Journal of Bone and Mineral Metabolism

, Volume 26, Issue 6, pp 595–602 | Cite as

The synergistic effect of bone mineral density and methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) on fractures

  • Masataka Shiraki
  • Tomohiko Urano
  • Tatsuhiko Kuroda
  • Mitsuru Saito
  • Shiro Tanaka
  • Mariko Miyao-Koshizuka
  • Satoshi Inoue
Original Article


A functional polymorphism in methylenetetrahydrofolate reductase (MTHFR) has been identified at codon 677 (C677T). The T-allele variant (valine type) has lower enzyme activity than the wild type (C-allele or alanine type), resulting in a slightly elevated homocysteine level, which has been recently recognized as a risk factor for fracture. However, whether subjects bearing the T allele have higher susceptibility to fractures is still controversial. We have investigated the effects of MTHFR polymorphism on fracture susceptibility in Japanese postmenopausal women. A total of 502 postmenopausal ambulatory Japanese women were followed up for 5.1 ± 3.4 (mean ± SD) years, and a total of 155 patients with incident fractures (121 patients with vertebral fractures and 34 cases with fractures at other sites) were recorded. When compared with the patients without any fractures, the patients with incident fractures were older, had more prevalent fractures, had higher urinary levels of bone turnover markers as well as plasma homocysteine level, but were shorter in body height and had lower bone mineral density. The prevalence of the TT genotype of MTHFR was significantly higher in the patients with incident fractures compared to the other genotypes. The subjects with the TT genotype had a higher incidence rate of fracture and higher plasma level of homocysteine than the subjects bearing the non-TT genotype. This relationship was observed in both osteoporotic and nonosteoporotic groups. The hazard ratio for TT genotype without osteoporosis, non-TT genotype with osteoporosis, and TT genotype with osteoporosis was 1.49 (0.91–2.45), 3.64 (2.50–5.29), and 7.21 (4.34–11.97), respectively, compared to the non-TT genotype without osteoporosis. A higher hazard ratio for the TT genotype with osteoporosis was still apparent after adjustment for age, body size, and number of prevalent vertebral fractures. These results indicate that the TT genotype of MTHFR may be a risk factor for future fracture in addition to the traditional risk factors.

Key words

osteoporosis fracture methylenetetrahydrofolate reductase (MTHFR) gene polymorphism homocysteine 


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Copyright information

© Springer Japan 2008

Authors and Affiliations

  • Masataka Shiraki
    • 1
  • Tomohiko Urano
    • 2
  • Tatsuhiko Kuroda
    • 3
  • Mitsuru Saito
    • 4
  • Shiro Tanaka
    • 5
  • Mariko Miyao-Koshizuka
    • 6
  • Satoshi Inoue
    • 2
  1. 1.Department of Internal MedicineResearch Institute and Practice for Involutional DiseasesNaganoJapan
  2. 2.Department of Coca-Cola Anti-Aging Medicine, Department of Geriatric Medicine, Graduate School of MedicineThe University of TokyoTokyoJapan
  3. 3.Department of Obstetrics and GynecologyTokyo Women’s Medical UniversityTokyoJapan
  4. 4.Department of Orthopedic SurgeryJikei University School of MedicineTokyoJapan
  5. 5.Department of Epidemiology and BiostatisticsTokyo UniversityTokyoJapan
  6. 6.Department of Endocrinology and MetabolismKantou Central HospitalTokyoJapan

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