Osteoporosis International

, Volume 20, Issue 7, pp 1183–1191

The effects of homocysteine and MTHFR genotype on hip bone loss and fracture risk in elderly women

  • K. Zhu
  • J. Beilby
  • I. M. Dick
  • A. Devine
  • M. Soós
  • R. L. Prince
Original Article



Few studies have evaluated the effects of homocysteine and methylenetetrahydrofolate reductase (MTHFR) genotype on age-related bone loss. In our 5-year cohort study with 1,213 women aged 70–85 years, high homocysteine is associated with greater hip bone loss but not fracture risk. The effect of MTHFR genotype on bone density and fracture is weak.


Previous studies on the effects of homocysteine and MTHFR genotype on bone mineral density (BMD) and osteoporotic fracture risk have shown inconsistent results. Few studies have evaluated their effects on age-related bone loss. We evaluated the effects of homocysteine and MTHFR genotype variation on hip BMD and fracture risk over 5 years in a cohort of 1,213 community-dwelling women aged 70–85 years.


Nutritional intake and prevalent fracture status were assessed at baseline, plasma homocysteine was measured at year 1, and hip dual-energy X-ray absorptiometry (DXA) BMD was measured at years 1 and 5. Clinical incident osteoporotic fractures confirmed by radiographic report were collected throughout the study and the MTHFR gene C677T and A1298C polymorphisms genotyped. Data were analyzed using analysis of covariance and Cox proportional hazard regression.


The highest tertile of homocysteine was associated with a greater hip BMD loss over 4 years (−2.8%) compared to the middle (−1.6%) and lowest tertiles (−1.2%) (P < 0.001). This effect remained after adjustment for covariates. There was no effect of homocysteine on fracture prevalence or incidence. MTHFR gene variation was only weakly related to one of the bone outcome measures.


In this study population, high homocysteine is associated with greater hip bone loss but not fracture risk.


