Childhood fractures pose a significant health concern, affecting approximately one-third of children and adolescents before the age of 18, with the risk peaking during the pubertal growth spurt.1, 2 The consequences of these fractures vary, ranging from temporary limitations in physical activity to hospitalization and, in some cases, permanent disability.3
In response to this issue, injury prevention strategies have been implemented, but an equally important avenue involves the development of interventions to enhance bone strength during childhood.5
Among these interventions, the potential role of vitamin D supplementation has garnered considerable attention due to the physiological impact of its active metabolite, calcitriol, on calcium absorption.6
Evidence Before this Study:
Prior to this study, a comprehensive search was conducted on PubMed, spanning from the inception of the database to September 30, 2023. The search aimed to identify randomized controlled trials (RCTs) published in any language that evaluated the effects of vitamin D supplementation on bone mineral content, bone mineral density, and fracture risk in HIV-uninfected schoolchildren. The search terms included “vitamin D AND [bone OR fracture] AND child* AND randomized controlled trial.”
An earlier meta-analysis of individual participant data from 1439 HIV-uninfected children across nine RCTs had reported a small positive effect of vitamin D on total hip areal bone mineral density. However, this analysis did not reveal statistically significant effects of vitamin D on total body bone mineral content or on bone mineral density at specific skeletal sites (femoral neck, lumbar spine, or forearm) after one year of supplementation. Notably, no RCTs investigating fracture outcomes in children were identified in the search.
Added Value of this Study:
The current study, a phase 3 RCT, stands as the first to investigate the effects of vitamin D supplementation on fracture risk in children, specifically those with a high prevalence of vitamin D deficiency. The intervention involved weekly oral supplementation with 14,000 international units of vitamin D3 over a span of three years in Mongolian schoolchildren. This regimen successfully elevated mean serum 25-hydroxyvitamin D (25[OH]D) concentrations and suppressed mean serum concentrations of parathyroid hormone.
Despite these physiological changes, the study found that the vitamin D supplementation did not influence fracture risk in the overall study population. Importantly, this lack of effect was consistent even in the large subgroup of participants with baseline serum 25(OH)D concentrations of less than 25 nmol/L.
Implications of All Available Evidence:
When considered alongside null findings from a recently completed phase 3 RCT of weekly oral vitamin D supplementation in South African schoolchildren, these results suggest that weekly vitamin D supplementation, without concomitant calcium supplementation, does not play a role in reducing fracture risk in children.
To address the existing evidence gap, the researchers conducted a phase 3 RCT involving 8,851 schoolchildren aged 6–13 years in Mongolia. This setting was chosen due to its high fracture burden and widespread prevalence of vitamin D deficiency. The primary outcome of the trial was the incidence of tuberculosis infection, and the results for this outcome were reported as null.
In this article, the researchers aimed to assess the impact of vitamin D supplementation on various outcomes, including the incidence of bone fracture, serum concentrations of 25(OH)D in all participants, radial speed of sound (SOS) Z scores in a subset of participants through a nested substudy, and serum concentrations of biochemical parameters (parathyroid hormone, calcium, albumin, total alkaline phosphatase, and bone-specific alkaline phosphatase) in a smaller subset of participants.
Associations between Vitamin D and Fracture Risk:
Numerous observational studies have explored the relationship between vitamin D status and the risk of fractures, yielding inconsistent findings.7 To delve deeper into this issue, a meta-analysis was conducted, pooling individual participant data from 1439 healthy children participating in nine randomized controlled trials.8
The analysis revealed a modest positive effect of vitamin D on total hip areal bone mineral density. However, no statistically significant effects were observed on total body bone mineral content or on bone mineral density at the femoral neck, lumbar spine, or forearm after one year of supplementation.
Lack of Randomized Controlled Trials:
Despite the attention vitamin D supplementation has received, there is a notable gap in the existing literature regarding randomized controlled trials specifically investigating the effects of vitamin D on children’s fracture risk. Moreover, there is a dearth of studies exploring the impact of vitamin D supplementation on bone outcomes in children with baseline serum 25-hydroxyvitamin D (25[OH]D) concentrations of less than 50 nmol/L.
The Potential of Vitamin D Supplementation:
The focus on vitamin D supplementation stems from its pivotal role in supporting calcium absorption, a fundamental process for bone health. The active metabolite, calcitriol, facilitates the absorption of calcium in the intestines, ensuring an adequate supply for bone mineralization. Given the peak in fracture risk during the pubertal growth spurt, interventions aimed at enhancing bone strength, such as vitamin D supplementation, become crucial.
