Oral vitamin B 12 for patients suspected of subtle cobalamin deficiency : a multicentre pragmatic randomised controlled trial

Background: Evidence regarding the effectiveness of oral vitamin B12 in patients with serum vitamin B12 levels between 125-200 pM/l is lacking. We compared the effectiveness of one-month oral vitamin B12 supplementation in patients with a subtle vitamin B12 deficiency to that of a placebo. Methods: This multicentre (13 general practices, two nursing homes, and one primary care center in western Switzerland), parallel, randomised, controlled, closed-label, observer-blind trial included 50 patients with serum vitamin B12 levels between 125-200 pM/l who were randomized to receive either oral vitamin B12 (1000 μg daily, N = 26) or placebo (N = 24) for four weeks. The institution’s pharmacist used simple randomisation to generate a table and allocate treatments. The primary outcome was the change in serum methylmalonic acid (MMA) levels after one month of treatment. Secondary outcomes were changes in total homocysteine and serum vitamin B12 levels. Blood samples were centralised for analysis and adherence to treatment was verified by an electronic device (MEMS; Aardex Europe, Switzerland). Trial registration: ISRCTN 22063938. Results: Baseline characteristics and adherence to treatment were similar in both groups. After one month, one patient in the placebo group was lost to follow-up. Data were evaluated by intention-to-treat analysis. One month of vitamin B12 treatment (N = 26) lowered serum MMA levels by 0.13 μmol/l (95%CI 0.06-0.19) more than the change observed in the placebo group (N = 23). The number of patients needed to treat to detect a metabolic response in MMA after one month was 2.6 (95% CI 1.7-6.4). A significant change was observed for the B12 serum level, but not for the homocysteine level, hematocrit, or mean corpuscular volume. After three months without active treatment (at four months), significant differences in MMA levels were no longer detected. Conclusions: Oral vitamin B12 treatment normalised the metabolic markers of vitamin B12 deficiency. However, a one-month daily treatment with1000 μg oral vitamin B12 was not sufficient to normalise the deficiency markers for four months, and treatment had no effect on haematological signs of B12 deficiency. Background Vitamin B12 deficiency (less than 150 pM/l) is common in elderly people, with the reported prevalence ranging from 15% to 20% [1,2]. Most patients show no evidence of megaloblastic anaemia; however, these patients are still at risk for neurological abnormalities [3]. Furthermore, vitamin B12 deficiency leads to hyperhomocysteinemia, an independent risk factor for ischemic heart disease [4] and dementia [5]. Comparisons between patients with known complications and “normal” control patients [6] have produced several definitions of cobalamin deficiency. Over the past 15 years, the definition of vitamin B12 deficiency has included determination of two metabolites due to their favourable sensitivities and specificities: serum methylmalonic acid (MMA) and homocysteine (Hcys) [7,8]. Over the past few decades, a number of publications and two randomised controlled trials have demonstrated that oral B12 is as efficacious as * Correspondence: bernard.favrat@hospvd.ch † Contributed equally Department of Ambulatory Care and Community Medicine, University of Lausanne, Bugnon 44, CH-1011 Lausanne, Switzerland Full list of author information is available at the end of the article Favrat et al. BMC Family Practice 2011, 12:2 http://www.biomedcentral. com/1471-2296/12/2 © 2011 Favrat et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. intramuscular injection, especially for normalising metabolic markers of cobalamin deficiency [9-13], and is also cost-effective [14]. Nevertheless, there is a lack of randomised placebocontrolled trials to validate the use of oral vitamin B12 therapy [15]. Furthermore, few randomised placebocontrolled trials have evaluated the biological impact of oral therapy (1000 μg/d) in general practice for borderline serum vitamin B12 concentrations (125-200 pM/l) among patients without pernicious anaemia [16,17]. Our objective was to evaluate the efficacy of oral cobalamin in reducing MMA levels in patients suspected of vitamin B12 deficiency but with borderline vitamin B12 concentrations. This type of study is important for helping to determine whether the MMA level “indicates or predicts a clinical condition in need of treatment” [18].