Elderly women Hip BMD Homocysteine MTHFR gene Osteoporotic fracture 


  1. 1.
    Lubec B, Fang-Kircher S, Lubec T, Blom HJ, Boers GH (1996) Evidence for McKusick’s hypothesis of deficient collagen cross-linking in patients with homocystinuria. Biochim Biophys Acta 1315:159–162PubMedGoogle Scholar
  2. 2.
    Golbahar J, Hamidi A, Aminzadeh MA, Omrani GR (2004) 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 35:760–765PubMedCrossRefGoogle Scholar
  3. 3.
    Gerdhem P, Ivaska KK, Isaksson A, Pettersson K, Vaananen HK, Obrant KJ, Akesson K (2007) Associations between homocysteine, bone turnover, BMD, mortality, and fracture risk in elderly women. J Bone Miner Res 22:127–134PubMedCrossRefGoogle Scholar
  4. 4.
    Morris MS, Jacques PF, Selhub J (2005) Relation between homocysteine and B-vitamin status indicators and bone mineral density in older Americans. Bone 37:234–242PubMedCrossRefGoogle Scholar
  5. 5.
    van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, van der Klift M, de Jonge R, Lindemans J, de Groot LC, Hofman A, Witteman JC, van Leeuwen JP, Breteler MM, Lips P, Pols HA, Uitterlinden AG (2004) Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 350:2033–2041PubMedCrossRefGoogle Scholar
  6. 6.
    McLean RR, Jacques PF, Selhub J, Tucker KL, Samelson EJ, Broe KE, Hannan MT, Cupples LA, Kiel DP (2004) Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 350:2042–2049PubMedCrossRefGoogle Scholar
  7. 7.
    Dhonukshe-Rutten RA, Pluijm SM, de Groot LC, Lips P, Smit JH, van Staveren WA (2005) Homocysteine and vitamin B12 status relate to bone turnover markers, broadband ultrasound attenuation, and fractures in healthy elderly people. J Bone Miner Res 20:921–929PubMedCrossRefGoogle Scholar
  8. 8.
    Cagnacci A, Baldassari F, Rivolta G, Arangino S, Volpe A (2003) Relation of homocysteine, folate, and vitamin B12 to bone mineral density of postmenopausal women. Bone 33:956–959PubMedCrossRefGoogle Scholar
  9. 9.
    Herrmann M, Kraenzlin M, Pape G, Sand-Hill M, Herrmann W (2005) Relation between homocysteine and biochemical bone turnover markers and bone mineral density in peri- and post-menopausal women. Clin Chem Lab Med 43:1118–1123PubMedCrossRefGoogle Scholar
  10. 10.
    Perier MA, Gineyts E, Munoz F, Sornay-Rendu E, Delmas PD (2007) Homocysteine and fracture risk in postmenopausal women: the OFELY study. Osteoporos Int 18:1329–1336PubMedCrossRefGoogle Scholar
  11. 11.
    Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K (2005) Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA 293:1082–1088PubMedCrossRefGoogle Scholar
  12. 12.
    Sawka AM, Ray JG, Yi Q, Josse RG, Lonn E (2007) Randomized clinical trial of homocysteine level lowering therapy and fractures. Arch Intern Med 167:2136–2139PubMedCrossRefGoogle Scholar
  13. 13.
    Green TJ, McMahon JA, Skeaff CM, Williams SM, Whiting SJ (2007) Lowering homocysteine with B vitamins has no effect on biomarkers of bone turnover in older persons: a 2-y randomized controlled trial. Am J Clin Nutr 85:460–464PubMedGoogle Scholar
  14. 14.
    Jacques PF, Bostom AG, Wilson PWF, Rich S, Rosenberg IH, Selhub J (2001) Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 73:613–621PubMedGoogle Scholar
  15. 15.
    Hustad S, Ueland PM, Vollset SE, Zhang Y, Bjorke-Monsen AL, Schneede J (2000) Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clin Chem 46:1065–1071PubMedGoogle Scholar
  16. 16.
    Dekou V, Whincup P, Papacosta O, Ebrahim S, Lennon L, Ueland PM, Refsum H, Humphries SE, Gudnason V (2001) The effect of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene on homocysteine levels in elderly men and women from the British regional heart study. Atherosclerosis 154:659–666PubMedCrossRefGoogle Scholar
  17. 17.
    Lievers KJ, Kluijtmans LA, Blom HJ, Wilson PW, Selhub J, Ordovas JM (2006) Association of a 31 bp VNTR in the CBS gene with postload homocysteine concentrations in the Framingham Offspring Study. Eur J Hum Genet 14:1125–1129PubMedCrossRefGoogle Scholar
  18. 18.
    Devoto M, Shimoya K, Caminis J, Ott J, Tenenhouse A, Whyte MP, Sereda L, Hall S, Considine E, Williams CJ, Tromp G, Kuivaniemi H, Ala-Kokko L, Prockop DJ, Spotila LD (1998) First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q. Eur J Hum Genet 6:151–157PubMedCrossRefGoogle Scholar
  19. 19.
    Wilson SG, Reed PW, Bansal A, Chiano M, Lindersson M, Langdown M, Prince RL, Thompson D, Thompson E, Bailey M, Kleyn PW, Sambrook P, Shi MM, Spector TD (2003) Comparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36. Am J Hum Genet 72:144–155PubMedCrossRefGoogle Scholar
  20. 20.
    Abrahamsen B, Madsen JS, Tofteng CL, Stilgren L, Bladbjerg EM, Kristensen SR, Brixen K, Mosekilde L (2003) A common methylenetetrahydrofolate 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 18:723–729PubMedCrossRefGoogle Scholar
  21. 21.
    McLean RR, Karasik D, Selhub J, Tucker KL, Ordovas JM, Russo GT, Cupples LA, Jacques PF, Kiel DP (2004) Association of a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene with bone phenotypes depends on plasma folate status. J Bone Miner Res 19:410–418PubMedCrossRefGoogle Scholar
  22. 22.
    Abrahamsen B, Madsen JS, Tofteng CL, Stilgren L, Bladbjerg EM, Kristensen SR, Brixen K, Mosekilde L (2005) 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 36:577–583PubMedCrossRefGoogle Scholar
