British Paediatric and Adolescent Bone Group’s position statement on vitamin D deficiency
BMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e8182 (Published 03 December 2012) Cite this as: BMJ 2012;345:e8182
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Response to Position Statement on Vitamin D Deficiency by the British Paediatric and Adolescent Bone Group.
Ann Bowron principal clinical biochemist 1, G D Carter DEQAS Organiser 2
1 University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
2 Imperial College Healthcare NHS Trust, Charing Cross Hospital, London, UK.
The recent position statement on vitamin D deficiency by the British Paediatric and Adolescent Bone Group1 is the latest of several sets of guidelines, the most comprehensive of which are those published by the US Institute of Medicine (IOS) 2. The conclusions and recommendations of the Bone Group are similar to those of the IOS.
Common to all recent guidelines is the use of single cut-off points for serum 25-hydroxyvitamin D (25-OHD), measurement of which is universally used for the assessment of vitamin D status. Whilst this has the merit of simplicity, we believe use of a single 25-OHD value ignores method related differences that have made comparisons of clinical studies so difficult.
Table 1 records the results of 4 samples distributed by the international Vitamin D External Quality Assessment Scheme (DEQAS) over the last year. These were samples with mean values close to 50 nmol/L, the suggested cut-off point between vitamin D insufficiency and sufficiency. Comparison of results given by the four most widely used 25-OHD assays shows that the incidence of vitamin D insufficiency will vary depending on which analytical method is used if the recommended cut-off values are applied universally.
In conclusion, rigid adherence to a single 25-OHD cut-off point for diagnosing vitamin D deficiency can be misleading due to method-related differences in reported values. Clinicians should make themselves aware of which method their local laboratory uses, and how this might influence the interpretation of 25-OHD results.
Similarly, editors reporting clinical trials involving 25-OHD measurements should require authors to give details of the method used and its performance in proficiency testing schemes.
References
1. Arundel P, Ahmed SF, Allgrove J, Bishop NJ, Burren CP et al. British Paediatric and Adolescent Bone Group’s position statement on vitamin D deficiency. BMJ 2012;345:e8121 (3 December)
2. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Edited by A Catharine Ross, Christine L Taylor, Ann L Yaktine, and Heather B Del Valle. Washington (DC): National Academies Press (US); 2011.
Competing interests: No competing interests
We have read with interest the British Paediatric and Adolescent Bone Group’s position statement on vitamin D deficiency (1). While we welcome the interest of this group on the effects of vitamin D on the skeleton, we concur with Shore et al (2) in that “rickets has clear histopathological findings and hence it is ultimately a histopathological entity” and as such, “it is too dogmatic to suggest that subclinical rickets does not exist” (2).
The correlation between clinical, radiological, biochemical and histological findings is poor (3). An autopsy series from 1909 comparing post mortem radiology and histology showed a higher incidence of rickets on histopathology than on radiology (4). The old literature is full of similar findings (5). Our experience is also similar: histopathological changes in the growth plate (from mild abnormalities to frank rickets) and abnormalities in the endochondral ossification can be present with normal radiology and with levels above 50nmol/L (Personal communication) (Figure 1).
Conventional radiography, while a useful clinical tool, is not sensitive enough to determine the presence of rickets.
Currently, there are no objective methods that allow assessment of bone fragility, either in clinical or in subclinical rickets. The implication of subclinical rickets as a risk factor for fractures is yet to be investigated.
Dr Irene Scheimberg, Consultant Paediatric and Perinatal Pathologist, Barts Health NHS Trust
Dr Marta Cohen, Consultant Paediatric and Perinatal Pathologist, Sheffield Children’s Hospital NHS Trust
References
1. Arundel P et al. British Paediatric and Adolescent Bone Group’s position statement on vitamin D deficiency. BMJ 2012; 345
2. Shore RM, Chesney RW. Rickets: part II. Minisymposium. Pediatr Radiol. Epub 21/11/12
3. Pettifor et al. diagnosis of subclinical rickets. Arch Dis Child. 1980; 55: 155-7
4. Schmorl G as cited in Shore and Chesney
5. Hess AF, Unger LJ. Infantile rickets: the significance of clinical, radiographic and chemical examinations in its diagnosis and incidence. Am J Dis Child 1922
Figure 1: Infant who died Suddenly and Unexpectedly. The histology of the ribs and the long bones showed marked irregularity of the columns of chondrocytes with accompanying vessels penetrating the growth plate (a); the cartilage failed to mineralise, leaving islands of cartilage an excess osteoid in the metaphysis (b). The radiology, twice reviewed by a paediatric radiologist, did not show any evidence of rickets.
