Comment
The role of vitamin D in paediatric bone health
Vitamin D is important in maintaining children’s in children receiving vitamin D than in those receiving
bone health. Certainly, there is good evidence that placebo, whereas among children who had vitamin D
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vitamin D deficiency and low dietary calcium intake deficiency at baseline (<25 nmol/L), albumin-adjusted
are major contributors in the pathogenesis of calcium concentrations were higher and total alkaline
nutritional rickets; however, it remains unclear what phosphatase were lower (although not significantly) in
the role of vitamin D sufficiency is in the prevention of those receiving vitamin D supplements than in those
childhood fractures. This knowledge gap is important receiving placebo.
Published Online because fractures in childhood are common events, with Many readers might be surprised by the lack of
December 1, 2023
https://doi.org/10.1016/
25–50% of children (depending on country, ethnicity, effect of vitamin D supplementation on fracture risk
S2213-8587(23)00353-4 and sex) presenting with at least one fracture during in a population of children, the vast majority of whom
See Articles page 29 their childhood and adolescence.1 had poor vitamin D status at baseline. However,
In The Lancet Diabetes & Endocrinology, these null findings are consistent with those found in
Davaasambuu Ganmaa and colleagues2 report a similar randomised controlled trial of schoolchildren
the findings of secondary outcome analyses from in Cape Town, South Africa.5 In the Mongolian study,
a randomised controlled trial of schoolchildren in vitamin D supplementation resulted in an improvement
Mongolia. Participants received weekly oral doses of in biochemical markers of altered mineral homeostasis,
14 000 international units of vitamin D3 or placebo for especially in children who, at baseline, had vitamin D
3 years, during which incident fractures were assessed. deficiency (<25 nmol/L), low serum concentrations
This study is the first randomised controlled trial to of calcium, and high concentrations of parathyroid
assess the effect of vitamin D supplementation on hormone and total alkaline phosphatase, probably
fracture rates in children. At baseline, participants’ reflecting low dietary calcium intake or vitamin D
vitamin D status was generally poor, with 2664 (31·9%) deficiency. However, the biochemical alterations
of 8348 children having serum 25-hydroxyvitamin D were mild and not of the severity seen in children
(25[OH]D) concentrations of less than 25 nmol/L, which with calciopenic rickets (children with clinical rickets
is considered to be indicative of vitamin D deficiency, were not eligible for the study). These biochemical
and only 369 (4·4%) children having concentrations of changes probably reflect the response to secondary
50 nmol/L or higher (ie, vitamin D sufficiency).3 Notably, hyperparathyroidism as a consequence of poor
the 25(OH)D concentrations were standardised by vitamin D status or low dietary calcium intake, resulting
using externally calibrated standards, thus ensuring the in intestinal calcium absorption falling below levels
reliability of the results.4 In children receiving vitamin D required to maintain mineral balance in a growing
supplements, 25(OH)D concentrations increased from a child, but not severe enough to induce osteomalacia
mean of 29·6 nmol/L (SD 10·5) to a mean of 72·1 nmol/L and rickets. In this study, the marginally increased
(23·8) during the 3-year period, but in children in the parathyroid hormone concentrations at baseline could
placebo group, concentrations remained unchanged have induced increased bone turnover rather than
(29·6 nmol/L [10·6] vs 26·1 nmol/L [14·9]). Yet, osteomalacia, as has been shown by Schnitzler and
during the study period, fracture rates were similar in colleagues6 from iliac crest bone biopsies in adolescents
the vitamin D (6·4% [268/4176]) and placebo (6·1% with habitually low dietary calcium intake and bone
[253/4172]) groups, despite a substantial improvement deformities. Studies of healthy adult participants also
in vitamin D status in children receiving vitamin D. provide little evidence that vitamin D supplementation
In a small substudy of 100 children (50 children in each alone reduces fracture risk.7,8
group) who had blood samples taken for biochemical The study by Ganmaa and colleagues2 also assessed
analyses, alterations in mineral homeostasis were found changes in bone strength using radial quantitative
especially in children with 25(OH)D concentrations of ultrasound measurements to assess speed of sound
less than 25 nmol/L at baseline. At the 3-year follow- (SOS) during the study period. No difference in
up, parathyroid hormone concentrations were lower SOS Z scores were noted between children in the
4 www.thelancet.com/diabetes-endocrinology Vol 12 January 2024
Comment
two groups. The lack of response to vitamin D eradicating vitamin D deficiency and rickets mainly in
supplementation is supported by the findings observed children younger than 3 years in many low-income and
in the South African study, in which no difference middle-income countries.
in bone mass, measured using dual energy x-ray We declare no competing interests.
