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Lökk J. Advice for assessors - how to read context and content of the Bolaman paper [debate]. Rondel 2008; 28. URL: http://www.rondellen.net

Advice for assessors
How to read context and content of the Bolaman paper

Form and content

A previous author has emphasised the difficulties of assessing the clinical documentation of parenteral and enteral therapy with vitamin B12 (2). From a formal point of view, the Bolaman paper is appraised by most assessors (1). At present, it is one out of two comparisons between tablets and injections in the shape of a randomised prospective trial (1,2).

The Bolaman study is open-labelled and two-armed (1). It was performed in the city of Aydin in Turkey and ran from Jan 1999 to Jan 2003. The treatment duration was 90 days. The age of the patients ranged between 32-87 years.  In the oral group, there were 16 men and 10 women. In the parenteral group, there were 17 men and 17 women.

The evaluation of the trial was mainly based on objective parameters such as haemoglobin values, mean corpuscular volumes, and assays of serum vitamin B12 levels (Table 1).

It is evident from Table 1 that the patients of the study suffered from megaloblastic anaemia due to vitmin B12 deficiency at baseline. The deficiency was thought to be due mainly to starvation, protein-poor diet, and atrophic gastritis. About 10-20% of the patients appeared to have neurological signs and symptoms due to vitamin B12 deficiency.

The main conclusion of the authors is that oral treatment of vitamin B12 deficiency was as efficient as parenteral treatment in the context of the Bolaman study (1).

Modern assessors appear to accept the design and the results of the Bolaman study with the reservation that no formal test of equivalence or inferiority was performed (cf Table 1).

The aim of the present analysis is to elucidate some major problems presented between the lines of the Bolaman paper (1).
 

The parenteral arm

The patients of the parenteral arm were treated with 1000 mcg cyanocobalamin i.m. daily for 10 days. This loading treatment was followed by similar injections weekly for four weeks, then one injection each month for life.

The retainment of vitamin B12 in body stores of each patient may be estimated by means of the rules of thumb given in the mainstream textbook of global hematology in the period 1942-1993 (3).

By the first injections, 150 mcg were retained; the rest were excreted into the urine. The following nine days, the transport capacity for B12 in plasma most certainly was saturated. It is approximated that another 150 mcg were retained (cf 3).

Furthermore, it is estimated that 900 mcg was retained during the rest of the trial, totalling approximately 1200 mcg to body stores, producing the serum levels seen in Table 1.
 

The oral arm

The body stores of vitamin B12 are thought to range between 800 and 11,000 mcg, usually between 3000 and 5000. When signs and symptoms of deficiency appear, body stores have shrunk to 500 mcg (100-700). From an oral preparation, approximately 1% is absorbed by passive diffusion independent of intrinsic factor. When tablets are not available, oral solutions may be prepared by mixing injectabile in fruit juice (3).

Since 1000 mcg tablets of cyanocobalamin were not available in Turkey at the time of the Bolaman study (1), oral preparations from injectabile were served in fruit juice. The time schedule was analogous to that of the parenteral arm. However, this regimen is calculated to result in only 160 mcg vitamin B12 retained in body stores, i.e. approximately 13% of the amount stored by the patients in the injection arm.

In spite of the obvious differences in calculated stores, the serum values were similar in the two arms (Table 1). The serum values were of the same order of magnitude as those observed in the parenteral arm of the Kuzminski study (2,4).

The results of the Bolaman trial support the old concept that initial clinical response, haematological and clinical, may be kindled by minute amounts of vitamin B12. The stores serve as safeguard against future relapses of overt deficiency (3).

It should be emphasised that even some of the neurological signs and symptoms responded to the undersized oral treatment in the Bolaman study (1).
 

Discussion

The Bolaman study is essential from several points of view (1). It shows that Turks respond to oral vitamin B12 treatment, like all other nationalities tested hitherto. The Bolaman study also confirms the observations from the period 1950-1970, when starvation and protein deficiency occurred in the patient groups diagnosed and treated. Such patient materials are rare now.

The classical objectives of deficiency treatment with vitamin B12 are (3):

1. supply amounts which correct deficiency signs and symptoms in the remission stage of treatment;
2. provide amounts which refill depleted body stores;
3. prevent relapses of overt deficiency, usually by life-long maintenance treatment.

It is evident that neither injection treatment nor oral treatment in the Bolaman trial (1) met demands B and C above. Nevertheless, both regimens cured the signs and symptoms of vitamin B12 deficiency during “remission treatment” (jfr 1,3).

Furthermore, the number of patients was small in the Bolaman study (Table 1). From previous experience, it is expected that the distribution of determinations of haemoglobin, mean corpuscular volume, and serum vitamin B12 was wide and skew. Thus, median values, interquartile ranges, and spans should have been used throughout for statistical description and analysis (5).

It is perhaps not impossible to design a randomised prospective analysis of oral versus parenteral therapy with vitamin B12. However, the specific pitfalls of vitamin B12 pharmacokinetics create difficulties.

It might be better to accept the testimony of clinical practice that both parenteral preparations and oral preparations may restore vitamin B12 deficiency, when served in adequate preparations according to regimens based on sound pharmacological principles (cf 2,3,6).
 

Conclusion

Some of the schedules of remission treatment with injections are not based on sound pharmacokinetics and sound clinical practice (1-3). In countries where physicians are not experienced with oral vitamin B12, this regimen might better be reserved for maintenance treatment only.

Johan Lökk
MD, PhD, Associate Professor
Specialist in Internal Medicine and Geriatrics
Senior Consultant
Karolinska University Hospital Huddinge;
Department of Neurobiology, Care Science, and Society;
Karolinska Institutet
Stockholm, Sweden 
 

References

1.   Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barultca S, Senturk T. Oral versus intramuscular cobalamin treatment in megaloblastic anemia: A single-center, prospective, randomized, open-label study. Clin Ther 2003; 25:3124-34.

2.   Nilsson M. Advice for assessors – how to read context and content of the Kuzminski paper [evaluation]. Rondel 2008; 28. URL: http://www.rondellen.net/evaluation28_eng.htm

3.   Lee GR, Bitchell TC, Forster J, Athens JW, Lukens JN, eds. Wintrobe´s Clinical Hematology, Ed 9. Philadelphia : Lea & Febiger. 1993;777-80

4.   Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency sith oral cobalamin. Blood 1998; 92:1191-8

5.   Siegel S, Castellan NJ Jr. Nonparametric statistics for behavioural sciences (1956). 2^nd ed. McGraw-Hill, New York 1988

6.   Norberg B. Deficiency of vitamin B12 and folate – the branded generic for optimal oral therapy [editorial]. Rondel 2008; 28. URL: http://www.rondellen.net/publisher28_eng.htm

Published December 31, 2008