December 1, 2023

expert reaction to vitamin D supplements and bone fractures in children in Mongolia

A study in the Lancet Diabetes & Endocrinology looks at the relationship between vitamin D supplementation and rates of bone fractures in Mongolian schoolchildren.

Dr Inez Schoenmakers, Associate Professor & Senior Lecturer, Norwich Medical School, UEA, said:

Does the press release accurately reflect the science?

“Although the press release reflects the main findings of the study, it fails to outline several important caveats and weaknesses of the study.

Is this good quality research?  Are the conclusions backed up by solid data?

“The study investigated the effect of vitamin D supplementation on fracture incidence and SOS Z-score (the latter as a measure of bone quality) in a population with high prevalence of vitamin D deficiency, average calcium intakes below the requirements and high fracture incidence.

“The authors conducted subgroup analyses in a subgroup with baseline low vitamin D status (below 25 and 50 nmol/L) and low calcium intake (below 500 milligrams per day), and found similar results compared to the overall cohort.

“However, there are several major limitations to the results of this study.

“Improving vitamin D status in Vitamin D deficient populations improves calcium absorption from the diet and incorporation of calcium into the skeleton.  However, when calcium intakes are well below the recommended intakes, or even below the average requirements, the amount of calcium absorbed from the diet may still be below the amounts needed for appropriate accrual of bone mass during growth.

“Based on the data reported, my estimation is that the calcium intakes were below the nutritional recommendations and even average requirements in the majority of children.  The authors have applied a threshold for their subgroup analysis of a calcium intake below 500 milligrams per day; this is well below the recommended intakes or estimated average requirements for children of the age group investigated in this study (see for example population guidelines for children formulated by the WHO (world), EFSA (Europe), NAM (US and Canada) and SACN (UK)).

“The effect of vitamin D supplementation in this population of bone health outcomes may therefore have been limited by their concomitant calcium deficiency.

“The biochemical method used for the measurement of vitamin D status (serum 25(OH)D concentrations) was suboptimal and is not widely used.  The major issue is the high limit of detection (to note, the limit of quantification should preferably be reported instead).  The limit of detection was not much below the accepted threshold of vitamin D deficiency (below 25 nmol/L).  Based on limited data from DEQAS (an external quality assurance scheme) for the method used, this method under-reports serum 25(OH)D concentrations.  This suggests that the ‘real’ limit of detection was even higher than reported in this paper.  Although this may have not affected the percentage of children reported with deficiency (< 25 nmol/L), it is difficult to assess how this may have influenced the reported mean values of serum 25(OH)D concentrations.  The authors did not describe how values below the limit of detection were considered in this mean value.

“Additionally, it is unclear how the method was standardised to DEQAS values.

How does this work fit with the existing evidence?

“Reporting the effect of vitamin D supplementation on fracture risk is important and data in children are scarce.  Also supplementation studies in vitamin D deficient populations, particularly children are scarce.  Therefore this study is important.

“However, fractures are very common in children and are frequently caused by high impact falls/trauma.  This is also the case in this study.  Fracture rates, particularly high impact fractures, are influenced in engagement in sports activities.  Physical activity and type of sports played, is often considered as a confounding factor as this influences both fracture risk as well as bone mineral density.  Achieving optimal peak bone mass (most commonly measured as bone mineral density by DEXA), which is reached around the end of the 2^nd decade of life is considered as an important predictor of fragility fracture later in life.

“The relevance of the relationship between vitamin D supplementation and fractures in childhood, peak bone mineral density and future bone health needs to be established.

Have the authors accounted for confounders?  Are there important limitations to be aware of?

“The authors have accounted for several important confounders.  However, as outlined above, there are several limitations to this study and the methods used.

What are the implications in the real world?  Is there any overspeculation?

“Recommendations for vitamin D requirements and threshold for vitamin D deficiency and sufficiency assume adequate intakes of other nutrients, e.g. calcium.  Although the impact of calcium intakes below the requirements may be partly overcome by ensuring optimal vitamin D status, when calcium intakes fall below the minimum requirement for accrual of bone mass, the effect of vitamin D supplementation above the recommendations, is expected to be limited.  Therefore, the impact of the findings in this paper on population guidance is unclear.

“Having said that, this study does fill an important gap in the evidence in the sense that it reflects the reality that both calcium and vitamin D deficiency is still common in children, particularly in certain parts of the world.  This needs to be addressed. ”

Prof Susan Lanham-New, Head of Department & Professor of Nutrition, University of Surrey, said:

“The study published by Dr Ganmaa and Professor Adrian Martineau and their respective Teams is a very important one for Nutrition and Bone Health field generally and the Vitamin D field specifically.  The work was robustly conducted, in a well characterised study population, using validated methods – particularly with respect to the standardisation of vitamin D status measurements, and included children recruited from multiple sites across a large number of schools and thus representative of the younger population in Mongolia.

