Osteoporosis International

, Volume 25, Issue 1, pp 131–140 | Cite as

Low holotranscobalamin and cobalamins predict incident fractures in elderly men: the MrOS Sweden

  • C. LewerinEmail author
  • H. Nilsson-Ehle
  • S. Jacobsson
  • H. Johansson
  • V. Sundh
  • M. K. Karlsson
  • Ö. Ljunggren
  • M. Lorentzon
  • J. A. Kanis
  • U. H. Lerner
  • S. R. Cummings
  • C. Ohlsson
  • D. Mellström
Original Article



In a population-based study on cobalamin status and incident fractures in elderly men (n = 790) with an average follow-up of 5.9 years, we found that low levels of metabolically active and total cobalamins predict incident fractures, independently of body mass index (BMI), bone mineral density (BMD), plasma total homocysteine (tHcy), and cystatin C.


Cobalamin deficiency in elderlies may affect bone metabolism. This study aims to determine whether serum cobalamins or holotranscobalamin (holoTC; the metabolic active cobalamin) predict incident fractures in old men.


Men participating in the Gothenburg part of the population-based Osteoporotic Fractures in Men (MrOS) Sweden cohort and without ongoing vitamin B medication were included in the present study (n = 790; age range, 70–81 years).


During an average follow-up of 5.9 years, 110 men sustained X-ray-verified fractures including 45 men with clinical vertebral fractures. The risk of fracture (adjusted for age, smoking, BMI, BMD, falls, prevalent fracture, tHcy, cystatin C, 25-OH-vitamin D, intake of calcium, and physical activity (fully adjusted)), increased per each standard deviation decrease in cobalamins (hazard ratio (HR), 1.38; 95 % confidence intervals (CI), 1.11–1.72) and holoTC (HR, 1.26; 95 % CI, 1.03–1.54), respectively. Men in the lowest quartile of cobalamins and holoTC (fully adjusted) had an increased risk of all fracture (cobalamins, HR = 1.67 (95 % CI, 1.06–2.62); holoTC, HR = 1.74 (95 % CI, 1.12–2.69)) compared with quartiles 2–4. No associations between folate or tHcy and incident fractures were seen.


We present novel data showing that low levels of holoTC and cobalamins predicting incident fracture in elderly men. This association remained after adjustment for BMI, BMD, tHcy, and cystatin C. However, any causal relationship between low cobalamin status and fractures should be explored in a prospective treatment study.


Cobalamins Holotranscobalamin Homocysteine Fractures Men 



The research was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, and the ALF/LUA research grant in Gothenburg.

