How we wish to be cited:
Norberg B. Oral high-dose vitamin B12 and folate – breakthrough by broken hips [editorial]. Rondel 2005; 24. URL: http://www.rondellen.net

Figure The evaluation of Swedish general practitioners (GPs) and geriatricians 1996-1998 of the statement "It is still acceptable to treat a patient with obscure neuropathy with vitamin B12 during 6-36 months and evaluate treatment efficiency by clinical parameters (e.g. performance, walking distance, reappearance of vibration sense and reflexes, reduction of sensory loss, reduction of hair loss, reduction of muscular pain)". The GPs were recruited by random sampling, the geriatricians by a total investigation. The statement was evaluated by 455 women and 513 men without gender differences of opinion. The figure is from Appendix, Statement 24, in the dissertation by Mats Nilsson ("Cobalamin communication in Sweden 1990-2000", Umeå University 2005).

Introduction

The study of Sato and coworkers on oral vitamin B12, 1.5 mg daily, and oral folic acid, 5 mg daily, for elderly people with proven vascular disease provides a breakthrough in B vitamin treatment (1). The study was randomized, prospective, placebo-controlled, double-blind, duration 2 years, adequate sample size (n=628). The treatment reduced the number of hip fractures to 10 per 1000 patient years, as compared with 43 hip fractures in the control group (p<0.001), despite the fact that bone mass and recorded falls were equal in treatment group and in control group. Thus, homocysteine lowering reduces the risk of hip fractures in elderly persons with vascular disease. Or?

It is always a risky project to confirm a research hypothesis by clinical intervention. In ancient Greece, hysteria was thought to be due to womb wandering wild in the body of the woman; hysteria was an exclusively female disease at that time. The hypothesis of etiology was tested by placing foul-smelling substances under the nose of the patient and sweet-scented substances on her private parts in order to allocate the womb to its proper place. The clinical treatment was often successful. Thus, the hypothesis of etiology was supported by the effect of clinical interventions.

The Japanese scientists discuss their observations in a context of homocysteine lowering, bone mass, and bone metabolism. No one doubts that there is a correlation between homocysteine, vascular disease, and osteoporosis. However, the results of clinical trials on homocysteine lowering have hitherto been poor (2-4). The results of a recent study were summarized in the Conclusions of its Abstract (3):

The TrioBe trial (3) with homocysteine lowering by cyanocobalamin 0.5 mg, folic acid 0.8 mg, and pyridoxine 3 mg has been subject to criticism previously (5); although sufficient in folic acid and pyridoxine, the preparation is underdosed in vitamin B12 (5-7). The research of the Berlin group demonstrated that cyanocobalamin, 1 mg daily, is the optimal oral vitamin B12 therapy (5, 7). This observation has been confirmed by modern research (8).

The clinical trials of homocysteine lowering tailored about a decade ago generally used underdoses of vitamin B12, lower than 1 mg daily. It is reasonable to assume that suboptimal B12 doses may have blocked possible positive results (7). Furthermore, it is difficult to see the need of pyridoxine doses 10-15 times greater than the daily need (4); such doses might bear disadvantages (9).

The virtues of the Sato study (1) are the selection of conclusive patients, a conclusive design, and conclusive doses of the two central B vitamins, cobalamin and folate. It is reasonable to assume that the effect of vitamin B12 and folic acid on hip fractures (1) was due to the healing of vitamin-dependent lesions in the nervous system. It is well known that cobalamin/folate deficiency affects plantar sensibility, proprioceptive impulses to the cerebellum, and balance (10). This interpretation opens for the design of future conclusive trials, which might verify or falsify the brilliant observations of the Sato group (1).

The present interpretation of the Sato findings (1) is based on the assumption that homocysteine is an innocent bystander, a marker of B12 deficiency and folate deficiency in old persons with vascular disease.

1. Sato Y, Honda Y, Iwamotu J, Kanoko T, Satoh K. Effect of folate and mecobalamin on hip fractures in patients with stroke. A randomized controlled trial. JAMA 2005; 293:1082-8
2. Jansson J-H. Hypothesis on shaky pillars - homocysteine and vascular disease [evaluation]. Rondel 2004; 21. URL: http://www.rondellen.net/evaluation21_eng.htm
3. Lewerin C, Matousek M, Steen G, Johansson B, Steen B, Nilsson-Ehle H. 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 2005; 81:1155-62
4. Böna KH. First report of the NORVIT study. Eur Soc Cardiol, Stockholm, Sept 5, 2005. MedPage abstract (länk) and Reuters abstract (länk)
5. Norberg B. Treatment of vitamin B12 deficiency – documentation of oral cyanocobalamin [editorial]. Rondel 2005; 22. URL: http://www.rondellen.net/publisher22_eng.htm
6. Lee GR, Bitchell TC, Forster J, Athens JW, Lukens JN (eds). Wintrobe´s Clinical Hematology, Ed 9, p 777-80. Philadelphia: Lea & Febiger; 1993
7. Nilsson M, Norberg B. Adequate dosage of oral cyanocobalamin in vitamin B12 deficiency and homocysteine lowering. Poster P025, Homocysteine Metabolism, 5^th International Conference, Milano, June 26-30, 2005 (pdf-fil)
8. Eussen SJPM, Groot LCPG, Clarke R, Schneede J, Ueland PM, Hoefnagels WHL, Staveren WA. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency. A dose-finding trial. Arch Intern Med 2005; 165:1167-72
9. Hultdin J. Downs syndrome  – should we increase homocysteine [debate]? Rondel 2001; 9. URL: http://www.rondellen.net/debate09_eng.htm
10. Ekstedt J. Cerebellar and proprioceptive function [debate]. Rondel 2001; 7. URL: http://www.rondellen.net/debate07_eng.htm

Published September 14, 2005