“Whilst the study did not show a benefit of vitamin D supplementation on fracture risk or on increases in bone strength (as assessed by quantitative ultrasound rather than the gold standard, Dual X-ray absorptiometry), the study should not be interpreted as meaning that vitamin D is not important to health (musculo-skeletal or otherwise).  Many of the children showed characteristics of vitamin D deficiency as defined by altered biochemical readings and increased bone turnover and the study was not able to address the concomitant effect of the potential benefit of increased calcium supply.  What is also key to note, is that the study did not show any detrimental effects of increased vitamin D supply to markers of bone health and further work on the mode of delivery of the vitamin D supplementation (large oral doses given weekly, as was the case in this study [14000 IU/d) vs. a daily low-dose supplement.

“It remains a stark reality, that many children and adolescents are vitamin D deficient – in both developing and developed countries; this is absolutely the case in the UK, as shown consistently in all our National Diet and Nutrition Survey’s (NDNS) in these groups (and indeed in adults from all age groups also) and avoiding vitamin D deficiency (a vitamin D status below 25nmol/l) is critical.  A daily supplement of 400IU/d, as recommended by SACN, is key to preventing vitamin D deficiency, particularly in the winter months but in some population groups (particularly ethnic minorities), all year round.”

Prof Nick Bishop, Professor of Paediatric Bone Disease, University of Sheffield, said:

“The study is very thorough in its design and execution although I don’t think that the use of ultrasound to assess “bone strength” is a widely accepted methodology; speed of sound will reflect bone size and so vary progressively with age.

“In the UK, fracture rates rise progressively through childhood, peaking when growth is most rapid in the teenage years.  Children fracture when either they run into something, or something runs into them.  We know from the ALSPAC study that lower bone size and mass for body size are associated with increased fracture risk, as is vigorous physical activity irrespective of bone mass; it is difficult to see how vitamin D supplementation would directly influence either of these factors in later childhood.  Vitamin D supplementation during pregnancy, however, may be associated with increased body size-adjusted bone size and mass in childhood and routine vitamin D supplementation during pregnancy is something that might not only influence an infant’s risk of vitamin D deficiency and rickets, but also reduce their fracture risk as they grow and develop.

“As it says in the editorial, the focus really needs to be on preventing vitamin D deficiency rickets in early life, especially in low and middle income countries.”

Dr Benjamin Jacobs, Consultant Paediatrician, Royal National Orthopaedic Hospital, said:

“This excellent study shows that, in Mongolia at least, Vitamin D deficiency is not a major cause of childhood fractures.  Clearly injuries and other factors are more relevant there.  Unfortunately in the UK we still see children suffering rickets due to Vitamin D deficiency.  Indeed we diagnosed a new case of rickets last week, so we must continue to improve the uptake of vitamin D supplements, and fortified foods, especially in the winter when we cannot make vitamin D from sunshine.”

‘Vitamin D supplements for fracture prevention in schoolchildren in Mongolia: analysis of secondary outcomes from a multicentre, double-blind, randomised, placebo controlled trial’ by Davaasambuu Ganmaa et al. was published in the Lancet Diabetes & Endocrinology at 23:30 UK time on Friday 1 December 2023.

DOI: 10.1016/S2213-8587(23)00317-0

Declared interests:

Dr Inez Schoenmakers: “I have no conflicts of interest to report.”

Prof Susan Lanham-New: “SLN is a member of the main Scientific Advisory Committee on Nutrition and the SACN Vitamin D Working Group and also the European Food Safety Authority (EFSA) Committee on the Tolerable Upper Limit for Vitamin D.  SLN holds several BBSRC and Charity grants on vitamin D which go directly to the University of Surrey and SLN does not benefit financially from any of this work.  SLN has given several talks on Vitamin D and any Honorarium received has been donated to the Royal Osteoporosis Society/The Surrey Hardship Fund.  The Viridian Supplement Company have provided Vitamin D Supplements at no cost for two Surrey recent Vitamin D RCTs.  SLN is Research Director of D3Tex Ltd which holds the UK and Gulf Corporation Council Patents for the use of UVB material for combatting vitamin D deficiency in women who dress for cultural style.”

Prof Nick Bishop: “No CoIs.”

Dr Benjamin Jacobs: “No conflicts to declare.”