Calcified Tissue International

, Volume 77, Issue 6, pp 339–347 | Cite as

Effects of the Cdx-2 Polymorphism of the Vitamin D Receptor Gene and Lifestyle Factors on Bone Mineral Density in a Representative Sample of Japanese Women: The Japanese Population-based Osteoporosis (JPOS) Study

  • A. Morita
  • M. Iki
  • Y. Dohi
  • Y. Ikeda
  • S. Kagamimori
  • Y. Kagawa
  • H. Yoneshima
Clinical Investigations


Using a large-scale representative sample of the Japanese female population, we examined the effects of a single nucleotide polymorphism within a binding site of Cdx-2 in the promoter region of the vitamin D receptor gene on bone mineral density (BMD), and the interactions between this polymorphism and lifestyle factors on BMD. Fifty women were randomly selected from each of the 5-year age-stratified populations (15–79 years) in each of three chosen municipalities as a part of the Japanese Population-based Osteoporosis Study. BMD at the lumbar spine, hip, and distal forearm was measured using dual-energy X-ray absorptiometry at baseline and again in a follow-up study conducted 3 years later. Information on lifestyle factors was collected in a questionnaire and followed up in interviews. The G-to-A polymorphism within the Cdx-2 binding site was determined by a TaqMan allelic discrimination assay. At baseline, 1,340 women were analyzed. The baseline BMD in the ultradistal forearm in premenopausal women with the GG genotype was significantly lower than in those with other genotypes. There was no association between the Cdx-2 genotype and the change in BMD at any of the skeletal sites. We found significant associations between daily milk consumption and baseline BMD at some skeletal sites but only in subjects with the GG genotype. In conclusion, the Cdx-2 polymorphism alone did not have a substantial effect on BMD in Japanese women. However, this polymorphism might have some effect in women with low calcium intake.


Cdx-2 polymorphism Lifestyle factor Bone mineral density Japanese women Representative sample 



This study was conducted by the JPOS Study Group, comprising Takashi Akiba (Tokyo Medical and Dental University), Etsuko Kajita (Nagoya University), Harumi Nishino (Toyama Institute of Health), Tomoharu Matsukura (Kanazawa University), Toshio Matsumoto (Tokushima University), Yuho Sato (Tenshi College), and Takashi Yamagami (Hokuriku Health Service Association), in addition to the authors, who have obtained financial support from the Japan Milk Promotion Board and the Japan Dairy Council. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and grants from the Japan Society for the Promotion of Science (A#11770211, B#10470114, C#12204105, 1998–2000) and from the Research Society for Metabolic Bone Disease (1999–2001). The authors express their special thanks to the personnel of the health departments of the three municipalities investigated for their excellent support of the study.