Conflicts of interest



  1. 1.
    Loikas S, Koskinen P, Irjala K, Lopponen M, Isoaho R, Kivela SL, Pelliniemi TT (2007) Vitamin B12 deficiency in the aged: a population-based study. Age Ageing 36:177–183PubMedCrossRefGoogle Scholar
  2. 2.
    Lewerin C, Jacobsson S, Lindstedt G, Nilsson-Ehle H (2008) Serum biomarkers for atrophic gastritis and antibodies against Helicobacter pylori in the elderly: implications for vitamin B12, folic acid and iron status and response to oral vitamin therapy. Scand J Gastroenterol 43:1050–1056PubMedCrossRefGoogle Scholar
  3. 3.
    Carmel R, Lau KH, Baylink DJ, Saxena S, Singer FR (1988) Cobalamin and osteoblast-specific proteins. N Engl J Med 319:70–75PubMedCrossRefGoogle Scholar
  4. 4.
    Espallargues M, Sampietro-Colom L, Estrada MD, Sola M, del Rio L, Setoain J, Granados A (2001) Identifying bone-mass-related risk factors for fracture to guide bone densitometry measurements: a systematic review of the literature. Osteoporos Int 12:811–822PubMedCrossRefGoogle Scholar
  5. 5.
    Herrmann M, Peter Schmidt J, Umanskaya N, Wagner A, Taban-Shomal O, Widmann T, Colaianni G, Wildemann B, Herrmann W (2007) The role of hyperhomocysteinemia as well as folate, vitamin B(6) and B(12) deficiencies in osteoporosis: a systematic review. Clin Chem Lab Med 45:1621–1632PubMedGoogle 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.
    van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM et al (2004) Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 350:2033–2041PubMedCrossRefGoogle Scholar
  8. 8.
    Yazdanpanah N, Zillikens MC, Rivadeneira F, de Jong R, Lindemans J, Uitterlinden AG, Pols HA, van Meurs JB (2007) Effect of dietary B vitamins on BMD and risk of fracture in elderly men and women: the Rotterdam study. Bone 41:987–994PubMedCrossRefGoogle Scholar
  9. 9.
    McLean RR, Jacques PF, Selhub J, Fredman L, Tucker KL, Samelson EJ, Kiel DP, Cupples LA, Hannan MT (2008) Plasma B vitamins, homocysteine, and their relation with bone loss and hip fracture in elderly men and women. J Clin Endocrinol Metab 93:2206–2212PubMedCrossRefGoogle Scholar
  10. 10.
    van Wijngaarden JP, Dhonukshe-Rutten RA, van Schoor NM et al (2011) Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence. BMC Geriatr 11:80PubMedCentralPubMedCrossRefGoogle 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.
    Carmel R (2011) Biomarkers of cobalamin (vitamin B-12) status in the epidemiologic setting: a critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II. Am J Clin Nutr 94:348S–358SPubMedCrossRefGoogle Scholar
  14. 14.
    Lewerin C, Ljungman S, Nilsson-Ehle H (2007) Glomerular filtration rate as measured by serum cystatin C is an important determinant of plasma homocysteine and serum methylmalonic acid in the elderly. J Intern Med 261:65–73PubMedCrossRefGoogle Scholar
  15. 15.
    Quadros EV (2010) Advances in the understanding of cobalamin assimilation and metabolism. Br J Haematol 148:195–204PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Ulleland M, Eilertsen I, Quadros EV, Rothenberg SP, Fedosov SN, Sundrehagen E, Orning L (2002) Direct assay for cobalamin bound to transcobalamin (holo-transcobalamin) in serum. Clin Chem 48:526–532PubMedGoogle Scholar
  17. 17.
    Herrmann W, Obeid R, Schorr H, Geisel J (2003) Functional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk. Clin Chem Lab Med 41:1478–1488PubMedGoogle Scholar
  18. 18.
    Mellstrom D, Johnell O, Ljunggren O, Eriksson AL, Lorentzon M, Mallmin H, Holmberg A, Redlund-Johnell I, Orwoll E, Ohlsson C (2006) Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden. J Bone Miner Res 21:529–535PubMedCrossRefGoogle Scholar
  19. 19.
    Washburn RA, Smith KW, Jette AM, Janney CA (1993) The Physical Activity Scale for the Elderly (PASE): development and evaluation. J Clin Epidemiol 46:153–162PubMedCrossRefGoogle Scholar
  20. 20.
    Ribom EL, Grundberg E, Mallmin H, Ohlsson C, Lorenzon M, Orwoll E, Holmberg AH, Mellstrom D, Ljunggren O, Karlsson MK (2009) Estimation of physical performance and measurements of habitual physical activity may capture men with high risk to fall—data from the Mr Os Sweden cohort. Arch Gerontol Geriatr 49:e72–e76PubMedCrossRefGoogle Scholar
  21. 21.
    Mellstrom D, Vandenput L, Mallmin H et al (2008) Older men with low serum estradiol and high serum SHBG have an increased risk of fractures. J Bone Miner Res 23:1552–1560PubMedCrossRefGoogle Scholar
  22. 22.
    Orning L, Rian A, Campbell A, Brady J, Fedosov SN, Bramlage B, Thompson K, Quadros EV (2006) Characterization of a monoclonal antibody with specificity for holo-transcobalamin. Nutr Metab Lond 3:3PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Brady J, Wilson L, McGregor L, Valente E, Orning L (2008) Active B12: a rapid, automated assay for holotranscobalamin on the Abbott AxSYM analyzer. Clin Chem 54:567–573PubMedCrossRefGoogle Scholar
  24. 24.
    Johansson H, Oden A, Lerner UH, et al. (2012) High serum adiponectin predicts incident fractures in elderly men. Mr OS Sweden. J Bone Miner Res 27:1390–1396Google Scholar
  25. 25.
    Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U, Mellstrom D (2009) Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Miner Res 24:785–791PubMedCrossRefGoogle Scholar
  26. 26.
    Harrell FE (ed) (2001) General aspects of fitting regression models: regression modeling strategies. Springer, New YorkGoogle Scholar
  27. 27.
    Lindenbaum J, Rosenberg IH, Wilson PW, Stabler SP, Allen RH (1994) Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr 60:2–11PubMedGoogle Scholar
  28. 28.
    Lewerin C, Nilsson-Ehle H, Jacobsson S, Karlsson MK, Ohlsson C, Mellstrom D (2013) Holotranscobalamin is not influenced by decreased renal function in elderly men: the MrOS Sweden study. Ann Clin Biochem (in press)Google Scholar
  29. 29.
    Obeid R, Herrmann W (2007) Holotranscobalamin in laboratory diagnosis of cobalamin deficiency compared to total cobalamin and methylmalonic acid. Clin Chem Lab Med 45:1746–1750PubMedGoogle Scholar
  30. 30.
    Nilsson K, Gustafson L, Isaksson A, Hultberg B (2005) Plasma homocysteine and markers of bone metabolism in psychogeriatric patients. Scand J Clin Lab Invest 65:671–680PubMedCrossRefGoogle Scholar
  31. 31.
    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
  32. 32.
    Herrmann M, Schmidt J, Umanskaya N, Colaianni G, Al Marrawi F, Widmann T, Zallone A, Wildemann B, Herrmann W (2007) Stimulation of osteoclast activity by low B-vitamin concentrations. Bone 41:584–591PubMedCrossRefGoogle Scholar
  33. 33.
    Vaes BL, Lute C, Blom HJ, Bravenboer N, de Vries TJ, Everts V, Dhonukshe-Rutten RA, Muller M, de Groot LC, Steegenga WT (2009) Vitamin B(12) deficiency stimulates osteoclastogenesis via increased homocysteine and methylmalonic acid. Calcif Tissue Int 84:413–422PubMedCrossRefGoogle Scholar
  34. 34.
    Herrmann M, Umanskaya N, Wildemann B, Colaianni G, Schmidt J, Widmann T, Zallone A, Herrmann W (2007) Accumulation of homocysteine by decreasing concentrations of folate, vitamin B12 and B6 does not influence the activity of human osteoblasts in vitro. Clin Chim Acta 384:129–134PubMedCrossRefGoogle Scholar
  35. 35.
    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
  36. 36.
    Tucker KL, Hannan MT, Qiao N, Jacques PF, Selhub J, Cupples LA, Kiel DP (2005) Low plasma vitamin B12 is associated with lower BMD: the Framingham Osteoporosis Study. J Bone Miner Res 20:152–158PubMedCrossRefGoogle Scholar
  37. 37.
    Gjesdal CG, Vollset SE, Ueland PM, Refsum H, Drevon CA, Gjessing HK, Tell GS (2006) Plasma total homocysteine level and bone mineral density: the Hordaland Homocysteine Study. Arch Intern Med 166:88–94PubMedCrossRefGoogle Scholar
  38. 38.
    Lewerin C, Matousek M, Steen G, Johansson B, Steen B, Nilsson-Ehle H (2005) Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study. Am J Clin Nutr 81:1155–1162PubMedGoogle Scholar
  39. 39.
    Samieri C, Ginder Coupez V, Lorrain S, Letenneur L, Alles B, Feart C, Paineau D, Barberger-Gateau P (2013) Nutrient patterns and risk of fracture in older subjects: results from the Three-City Study. Osteoporos Int 24:1295–1305PubMedCrossRefGoogle Scholar
  40. 40.
    Ensrud KE, Parimi N, Cauley JA, Ishani A, Slinin Y, Hillier TA, Taylor BC, Steffes M, Cummings SR (2013) Cystatin C and risk of hip fractures in older women. J Bone Miner Res (in press)Google Scholar
  41. 41.
    Leboff MS, Narweker R, LaCroix A et al (2009) Homocysteine levels and risk of hip fracture in postmenopausal women. J Clin Endocrinol Metab 94:1207–1213PubMedCrossRefGoogle Scholar
  42. 42.
    LaCroix AZ, Lee JS, Wu L et al (2008) Cystatin-C, renal function, and incidence of hip fracture in postmenopausal women. J Am Geriatr Soc 56:1434–1441PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Ensrud KE, Lui LY, Taylor BC, Ishani A, Shlipak MG, Stone KL, Cauley JA, Jamal SA, Antoniucci DM, Cummings SR (2007) Renal function and risk of hip and vertebral fractures in older women. Arch Intern Med 167:133–139PubMedCrossRefGoogle Scholar
  44. 44.
    Fried LF, Biggs ML, Shlipak MG et al (2007) Association of kidney function with incident hip fracture in older adults. J Am Soc Nephrol 18:282–286PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2013

