Top

Osteoporosis International

Published in:

01-07-2009 | Original Article

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

Authors: K. Zhu, J. Beilby, I. M. Dick, A. Devine, M. Soós, R. L. Prince

Published in: Osteoporosis International | Issue 7/2009

Abstract

Summary

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.

Introduction

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.

Methods

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.

Results

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.

Conclusion

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

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 1315:159–162PubMed

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 35:760–765PubMedCrossRef

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 22:127–134PubMedCrossRef

Morris MS, Jacques PF, Selhub J (2005) Relation between homocysteine and B-vitamin status indicators and bone mineral density in older Americans. Bone 37:234–242PubMedCrossRef

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 350:2033–2041PubMedCrossRef

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 350:2042–2049PubMedCrossRef

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 20:921–929PubMedCrossRef

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 33:956–959PubMedCrossRef

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 43:1118–1123PubMedCrossRef

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 18:1329–1336PubMedCrossRef

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 293:1082–1088PubMedCrossRef

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 167:2136–2139PubMedCrossRef

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 85:460–464PubMed

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 73:613–621PubMed

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 46:1065–1071PubMed

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 154:659–666PubMedCrossRef

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 14:1125–1129PubMedCrossRef

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 6:151–157PubMedCrossRef

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 72:144–155PubMedCrossRef

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 18:723–729PubMedCrossRef

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 19:410–418PubMedCrossRef

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 36:577–583PubMedCrossRef

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 35:957–964PubMedCrossRef

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 166:869–875PubMedCrossRef

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 50:84–89PubMedCrossRef

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 3:19–31

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 24:576–583PubMedCrossRef

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 19:1634–1639PubMedCrossRef

29.

McArdle WD, Katch FI, Katch VL (1991) Energy, nutrition and human performance. Lea & Febiger, Philadelphia, PA

30.

Pollock ML, Wilmore JH, Fox SM (1978) Health and fitness through physical activity. Wiley, New York, NY

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 3:359–364PubMedCrossRef

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 422:43–52PubMedCrossRef

33.

Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41PubMedCrossRef

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 99:2383–2388PubMed

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 62:1044–1051PubMedCrossRef

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 85:1598–1605PubMed

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 69:467–475PubMed

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 274:1526–1533PubMedCrossRef

39.

Friedman AN, Bostom AG, Selhub J, Levey AS, Rosenberg IH (2001) The kidney and homocysteine metabolism. J Am Soc Nephrol 12:2181–2189PubMed

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 15:79–85PubMedCrossRef

41.

Dierkes J, Luley C, Westphal S (2007) Effect of lipid-lowering and anti-hypertensive drugs on plasma homocysteine levels. Vasc Health Risk Manag 3:99–108PubMed

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 133:1281–1285PubMed

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 58:10–16PubMedCrossRef

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 81:1423–1428PubMed

Title: The effects of homocysteine and MTHFR genotype on hip bone loss and fracture risk in elderly women
Authors: K. Zhu
J. Beilby
I. M. Dick
A. Devine
M. Soós
R. L. Prince
Publication date: 01-07-2009
Publisher: Springer-Verlag
Published in: Osteoporosis International / Issue 7/2009
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-008-0804-y

At a glance: The STEP trials

Springer Medicine

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

Abstract

Summary

Introduction

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 7/2009

The Global Longitudinal Study of Osteoporosis in Women (GLOW): rationale and study design

Remaining lifetime and absolute 10-year probabilities of osteoporotic fracture in Swiss men and women

Vitamin D insufficiency does not affect response of bone mineral density to alendronate

A case of familial tumoral calcinosis/hyperostosis–hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features

Effects of a multi-component exercise program and calcium–vitamin-D3-fortified milk on bone mineral density in older men: a randomised controlled trial

High bone mineral density is associated with high body mass index