low cobalamin status in adolescents. Eur J Nutr2004; August.10.1007/s00394-004-0531-xSearch in Google Scholar PubMed

40. Tucker KL, Hannan MT, Qiao N, Jacques PF, Selhub J, Cupples LA, et al. Low plasma vitamin B(12) is associated with lower BMD: The Framingham Osteoporosis Study. J Bone Miner Res 2005; 20:152–8.10.1359/jbmr.2005.20.1.152Search in Google Scholar

41. Stone KL, Bauer DC, Sellmeyer D, Cummings SR. Low serum vitamin B-12 levels are associated with increased hip bone loss in older women: a prospective study. J Clin Endocrinol Metab 2004; 89:1217–21.10.1210/jc.2003-030074Search in Google Scholar PubMed

42. Cagnacci A, Baldassari F, Rivolta G, Arangino S, Volpe A. Relation of homocysteine, folate, and vitamin B12 to bone mineral density of postmenopausal women. Bone 2003; 33:956–9.10.1016/j.bone.2003.07.001Search in Google Scholar PubMed

43. Li M, Lau EM, Woo J. Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) and bone mineral density in Chinese men and women. Bone 2004; 35:1369–74.10.1016/j.bone.2004.09.008Search in Google Scholar PubMed

44. Macdonald HM, McGuigan FE, Fraser WD, New SA, Ralston SH, Reid DM. Methylenetetrahydrofolate reductase polymorphism interacts with riboflavin intake to influence bone mineral density. Bone 2004; 35:957–64.10.1016/j.bone.2004.05.018Search in Google Scholar PubMed

45. Abrahamsen B, Madsen JS, Tofteng CL, Stilgren L, Bladbjerg EM, Kristensen SR, et al. Are effects of MTHFR (C677T) genotype on BMD confined to women with low folate and riboflavin intake? Analysis of food records from the Danish osteoporosis prevention study. Bone 2005; 36:577–83.10.1016/j.bone.2004.12.014Search in Google Scholar PubMed

46. McLean RR, Karasik D, Selhub J, Tucker KL, Ordovas JM, Russo GT, et al. Association of a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene with bone phenotypes depends on plasma folate status. J Bone Miner Res 2004; 19:410–8.10.1359/JBMR.0301261Search in Google Scholar

47. Carmel R, Lau KH, Baylink DJ, Saxena S, Singer FR. Cobalamin and osteoblast-specific proteins. N Engl J Med 1988; 319:70–5.10.1056/NEJM198807143190202Search in Google Scholar

48. Kim GS, Kim CH, Park JY, Lee KU, Park CS. Effects of vitamin B12 on cell proliferation and cellular alkaline phosphatase activity in human bone marrow stromal osteoprogenitor cells and UMR106 osteoblastic cells. Metabolism 1996; 45:1443–6.10.1016/S0026-0495(96)90171-7Search in Google Scholar

49. Melton ME, Kochman ML. Reversal of severe osteo-porosis with vitamin B12 and etidronate therapy in apatient with pernicious anemia. Metabolism 1994; 43:468–9.10.1016/0026-0495(94)90078-7Search in Google Scholar

50. Dodds RA, Catterall A, Bitensky L, Chayen J. Abnormalities in fracture healing induced by vitamin B6-deficiency in rats. Bone 1986; 7:489–95.10.1016/8756-3282(86)90008-6Search in Google Scholar

51. Maggio D, Barabani M, Pierandrei M, Polidori MC, Catani M, Mecocci P, et al. Marked decrease in plasma antioxidants in aged osteoporotic women: results of a cross-sectional study. J Clin Endocrinol Metab 2003; 88:1523–7.10.1210/jc.2002-021496Search in Google Scholar PubMed

52. Basu S, Michaelsson K, Olofsson H, Johansson S, Melhus H. Association between oxidative stress and bone mineral density. Biochem Biophys Res Commun 2001; 288:275–9.10.1006/bbrc.2001.5747Search in Google Scholar PubMed

53. Morton DJ, Barrett-Connor EL, Schneider DL. Vitamin C supplement use and bone mineral density in postmenopausal women. J Bone Miner Res 2001; 16:135–40.10.1359/jbmr.2001.16.1.135Search in Google Scholar PubMed

54. Bai XC, Lu D, Bai J, Zheng H, Ke ZY, Li XM, et al. Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-kappaB. Biochem Biophys Res Commun 2004; 314:197–207.10.1016/j.bbrc.2003.12.073Search in Google Scholar PubMed

55. Garrett IR, Boyce BF, Oreffo RO, Bonewald L, Poser J, Mundy GR. Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro andin vivo. J Clin Invest 1990; 85:632–9.10.1172/JCI114485Search in Google Scholar PubMed PubMed Central

56. Mody N, Parhami F, Sarafian TA, Demer LL. Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radic Biol Med 2001; 31:509–19.10.1016/S0891-5849(01)00610-4Search in Google Scholar

57. Masse PG, Rimnac CM, Yamauchi M, Coburn SP, Rucker RB, Howell DS, et al. Pyridoxine deficiency affects biomechanical properties of chick tibial bone. Bone 1996; 18:567–74.10.1016/8756-3282(96)00072-5Search in Google Scholar