absorptiometry, was observed between children *John M Pettifor, Kebashni Thandrayen
receiving vitamin D and those receiving placebo.5 [email protected]
A recent systematic review and meta-analysis of the SAMRC/Wits Developmental Pathways for Health Research Unit, Department
of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand,
effect of vitamin D on bone mineral density in children Wits 2050, South Africa (JMP); Division of Paediatric Endocrinology,
and adolescents found only a small effect of vitamin D Department of Paediatrics, Chris Hani Baragwanath Academic Hospital and
Faculty of Health Sciences, University of the Witwatersrand, Johannesburg,
supplementation on total hip bone mineral density and South Africa (KT)
suggested that clinically important benefits for bone 1 Cooper C, Dennison EM, Leufkens HGM, Bishop N, van Staa TP.
density from vitamin D supplementation during a 1-year Epidemiology of childhood fractures in Britain: a study using the general
practice research database. J Bone Miner Res 2004; 19: 1976–81.
period are unlikely.9 2 Ganmaa D, Khudyakov P, Buyanjargal U, et al. Vitamin D supplements for
Thus, the findings of the Mongolian study are fracture prevention in schoolchildren in Mongolia: analysis of secondary
outcomes from a multicentre, double-blind, randomised, placebo-
important because they provide evidence from controlled trial. Lancet Diabetes Endocrinol 2023; published online Dec 1.
https://doi.org/10.1016/S2213-8587(23)00317-0.
a randomised controlled trial suggestive that, in 3 Scientific Advisory Committee on Nutrition. SACN vitamin D and health
schoolchildren, vitamin D supplementation might not report. 2016. https://www.gov.uk/government/publications/sacn-
vitamin-d-and-health-report (accessed Nov 23, 2023).
influence fracture risk or bone strength during a 3-year 4 Sempos CT, Binkley N. 25-hydroxyvitamin D assay standardisation and
period. However, many children had biochemically vitamin D guidelines paralysis. Public Health Nutr 2020; 23: 1153–64.
5 Middelkoop K, Micklesfield LK, Walker N, et al. Influence of vitamin D
defined vitamin D deficiency and altered mineral supplementation on bone mineral content, bone turnover markers and
homeostasis suggestive of increased bone turnover. fracture risk in South African schoolchildren: multicentre double-blind
randomised placebo-controlled trial (ViDiKids). medRxiv 2023; published
Because the progression of biochemical and histological online May 19. https://doi.org/10.1101/2023.05.18.23290153
(preprint).
changes of progressively worsening vitamin D deficiency 6 Schnitzler CM, Pettifor JM, Patel D, Mesquita JM, Moodley GP, Zachen D.
on bone health is unclear, further studies are needed Metabolic bone disease in black teenagers with genu valgum or varum
without radiologic rickets: a bone histomorphometric study.
to investigate this aspect. Furthermore, the synergistic J Bone Miner Res 1994; 9: 479–86.
role that low dietary calcium intake might have in 7 Reis AR, Santos RKF, Dos Santos CB, et al. Supplementation of vitamin D
isolated or calcium-associated with bone remodeling and fracture risk in
exacerbating these changes needs elucidating. postmenopausal women without osteoporosis: a systematic review of
randomized clinical trials. Nutrition 2023; 116: 112151.
Overall, the findings support previous calls8 that 8 Bouillon R, LeBoff MS, Neale RE. Health effects of vitamin D
vitamin D is not the panacea for all ills, and that its use supplementation: lessons learned from randomized controlled trials and
Mendelian randomization studies. J Bone Miner Res 2023; 38: 1391–403.
should be reserved for those conditions where evidence 9 Wu F, Fuleihan GE-H, Cai G, et al. Vitamin D supplementation for improving
from randomised controlled trials shows benefit. In the bone density in vitamin D-deficient children and adolescents: systematic
review and individual participant data meta-analysis of randomized
paediatric population, attention still needs to be paid to controlled trials. Am J Clin Nutr 2023; 118: 498–506.
Empagliflozin in chronic kidney disease: nephroprotection is
independent of albuminuria, primary kidney disease, and
baseline eGFR
Chronic kidney disease, a disease attributable to non-steroidal mineralocorticoid receptor antagonist Published Online
December 4, 2023
diabetes in 30–40% of patients, is a major health finerenone reduce the risk of progression to kidney https://doi.org/10.1016/
burden worldwide because it underlies an excess risk failure in patients with diabetes who have albuminuria. S2213-8587(23)00355-8
for kidney failure cardiovascular disease events.1 Large, Because, on a world scale, the majority of people with See Articles pages 39 and 51
randomised placebo-controlled trials have shown that chronic kidney disease have low levels of albuminuria
renin–angiotensin system (RAS) inhibitors, sodium– (<300 mg/g creatinine) and do not have diabetes,2
glucose co-transporter-2 (SGLT2) inhibitors, and the accruing information on the nephroprotective
www.thelancet.com/diabetes-endocrinology Vol 12 January 2024 5