  23. 23.
    Macdonald HM, McGuigan FE, Fraser WD, New SA, Ralston SH, Reid DM (2004) Methylenetetrahydrofolate reductase polymorphism interacts with riboflavin intake to influence bone mineral density. Bone 35:957–964PubMedCrossRefGoogle Scholar
  24. 24.
    Prince RL, Devine A, Dhaliwal SS, Dick IM (2006) Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med 166:869–875PubMedCrossRefGoogle Scholar
  25. 25.
    Bruce DG, Devine A, Prince RL (2002) Recreational physical activity levels in healthy older women: the importance of fear of falling. J Am Geriatr Soc 50:84–89PubMedCrossRefGoogle Scholar
  26. 26.
    Ireland P, Jolley D, Giles G, O’Dea K, Powles J, Ritishauser I, Wahlqvist ML, Williams J (1994) Development of the Melbourne FFQ: a food frequency questionnaire for use in an Australian prospective study involving an ethnically diverse cohort. Asia Pac J Clin Nutr 3:19–31Google Scholar
  27. 27.
    Hodge A, Patterson AJ, Brown WJ, Ireland P, Giles G (2000) The Anti Cancer Council of Victoria FFQ: relative validity of nutrient intakes compared with weighed food records in young to middle-aged women in a study of iron supplementation. Aust N Z J Public Health 24:576–583PubMedCrossRefGoogle Scholar
  28. 28.
    Devine A, Dhaliwal SS, Dick IM, Bollerslev J, Prince RL (2004) Physical activity and calcium consumption are important determinants of lower limb bone mass in older women. J Bone Miner Res 19:1634–1639PubMedCrossRefGoogle Scholar
  29. 29.
    McArdle WD, Katch FI, Katch VL (1991) Energy, nutrition and human performance. Lea & Febiger, Philadelphia, PAGoogle Scholar
  30. 30.
    Pollock ML, Wilmore JH, Fox SM (1978) Health and fitness through physical activity. Wiley, New York, NYGoogle Scholar
  31. 31.
    Henzell S, Dhaliwal S, Pontifex R, Gill F, Price R, Retallack R, Prince R (2000) Precision error of fan-beam dual x-ray absorptiometry scans at spine, hip, and forearm. J Clin Densitom 3:359–364PubMedCrossRefGoogle Scholar
  32. 32.
    Araki A, Sako Y (1987) Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 422:43–52PubMedCrossRefGoogle Scholar
  33. 33.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41PubMedCrossRefGoogle Scholar
  34. 34.
    McQuillan BM, Beilby JP, Nidorf M, Thompson PL, Hung J (1999) Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS). Circulation 99:2383–2388PubMedGoogle Scholar
  35. 35.
    van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62:1044–1051PubMedCrossRefGoogle Scholar
  36. 36.
    Berstad P, Konstantinova SV, Refsum H, Nurk E, Vollset SE, Tell GS, Ueland PM, Drevon CA, Ursin G (2007) Dietary fat and plasma total homocysteine concentrations in 2 adult age groups: the Hordaland Homocysteine Study. Am J Clin Nutr 85:1598–1605PubMedGoogle Scholar
  37. 37.
    Stolzenberg-Solomon RZ, Miller ER 3rd, Maguire MG, Selhub J, Appel LJ (1999) Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population. Am J Clin Nutr 69:467–475PubMedGoogle Scholar
  38. 38.
    Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, Ueland M, Kvale G (1995) Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA 274:1526–1533PubMedCrossRefGoogle Scholar
  39. 39.
    Friedman AN, Bostom AG, Selhub J, Levey AS, Rosenberg IH (2001) The kidney and homocysteine metabolism. J Am Soc Nephrol 12:2181–2189PubMedGoogle Scholar
  40. 40.
    Sener U, Zorlu Y, Karaguzel O, Ozdamar O, Coker I, Topbas M (2006) Effects of common anti-epileptic drug monotherapy on serum levels of homocysteine, vitamin B12, folic acid and vitamin B6. Seizure 15:79–85PubMedCrossRefGoogle Scholar
  41. 41.
    Dierkes J, Luley C, Westphal S (2007) Effect of lipid-lowering and anti-hypertensive drugs on plasma homocysteine levels. Vasc Health Risk Manag 3:99–108PubMedGoogle Scholar
  42. 42.
    Girelli D, Martinelli N, Pizzolo F, Friso S, Olivieri O, Stranieri C, Trabetti E, Faccini G, Tinazzi E, Pignatti PF, Corrocher R (2003) The interaction between MTHFR 677 C→T genotype and folate status is a determinant of coronary atherosclerosis risk. J Nutr 133:1281–1285PubMedGoogle Scholar
  43. 43.
    Kim KN, Kim YJ, Chang N (2004) Effects of the interaction between the C677T 5,10-methylenetetrahydrofolate reductase polymorphism and serum B vitamins on homocysteine levels in pregnant women. Eur J Clin Nutr 58:10–16PubMedCrossRefGoogle Scholar
  44. 44.
    Devine A, Dick IM, Islam AF, Dhaliwal SS, Prince RL (2005) Protein consumption is an important predictor of lower limb bone mass in elderly women. Am J Clin Nutr 81:1423–1428PubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2008

Authors and Affiliations

  • K. Zhu
    • 1
    • 2
  • J. Beilby
    • 3
  • I. M. Dick
    • 1
    • 2
  • A. Devine
    • 4
  • M. Soós
    • 2
  • R. L. Prince
    • 1
    • 2
  1. 1.School of Medicine and PharmacologyUniversity of Western AustraliaCrawleyAustralia
  2. 2.Department of Endocrinology and DiabetesSir Charles Gairdner HospitalNedlandsAustralia
  3. 3.The Western Australian Centre for Pathology and Medical ResearchNedlandsAustralia
  4. 4.School of Exercise, Biomedical and Health SciencesEdith Cowan UniversityJoondalupAustralia

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