Published Online: 2011-9-21
Published in Print: 2005-10-1

©2005 by Walter de Gruyter Berlin New York

Articles in the same Issue

  1. Homocysteine research – where do we stand and where are we going?
  2. Hyperhomocysteinemia and arteriosclerosis: historical perspectives
  3. Homocysteine and heart failure: a review of investigations from the Framingham Heart Study
  4. Homocysteine and vascular disease in diabetes: a double hit?
  5. Reduced adenosine receptor stimulation as a pathogenic factor in hyperhomocysteinemia
  6. Effects of homocysteine on vascular and tissue adenosine: a stake in homocysteine pathogenicity?
  7. Anti-N-homocysteinylated protein autoantibodies and cardiovascular disease
  8. Carotid narrowing degree and plasma thiol levels in carotid endarterectomy patients
  9. Impairment of homocysteine metabolism in patients with retinal vascular occlusion and non-arteritic ischemic optic neuropathy
  10. Hyperhomocysteinaemia in chronic kidney disease: focus on transmethylation
  11. Hyperhomocysteinemia and macromolecule modifications in uremic patients
  12. Hyperhomocysteinemia and response of methionine cycle intermediates to vitamin treatment in renal patients
  13. Vitamin B12 deficiency is the dominant nutritional cause of hyperhomocysteinemia in a folic acid-fortified population
  14. Homocysteine, folic acid and vitamin B12 in relation to pre- and postnatal health aspects
  15. Evaluation of the technical performance of novel holotranscobalamin (holoTC) assays in a multicenter European demonstration project
  16. A laboratory algorithm with homocysteine as the primary parameter reduces the cost of investigation of folate and cobalamin deficiency
  17. Betaine: a key modulator of one-carbon metabolism and homocysteine status
  18. Molecular targeting by homocysteine: a mechanism for vascular pathogenesis
  19. Anti-inflammatory compound resveratrol suppresses homocysteine formation in stimulated human peripheral blood mononuclear cells in vitro
  20. Homocysteine in relation to cognitive performance in pathological and non-pathological conditions
  21. Homocysteine and B vitamins in mild cognitive impairment and dementia
  22. Homocysteine, type 2 diabetes mellitus, and cognitive performance: The Maine-Syracuse Study
  23. Plasma homocysteine levels in L-dopa-treated Parkinson's disease patients with cognitive dysfunctions
  24. Homocysteine – a newly recognised risk factor for osteoporosis
  25. Relation between homocysteine and biochemical bone turnover markers and bone mineral density in peri- and post-menopausal women
  26. Elevated levels of asymmetric dimethylarginine (ADMA) as a marker of cardiovascular disease and mortality
  27. Measurement of asymmetric dimethylarginine in plasma: methodological considerations and clinical relevance
  28. Concentrations of homocysteine, related metabolites and asymmetric dimethylarginine in preeclamptic women with poor nutritional status
  29. Asymmetric dimethylarginine, homocysteine and renal function – is there a relation?
  30. Interactions between folate and aging for carcinogenesis
  31. The potential cocarcinogenic effect of vitamin B12 deficiency
  32. The vegetarian lifestyle and DNA methylation
https://doi.org/10.1515/CCLM.2005.194
Keywords for this article
bone mineral density; bone turnover markers; homocysteine

Articles in the same Issue

  1. Homocysteine research – where do we stand and where are we going?
  2. Hyperhomocysteinemia and arteriosclerosis: historical perspectives
  3. Homocysteine and heart failure: a review of investigations from the Framingham Heart Study
  4. Homocysteine and vascular disease in diabetes: a double hit?
  5. Reduced adenosine receptor stimulation as a pathogenic factor in hyperhomocysteinemia
  6. Effects of homocysteine on vascular and tissue adenosine: a stake in homocysteine pathogenicity?
  7. Anti-N-homocysteinylated protein autoantibodies and cardiovascular disease
  8. Carotid narrowing degree and plasma thiol levels in carotid endarterectomy patients
  9. Impairment of homocysteine metabolism in patients with retinal vascular occlusion and non-arteritic ischemic optic neuropathy
  10. Hyperhomocysteinaemia in chronic kidney disease: focus on transmethylation
  11. Hyperhomocysteinemia and macromolecule modifications in uremic patients
  12. Hyperhomocysteinemia and response of methionine cycle intermediates to vitamin treatment in renal patients
  13. Vitamin B12 deficiency is the dominant nutritional cause of hyperhomocysteinemia in a folic acid-fortified population
  14. Homocysteine, folic acid and vitamin B12 in relation to pre- and postnatal health aspects
  15. Evaluation of the technical performance of novel holotranscobalamin (holoTC) assays in a multicenter European demonstration project
  16. A laboratory algorithm with homocysteine as the primary parameter reduces the cost of investigation of folate and cobalamin deficiency
  17. Betaine: a key modulator of one-carbon metabolism and homocysteine status
  18. Molecular targeting by homocysteine: a mechanism for vascular pathogenesis
  19. Anti-inflammatory compound resveratrol suppresses homocysteine formation in stimulated human peripheral blood mononuclear cells in vitro
  20. Homocysteine in relation to cognitive performance in pathological and non-pathological conditions
  21. Homocysteine and B vitamins in mild cognitive impairment and dementia
  22. Homocysteine, type 2 diabetes mellitus, and cognitive performance: The Maine-Syracuse Study
  23. Plasma homocysteine levels in L-dopa-treated Parkinson's disease patients with cognitive dysfunctions
  24. Homocysteine – a newly recognised risk factor for osteoporosis
  25. Relation between homocysteine and biochemical bone turnover markers and bone mineral density in peri- and post-menopausal women
  26. Elevated levels of asymmetric dimethylarginine (ADMA) as a marker of cardiovascular disease and mortality
  27. Measurement of asymmetric dimethylarginine in plasma: methodological considerations and clinical relevance
  28. Concentrations of homocysteine, related metabolites and asymmetric dimethylarginine in preeclamptic women with poor nutritional status
  29. Asymmetric dimethylarginine, homocysteine and renal function – is there a relation?
  30. Interactions between folate and aging for carcinogenesis
  31. The potential cocarcinogenic effect of vitamin B12 deficiency
  32. The vegetarian lifestyle and DNA methylation
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