  1. 1.
    Cummings SR, Kelsey JL, Nevitt MC, O’Dowd KJ (1985) Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol Rev 7:178–208PubMedGoogle Scholar
  2. 2.
    Riggs BL (1986) Involutional osteoporosis. N Engl J Med 314:1676–1686PubMedCrossRefGoogle Scholar
  3. 3.
    Sone T, Fukunaga M (2004) Prevalence of osteoporosis in Japan and the international comparison. Nippon Rinsho 62(suppl 2):197–200PubMedGoogle Scholar
  4. 4.
    Cummings SR, Melton LJ (2002) Epidemiology and outcomes of osteoporotic fractures. Lancet 359:1761–1767PubMedCrossRefGoogle Scholar
  5. 5.
    Kanis JA, Johnell O, De Laet C, Jonsson B, Oden A, Ogelsby AK (2002) International variations in hip fracture probabilities: implications for risk assessment. J Bone Miner Res 17:1237–1244PubMedGoogle Scholar
  6. 6.
    Kanis JA, Pitt FA (1992) Epidemiology of osteoporosis. Bone 13(suppl 1):S7–S15PubMedGoogle Scholar
  7. 7.
    Salamone LM, Glynn NW, Black DM, Ferrell RE, Palermo L, Epstein RS, Kuller LH, Cauley JA (1996) Determinants of premenopausal bone mineral density: the interplay of genetic and lifestyle factors. J Bone Miner Res 11:1557–1565PubMedGoogle Scholar
  8. 8.
    Hayakawa Y, Yanagi H, Hara S, Amagai H, Endo K, Hamaguchi H, Tomura S (2001) Genetic and environmental factors affecting peak bone mass in premenopausal Japanese women. Environ Health Prev Med 6:177–183CrossRefGoogle Scholar
  9. 9.
    McGuigan FE, Murray L, Gallagher A, Davey-Smith G, Neville CE, Van’t Hof R, Boreham C, Ralston SH (2002) Genetic and environmental determinants of peak bone mass in young men and women. J Bone Miner Res 17:1273–1279PubMedGoogle Scholar
  10. 10.
    Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367:284–287. Erratum Nature 1997;387:106PubMedCrossRefGoogle Scholar
  11. 11.
    Fleet JC, Harris SS, Wood RJ, Dawson-Hughes B (1995) The BsmI vitamin D receptor restriction fragment length polymorphism (BB) predicts low bone density in premenopausal black and white women. J Bone Miner Res 10:985–990PubMedGoogle Scholar
  12. 12.
    Tokita A, Matsumoto H, Morrison NA, Tawa T, Miura Y, Fukamauchi K, Mitsuhashi N, Irimoto M, Yamamori S, Miura M, Watanabe T, Kuwabara Y, Yabuta K, Eisman JA (1996) Vitamin D receptor alleles, bone mineral density and turnover in premenopausal Japanese women. J Bone Miner Res 11:1003–1009PubMedGoogle Scholar
  13. 13.
    Gennari L, Becherini L, Masi L, Gonnelli S, Cepollaro C, Martini S, Mansani R, Brandi M (1997) Vitamin D receptor genotypes and intestinal calcium absorption in postmenopausal women. Calcif Tissue Int 61:460–463PubMedCrossRefGoogle Scholar
  14. 14.
    Langdahl BL, Gnavholt Ch, Brixen K, Eriksan EF (2000) Polymorphisms in the vitamin D receptor gene and bone mass, bone turnover and osteoporotic fractures. Eur J Clin Invest 30:608–617Google Scholar
  15. 15.
    Gross C, Eccleshall TR, Malloy PJ, Villa ML, Marcus R, Feldman D (1996) The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women. J Bone Miner Res 11:1850–1855PubMedGoogle Scholar
  16. 16.
    Arai H, Miyamoto K, Taketani Y, Yamamoto H, Iemori Y, Morita K, Tonai T, Nishisho T, Mori S, Takeda E (1997) A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res 12:915–921PubMedGoogle Scholar
  17. 17.
    Harris SS, Eccleshall TR, Gross C, Dawson-Hughes B, Feldman D (1997) The vitamin D receptor start codon polymorphism (FokI) and bone mineral density in premenopausal American black and white women. J Bone Miner Res 12:1043–1048PubMedGoogle Scholar
  18. 18.
    Peacock M (1995) Vitamin D receptor gene alleles and osteoporosis: a contrasting view. J Bone Miner Res 10:1294–1297PubMedGoogle Scholar
  19. 19.
    Garnero P, Borel O, Sornay-Rendu E, Delmas PD (1995) Vitamin D receptor gene polymorphisms do not predict bone turnover and bone mass in healthy premenopausal women. J Bone Miner Res 10:1283–1288PubMedGoogle Scholar
  20. 20.
    Cooper GS (1996) Genetic studies of osteoporosis: what have we learned? J Bone Miner Res 14:1646–1648Google Scholar
  21. 21.
    Cooper GS, Umbach DM (1996) Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis. J Bone Miner Res 11:1841–1849PubMedCrossRefGoogle Scholar
  22. 22.
    Gong G, Stern HS, Cheng SC, Fong N, Mordeson J, Deng HW, Recker R (1999) The association of bone mineral density with vitamin D receptor gene polymorphisms. Osteoporos Int 9:55–64PubMedGoogle Scholar
  23. 23.
    Mocharla H, Butch AW, Pappas AA, Flick JT, Weinstein RS, De Togni P, Jilka RL, Roberson PK, Parfitt AM, Manolagas SC (1997) Quantification of vitamin D receptor mRNA by competitive polymerase chain reaction in PBMC: lack of correspondence with common allelic variants. J Bone Miner Res 12:726–733PubMedGoogle Scholar
  24. 24.
