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Original article

Vol. 147 No. 1314 (2017)

Early biomarker response and patient preferences to oral and intramuscular vitamin B12 substitution in primary care: a randomised parallel-group trial

Cite this as:
Swiss Med Wkly. 2017;147:w14421



Vitamin B12 (VB12) deficiency can be treated with oral high-dose substitution or intramuscular (IM) injection of VB12. Whenever alternative routes of administration exist, patient preferences should be considered when choosing the treatment. We aimed to assess outpatient preferences towards oral or IM VB12 substitution and confirm noninferiority of early biomarker response with oral treatment, in a typical primary care population.


Prospective randomised nonblinded parallel-group trial. Patients were recruited by their general practitioner and randomly assigned to oral or IM treatment. Group O-oral was given 28 tablets of 1000 µg cyanocobalamin in a monthly punch card fitted with an electronic monitoring system. Group I-IM received four weekly injections of 1000 µg hydroxocobalamin. Blood samples were drawn before the first administration and after 1, 2 and 4 weeks of treatment, and analysed for VB12, holotranscobalamin (HoloTc), homocysteine (Hcy) and methylmalonic acid (MMA). For group O-oral, treatment adherence and percentage of days with ≥2 dosing events were calculated. Before and after 28 days of treatment, patients were asked to fill in a questionnaire about their preference for the therapy options and associated factors.


Between November 2013 and December 2015, 37 patients (age: 49.5 ± 18.5 years; women: 60.5%) were recruited for oral (19) or IM (18) treatment. Baseline values with 95% confidence intervals for serum VB12, HoloTc, Hcy and MMA were 158 pmol/l [145–172], 49.0 pmol/l [40.4–57.5], 14.8 µmol/l [12.0–17.7] and 304 nmol/l [219–390], respectively, in group O-oral and 164 pmol/l [154–174], 50.1 pmol/l [38.7–61.6], 13.0 µmol/l [11.0–15.1] and 321 nmol/l [215–427], respectively, in group I-IM (not significant). After 1 month of treatment, levels of VB12 and HoloTc showed a significant increase compared with baseline (group O-oral: VB12 354 pmol/l [298–410] and HoloTc 156 pmol/l [116–196]; group I-IM: VB12 2796 pmol/l [1277–4314] and HoloTc 1269 pmol/l [103–2435]). Hcy and MMA levels showed a significant decrease compared with baseline (group O-oral: Hcy 13.8 µmol/l [10.7–16.8] and MMA 168 nmol/l [134–202]; group I-IM: Hcy 8.5 µmol/l [7.1–9.8] and MMA 156 nmol/l [121–190]). HoloTc and MMA levels were normalised in all patients after 4 weeks of treatment, whereas normalisation of VB12 and Hcy was reached by all patients in group I-IM only. Response of VB12, HoloTc and Hcy was more pronounced in group I-IM (p <0.01) and the primary hypothesis that oral VB12 treatment would be noninferior to IM treatment was rejected. Average adherence to therapy was 99.6 ± 1.1% and days with ≥2 dosing events reached 5.6%. Before randomisation, preference was in favour of oral treatment (45.9%, n = 17) over IM administration (21.6%, n = 8). Twelve patients (32.4%) had no preference. Nine (24.3%) patients changed their preference after treatment. Patients who obtained their preferred route of administration maintained their preference in the case of oral treatment and changed their preference after IM treatment.


Differences in VB12 levels between groups were higher than expected. Therefore, noninferiority of oral treatment had to be rejected. However, normalisation of HoloTc and MMA was reached by all patients after a 1-month treatment period. The clinical benefit of the exaggerated biomarker response after IM treatment within a typical primary care population is questionable. Midterm biomarker effects and patient preferences should be considered when a therapeutic scheme is chosen. Initial rating in favour of either IM or oral therapy can change over time and justifies repeated re-evaluation of patient preferences. ( ID NCT01832129)