Challenges and Inconsistencies:
While observational studies have suggested a link between low vitamin D status and increased fracture risk, the meta-analysis results highlight the complexity of the relationship. The modest positive effect observed in total hip areal bone mineral density raises questions about the overall efficacy of vitamin D supplementation and its impact on different bone parameters.
Discussion: Unraveling the Complexities of Vitamin D Supplementation in Childhood Fracture Risk
In presenting the findings of our extensive study, which represents the largest randomized controlled trial to investigate the effects of vitamin D supplementation on bone fracture risk in children, several key insights emerge. Our research delves into the complexities of vitamin D deficiency, the impact of supplementation, and the intricacies of bone health in a vulnerable population.
Baseline Characteristics and Intervention Efficacy:
At the outset, our participants exhibited common issues of vitamin D deficiency and low calcium intake, underscored by a baseline scenario where weekly oral administration of 14,000 IU vitamin D3 effectively raised serum 25(OH)D concentrations to 75 nmol/L or higher. This successful intervention was particularly crucial in a population where deficiencies in these essential nutrients were prevalent.
Moreover, biochemical analyses of a subset of participants revealed notable outcomes, including the reduction of serum parathyroid hormone (PTH) concentrations across all baseline vitamin D statuses. Suppression of total alkaline phosphatase (ALP) and bone-specific ALP (BALP) was evident in those with a baseline serum 25(OH)D concentration of less than 25 nmol/L. These findings suggest that the vitamin D supplementation addressed specific markers associated with bone health and calcium regulation.
Impact on Fracture Risk and Bone Strength:
Despite the efficacy of the intervention in raising vitamin D levels and influencing biochemical markers, our study revealed null results concerning fracture risk and radial speed of sound (SOS) Z scores. Importantly, these results were consistent across the entire study population and subgroups with low baseline vitamin D status or low calcium intake.
Our findings align with those from a comparable trial in South African schoolchildren and other studies in adults, collectively suggesting that vitamin D alone does not mitigate fracture risk in the absence of concurrent calcium supplementation. The influence of calcium is particularly noteworthy, given that a substantial proportion of our participants had calcium intake below the recommended levels during childhood and adolescence.
Biological Mechanisms and Skeletal Outcomes:
Suppression of serum PTH concentrations due to vitamin D supplementation likely reflects the correction of secondary hyperparathyroidism associated with the participants’ very low vitamin D status at baseline. Additionally, the suppression of BALP in participants with the lowest baseline 25(OH)D concentrations suggests a potential role of vitamin D in reducing bone remodeling secondary to the decline in serum PTH concentration. However, these biochemical changes did not translate into observable differences in bone mineral density or fracture risk, even in participants with the lowest baseline vitamin D levels.
Strengths and Limitations:
Our study boasts several strengths, including a rigorous double-blind trial design, a substantial 3-year duration, and a large sample size that conferred significant statistical power. The high incidence of fractures in our study population further enhanced the robustness of our findings. However, limitations must be acknowledged, such as the use of radial quantitative ultrasound instead of dual-energy x-ray absorptiometry for bone strength measurement. This choice was guided by considerations of cost, simplicity, mobility, and avoidance of ionizing radiation.
Moreover, the absence of concomitant calcium supplementation in our trial, especially among those with low calcium intake, might have influenced the outcomes. The study’s focus on a specific geographical and ethnic locale also prompts caution in generalizing the results to broader populations.
Conclusion: Unraveling Complexity and Paving the Way for Further Exploration:
In conclusion, our study, while unveiling the intricacies of vitamin D supplementation in a high-fracture-burden population, underscores the need for a nuanced understanding of the interplay between vitamin D, calcium, and bone health in childhood. The consistent lack of an effect on fracture risk and bone strength, despite notable biochemical changes, challenges the prevailing notions regarding the standalone efficacy of vitamin D in fracture prevention.
Our research, with its strengths and limitations, paves the way for further exploration. It prompts considerations of alternative dosing regimens, potential synergies with calcium supplementation, and the need for investigations in diverse populations. As we unravel the complexities, the pursuit of effective strategies to enhance childhood bone health remains paramount.
reference link :https://www.thelancet.com/journals/landia/article/PIIS2213-8587(23)00317-0/fulltext