    Gross C, Krishnan AV, Malloy PJ, Eccleshall TR, Zhao XY, Feldman D (1998) The vitamin D receptor gene start codon polymorphism: a functional analysis of FokI variants. J Bone Miner Res 13:1691–1699PubMedGoogle Scholar
  25. 25.
    Yamamoto H, Miyamoto K, Li B, Taketani Y, Kitano M, Inoue Y, Morita K, Pike JW, Takeda E (1999) The caudal-related homeodomain protein Cdx-2 regulates vitamin D receptor gene expression in the small intestine. J Bone Miner Res 14:240–247PubMedGoogle Scholar
  26. 26.
    Arai H, Miyamoto KI, Yoshida M, Yamamoto H, Taketani Y, Morita K, Kubota M, Yoshida S, Ikeda M, Watabe F, Kanemasa Y, Takeda E (2001) The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Miner Res 16:1256–1264PubMedGoogle Scholar
  27. 27.
    Fang Y, van Meurs JBJ, Arjan P (2003) Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly. J Bone Miner Res 18:1632–1641PubMedGoogle Scholar
  28. 28.
    Iki M, Kagamimori S, Kagawa Y, Matsuzaki T, Yoneshima H, Marumo F (2001) Bone mineral density of the spine, hip and distal forearm in representative samples of the Japanese female population: Japanese Population-Based Osteoporosis (JPOS) Study. Osteoporos Int 12:529–537PubMedCrossRefGoogle Scholar
  29. 29.
    Erdfelder E, Faul F, Buchner A (1996) GPOWER: a general power analysis program. Behav Res Methods Instr Comput 28:1–11Google Scholar
  30. 30.
    McCloskey EV, Spector TD, Eyres KS, Fern ED, O’Rourke N, Vasikaran S, Kanis JA (1993) The assessment of vertebral deformity: a method for use in population studies and clinical trials. Osteoporos Int 3:138–147PubMedCrossRefGoogle Scholar
  31. 31.
    Nathan H (1962) Osteophytes of the vertebral column. J Bone Joint Surg Am 44:243–269Google Scholar
  32. 32.
    Sato Y, Tamaki J, Kitayama F, Kusaka Y, Kodera Y, Koutani A, Iki M (2005) Development of a food-frequency questionnaire to measure the dietary calcium intake of adult Japanese women. Tohoku J Exp Med 207:217–222PubMedGoogle Scholar
  33. 33.
    Livak KJ (1999) Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 14:143–149PubMedGoogle Scholar
  34. 34.
    Barger-Lux MJ, Heaney RP, Hayes J, DeLuca HF, Johnson ML, Gong (1995) Vitamin D receptor gene polymorphism, bone mass, body size and vitamin D receptor density. Calcif Tissue Int 7:161–162Google Scholar
  35. 35.
    Ministry of Health, Labour and Welfare, Japan (2004) The National Nutrition Survey in Japan, 2002. Tokyo, Dai-Ichi ShuppanGoogle Scholar
  36. 36.
    Dawson-Hughes B, Harris SS, Finneran S (1995) Calcium absorption on high and low calcium intakes in relation to vitamin D receptor genotype. J Clin Endocrinol Metab 80:3657–3661PubMedGoogle Scholar
  37. 37.
    Kiel DP, Myers RH, Cupples LA, Kong XF, Zhu XH, Ordovas J, Schaefer EJ, Felson DT, Rush D, Wilson PW, Eisman JA, Holick MF (1997) The BsmI vitamin D receptor restriction fragment length polymorphism (bb) influences the effect of calcium intake on bone mineral density. J Bone Miner Res 12:1049–1057PubMedGoogle Scholar
  38. 38.
    Tsuritani I, Brooke-Wavell KS, Mastana SS, Jones PR, Hardman AE, Yamada Y (1998) Does vitamin D receptor polymorphism influence the response of bone to brisk walking in postmenopausal women? Horm Res 50:315–319PubMedCrossRefGoogle Scholar
  39. 39.
    Omasu F, Kitagawa J, Koyama K, Asakawa K, Yokouchi J, Ando D, Nakahara Y (2004) The influence of VDR genotype and exercise on ultrasound parameters in young adult Japanese women. J Physiol Anthropol Appl Hum Sci 23:49–55CrossRefGoogle Scholar
  40. 40.
    Willing M, Sowers M, Aron D, Clark MK, Burns T, Bunten C, Crutchfield M, D’Agostino D, Jannausch M (1998) Bone mineral density and its change in white women: estrogen and vitamin D receptor genotypes and their interaction. J Bone Miner Res 13:695–705PubMedGoogle Scholar
  41. 41.
    Gennari L, Becherini L, Masi L, Mansani R, Gonnelli S, Cepollaro C, Martini S, Montagnani A, Lentini G, Becorpi AM, Brandi ML (1998) Vitamin D and estrogen receptor allelic variants in Italian postmenopausal women: evidence of multiple gene contribution to bone mineral density. J Clin Endocrinol Metab 83:939–944PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • A. Morita
    • 1
  • M. Iki
    • 1
  • Y. Dohi
    • 2
  • Y. Ikeda
    • 1
  • S. Kagamimori
    • 3
  • Y. Kagawa
    • 4
  • H. Yoneshima
    • 5
  1. 1.Department of Public HealthKinki University School of MedicineOsaka-SayamaJapan
  2. 2.Department of Public HealthNara Medical UniversityKashiharaJapan
  3. 3.Department of Welfare Promotion and EpidemiologyToyama Medical and Pharmaceutical UniversityToyamaJapan
  4. 4.Kagawa Nutrition UniversityTokyoJapan
  5. 5.Kasukabe Shuuwa HospitalKasukabeJapan

Personalised recommendations