Competing interests: No competing interests
Sir:
The recent statement in your letter column by the British Paediatric and Adolescent Bone Group1 causes concern in an era that demands objectivity.
Where is the evidence for the statements made? Upon which criteria is the definition of vitamin D deficiency based? None is stated.
What is the reason for the use of a cut-off of 25nmol/l for serum 25-hydroxyvitamin D concentration? None is given. This value is significantly lower than that used by other expert bodies including Paediatric societies2. Autopsy data3 (albeit from an adult population) showed elevated osteoid volumes (the marker of osteomalacia) in half of those with 25-hydroxyvitamin D concentrations between 50 and 75nmol/l. No evidence is provided by Arundel et al1 that children are any different.
The relationship between rickets and fractures is problematic. The majority of rachitic infants have no evident fractures (but skeletal surveys are not routinely done). The extent to which vitamin D deficiency increases bone fragility is unknown. Nor is it known why a minority of rachitic children have a fracture and a few several. It was evident from post-mortem studies in the first decade of the twentieth century that rickets has clear histopathological findings and hence is ultimately a histopathological entity4. The Medical Research Council studies in post-war Vienna published as a monograph in 1923 showed that histological rickets could precede radiological change “by up to several weeks”5. Furthermore it is well known that the correlations between clinical, radiological, biochemical and histological features of rickets are poor6. Thus, it is not clear on what evidence Arundel et al can so categorically exclude vitamin D as an aetiological factor in fracture because other features have yet to develop. Indeed, ”… it is too dogmatic to suggest that subclinical rickets does not exist”4.
It is evident that some infants with vitamin D deficiency may be abused and have (a) fracture(s). Analysis and judgement in such cases can only be done on an individual basis with all aspects examined objectively and in detail. In this regard appropriate vitamin D supplementation of the diets of all pregnant and lactating women and children would go a long way to removing vitamin D deficiency as a potential confounding factor. The US Institute of Medicine increased its recommended doses in 20112. Importantly, Arundel et al do not address the important question of whether the current UK recommended doses of vitamin D raise serum vitamin D concentrations adequately.
A lack of well-designed studies should lead to a call for them to be done where appropriate. Are citations of support from committees to be a substitute for citations of referenced material?
References
1. Arundel P, Ahmed SF, Allgrove J, Bishop NJ, Burren CP, Jacobs B, Mughal MZ, Offiah AC, Shaw NJ. British Paediatric and Adolescent Bone Group’s position statement on vitamin D deficiency. BMJ 2012;345:e8182 (03 December 2012)
2. Shore RM, Chesney RW. Rickets: Part I. Pediatr Radiol 2012:DOI 10.1007/s00247-012-2532-x
3. Shore RM, Chesney RW. Rickets: Part II. Pediatr Radiol 2012:DOI 10.1007/s00247-012-2536-6
4. Priemel M, von Domarus C, Klatte TO, Kessler S, Schlie J, Meier S, Proksch N, Pastor F, Netter C, Streichert T, Pueschel K, Amling M. Bone Mineralization Defects and Vitamin D Deficiency: Histomorphometric Analysis of Iliac Crest Bone Biopsies and Circulating 25-Hydroxyvitamin D in 675 Patients. J Bone Min Res 2010;25:305-12.
5. Wimberger H. 1923. A study of developing, florid and healing rickets as demonstrated by X-ray photography. Med Res Counc Spec Rept Ser. 77: 95–114.
6. Pettifor JM (2012) Nutritional Rickets. In Paediatric Bone: Biology & Diseases Eds Glorieux FH, Pettifor JM, Juppner H, Academic Press pp 625-654.
Competing interests: The author takes 25 microgrammes of vitamin D3 daily and has acted as an expert witness in cases of vitamin D deficiency.
Re: British Paediatric and Adolescent Bone Group’s position statement on vitamin D deficiency
We read with interest the responses to our position statement from Professor Nussey and Drs Scheimberg and Cohen (1). We are not a committee but a current comprehensive group of clinicians managing children with bone disease in the UK. Our opinions are based on our combined clinical experience of vitamin D deficiency in infants, children and adolescents across the UK. Our statement was a concise expression of our position rather than an exposition of the evidence. However, careful consideration of the extant literature does underpin our statement (whilst we acknowledge the paucity of studies which examine clinical outcomes in relation to serum 25-hydroxy vitamin D (25OHD) concentrations).