Authors and Affiliations

  • C. Lewerin
    • 1
    • 11
    Email author
  • H. Nilsson-Ehle
    • 1
  • S. Jacobsson
    • 2
  • H. Johansson
    • 4
  • V. Sundh
    • 7
  • M. K. Karlsson
    • 8
  • Ö. Ljunggren
    • 9
  • M. Lorentzon
    • 4
  • J. A. Kanis
    • 5
  • U. H. Lerner
    • 3
    • 6
  • S. R. Cummings
    • 10
  • C. Ohlsson
    • 3
  • D. Mellström
    • 4
  1. 1.Section of Hematology and Coagulation, Department of Internal MedicineInstitute of Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
  2. 2.Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
  3. 3.Center for Bone and Arthritis Research (CBAR), Department of Internal Medicine, Institute of Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
  4. 4.Center for Bone and Arthritis Research (CBAR) and Geriatric Medicine, Institute of Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
  5. 5.WHO Collaborating Centre for Metabolic Bone DiseasesUniversity of SheffieldSheffieldUK
  6. 6.Molecular PeriodontologyUmeå UniversityUmeåSweden
  7. 7.Department of Geriatric Medicine, Internal Medicine, Institute of Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
  8. 8.Department of Clinical Sciences and OrthopaedicsLund UniversityMalmöSweden
  9. 9.Department of Medical SciencesUniversity of UppsalaUppsalaSweden
  10. 10.San Francisco Coordinating CenterCalifornia Pacific Medical Center Research Institute and the University of CaliforniaSan FranciscoUSA
  11. 11.Section of Hematology and Coagulation, Department of MedicineSahlgrenska University HospitalGothenburgSweden

Personalised recommendations