  1. Tucker KL, Rich S, Rosenberg I, Jacques P, Dallal G, Wilson PW, et al. Plasma vitamin B-12 concentrations relate to intake source in the Framingham Offspring study. Am J Clin Nutr. 2000;71(2):514–22.
  2. Wong CW. Vitamin B12 deficiency in the elderly: is it worth screening? Hong Kong Med J. 2015;21(2):155–64.
  3. Andrès E, Affenberger S, Vinzio S, Kurtz JE, Noel E, Kaltenbach G, et al. Food-cobalamin malabsorption in elderly patients: clinical manifestations and treatment. Am J Med. 2005;118(10):1154–9.
  4. Andrès E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ. 2004;171(3):251–9.
  5. Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003;67(5):979–86.
  6. Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003;78(1):131–6.
  7. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med. 1999;159(12):1289–98.
  8. Dali-Youcef N, Andrès E. An update on cobalamin deficiency in adults. QJM. 2009;102(1):17–28.
  9. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435–42.
  10. Dharmarajan TS, Kanagala MR, Murakonda P, Lebelt AS, Norkus EP. Do acid-lowering agents affect vitamin B12 status in older adults? J Am Med Dir Assoc. 2008;9(3):162–7.
  11. de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010;340(may19 4):c2181.
  12. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013;368(2):149–60.
  13. Bergen C, Compher C. Total homocysteine concentration and associated cardiovascular and renal implications in adults. J Cardiovasc Nurs. 2006;21(1):40–6.
  14. Pawlak R. Is vitamin B12 deficiency a risk factor for cardiovascular disease in vegetarians? Am J Prev Med. 2015;48(6):e11–26.
  15. Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337(4):230–7.
  16. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002;346(7):476–83.
  17. Schrier SL. Diagnosis and treatment of vitamin B 12 and folic acid deficiency (last update September 2016). UpToDate [Internet]. Available from:
  18. Hvas AM, Nexo E. Holotranscobalamin--a first choice assay for diagnosing early vitamin B deficiency? J Intern Med. 2005;257(3):289–98.
  19. Nexo E, Hoffmann-Lücke E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am J Clin Nutr. 2011;94(1):359S–65S.
  20. Yetley EA, Pfeiffer CM, Phinney KW, Bailey RL, Blackmore S, Bock JL, et al. Biomarkers of vitamin B-12 status in NHANES: a roundtable summary. Am J Clin Nutr. 2011;94(1):313S–21S.
  21. Kind A, Marty F. Vitamin B12 alle drei Monate substituieren? Prim Care. 2008;8(10):177–8. [Article in German.].
  22. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998;92(4):1191–8.
  23. Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barutca S, Senturk T. Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study. Clin Ther. 2003;25(12):3124–34.
  24. Favrat B, Vaucher P, Herzig L, Burnand B, Ali G, Boulat O, et al. Oral vitamin B12 for patients suspected of subtle cobalamin deficiency: a multicentre pragmatic randomised controlled trial. BMC Fam Pract. 2011;12(1):2.
  25. Adachi S, Kawamoto T, Otsuka M, Todoroki T, Fukao K. Enteral vitamin B12 supplements reverse postgastrectomy B12 deficiency. Ann Surg. 2000;232(2):199–201.
  26. Vidal-Alaball J, Butler CC, Cannings-John R, Goringe A, Hood K, McCaddon A, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev. 2005;(3):CD004655.
  27. van Walraven C, Austin P, Naylor CD. Vitamin B12 injections versus oral supplements. How much money could be saved by switching from injections to pills? Can Fam Physician. 2001;47:79–86.
  28. Webb DG, Horne R, Pinching AJ. Treatment-related empowerment: preliminary evaluation of a new measure in patients with advanced HIV disease. Int J STD AIDS. 2001;12(2):103–7.
  29. Arnet I, Walter PN, Hersberger KE. Polymedication Electronic Monitoring System (POEMS) - a new technology for measuring adherence. Front Pharmacol. 2013;4:26.
  30. Eussen SJ, de Groot LC, Joosten LW, Bloo RJ, Clarke R, Ueland PM, et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr. 2006;84(2):361–70.
  31. Castelli MC, Friedman K, Sherry J, Brazzillo K, Genoble L, Bhargava P, et al. Comparing the efficacy and tolerability of a new daily oral vitamin B12 formulation and intermittent intramuscular vitamin B12 in normalizing low cobalamin levels: a randomized, open-label, parallel-group study. Clin Ther. 2011;33(3):358–371.e2.
  32. Hall CA, Begley JA, Green-Colligan PD. The availability of therapeutic hydroxocobalamin to cells. Blood. 1984;63(2):335–41.
  33. Torsvik I, Ueland PM, Markestad T, Bjørke-Monsen AL. Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study. Am J Clin Nutr. 2013;98(5):1233–40.
  34. Obeid R, Fedosov SN, Nexo E. Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency. Mol Nutr Food Res. 2015;59(7):1364–72.
  35. Marshall Chalmers JN, Shinton NK. Comparison of hydroxocobalamin and cyanocobalamin in the treatment of pernicious anaemia. Lancet. 1965;286(7426):1305–8.
  36. Tillemans MP, Donders EM, Verweij SL, Van der Hoeven RT, Kalisvaart KJ. Effect of administration route on the pharmacokinetics of cobalamin in elderly patients: a randomized controlled trial. Curr Ther Res Clin Exp. 2014;76:21–5.
  37. Hertz H, Kristensen HP, Hoff-Jorgensen E. Studies on Vitamin B12 Retention. Comparison of Retention Following Intramuscular Injection of Cyanocobalamin and Hydroxocobalamin. Scand J Haematol. 1964;1(1):5–15.
  38. Nyholm E, Turpin P, Swain D, Cunningham B, Daly S, Nightingale P, et al. Oral vitamin B12 can change our practice. Postgrad Med J. 2003;79(930):218–20.
  39. Aparicio-Ugarriza R, Palacios G, Alder M, González-Gross M. A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population. Clin Chem Lab Med. 2015;53(8):1149–59.
  40. Hvas AM, Nexo E. Diagnosis and treatment of vitamin B12 deficiency--an update. Haematologica. 2006;91(11):1506–12.
  41. Pezacka E, Green R, Jacobsen DW. Glutathionylcobalamin as an intermediate in the formation of cobalamin coenzymes. Biochem Biophys Res Commun. 1990;169(2):443–50.
  42. Kwong JC, Carr D, Dhalla IA, Tom-Kun D, Upshur RE. Oral vitamin B12 therapy in the primary care setting: a qualitative and quantitative study of patient perspectives. BMC Fam Pract. 2005;6(1):8.