Our cut-off value for 25OHD, 25nmol/l, is that used by NICE for deficiency - based on the systematic reviews undertaken by Cochrane, the Scientific Advisory Committee on Nutrition and the Institute of Medicine, and by the Department of Health for “low vitamin D status” (recently endorsed in the recent letter from the UK Chief Medical Officers) (2). Nonetheless, rather than the value for serum 25OHD alone (dependent in part upon the laboratory method) determining the development of rickets, other crucial factors need to be taken into consideration including low serum phosphate and/or a low dietary intake of calcium resulting in elevation of serum parathyroid hormone. In contrast to the adult autopsy data cited, Edouard et al found no evidence of defects of bone mineralisation in bone biopsies from 37 children with serum 25OHD concentrations between 13 and 50nmol/l (3). It is true that we have not addressed the important question of whether current recommended doses of vitamin D raise serum 25OHD levels adequately but there is not yet an agreed definition of “adequate”.
No reference is presented by Nussey to support the statement that a few children with rickets have “several” fractures. The evidence suggests that, in a mobile child with rickets, if they fracture a single fracture is the norm. The National Diet and Nutrition Survey showed that up to 30% of South Asian toddlers in the UK have a 25OHD concentration <25nmol/l (4). Vitamin D status in infants in this group is likely to be the same or even lower. If serum 25OHD <25nmol/l was associated with fragility fractures then we might expect to see hundreds of cases of fractures of ribs or proximal humeri captured on the thousands of chest radiographs performed for indications such as bronchiolitis each year. This is not our experience. We also know that the prevalence of clinical signs of rickets is far lower than the incidence of deficiency, <1 in 1000 (5).
The sensitivity of conventional radiology in detecting rickets may be unclear (quoted reports from 1909 and 1923 regarding the timing of radiological changes, are of limited value given the improvements in radiography over the last century). However, we suppose that the authors are not proposing bone biopsy as a clinical tool to diagnose rickets. Whilst we accept radiological changes of rickets can be subtle, we stress that biochemical changes should be present in all cases of vitamin D deficiency.
The use of the term “subclinical rickets” is problematic in the absence of a clear definition. Supposing a definition could be found there would remain the question as to whether it matters. This would have to be established through assessment of bone strength and resistance to fracture which ought not to be assumed to be reduced.
Finally the histopathological changes of dead infants with 25OHD levels >50nmol/l described by Scheimberg and Cohen are interesting but lack crucial details, including any dietary information (e.g. calcium intake) and biochemical data, including the actual 25OHD concentration.
We stand by our original statement and trust that the guidance provided will be useful for clinicians managing children with vitamin D-related problems.
References
1. Arundel P, Ahmed SF, Allgrove J, Bishop NJ, Burren CP, Jacobs, B, Mughal MZ, Offiah AC, Shaw NJ. British Paediatric and Adolescent Bone Group’s position statement on vitamin D deficiency. BMJ. 2012 Dec 3;345:e8182
2. Letter from Chief Medical Officers of the United Kingdom. Vitamin D – Advice on supplements for at risk groups. Department of Health. 02 February 2012
3. Edouard T, Glorieux FH, Rauch F. Relationship between vitamin D status and bone mineralization, mass, and metabolism in children with osteogenesis imperfecta: histomorphometric study. J Bone Miner Res. 2011 Sep;26(9):2245-51
4. Lawson M, Thomas M. Vitamin d concentrations in Asian children aged 2 years living in England: population survey. BMJ. 1999 Jan 2;318(7175):28
5. Callaghan AL, Moy RJ, Booth IW, Debelle G, Shaw NJ. Incidence of symptomatic vitamin D deficiency. Arch Dis Child. 2006 Jul;91(7):606-7
Authors
P Arundel, consultant in paediatric metabolic bone disease and secretary of British Paediatric and Adolescent Bone Group (1)
S F Ahmed, Samson Gemmell Chair of Child Health (2)
J Allgrove, consultant paediatric endocrinologist (3)
N J Bishop, professor of paediatric bone disease (4)
C P Burren, consultant paediatric endocrinologist and diabetologist (5)
B Jacobs, consultant paediatrician (6)
M Z Mughal, consultant in paediatric bone disorders (7)
A C Offiah, HEFCE clinical senior lecturer (4)
N J Shaw, consultant paediatric endocrinologist (8)
Author Affiliations
1. Sheffield Children’s NHS Foundation Trust, Sheffield, UK
2. School of Medicine, University of Glasgow, Glasgow, UK
3. Great Ormond Street Hospital, London. UK
4. Academic Unit of Child Health, University of Sheffield, Sheffield, UK
5. Bristol Royal Hospital for Children, Bristol, UK
6. Royal National Orthopaedic Hospital, Stanmore, UK
7. Royal Manchester Children’s Hospital, Manchester, UK
8. Birmingham Children’s Hospital, Birmingham, UK
Competing interests: No competing interests