As 25OHD and IGF1 are important for maintaining bone health, the main purpose of our study was to explore whether there is an association between the two, and if so, how they are associated. Accordingly, a cross-sectional study of a nationally representative non-hospitalized population in the USA was performed. After considering the influencing factors, we found that there was an independent correlation between 25OHD and IGF1. In addition, we found that there was a nonlinear relationship between them. When the 25OHD level increased to 75 nmol/L, the relationship between 25OHD and IGF1 changed from positive to negative. The subgroup analysis helped us better understand the trend of the association between 25OHD and IGF1 in different populations.

Our study also found that high drinkers had lower IGF1 levels than low drinkers. Previous studies found that the expression of IGF1 in the liver, skeletal muscle, or brain of mice exposed to alcohol significantly decreased. The specific mechanism may be related to the extensive damage to the signal pathway of insulin-like growth factor caused by alcohol [20,21,22,23]. Furthermore, the result of the subgroup analysis showed that 25OHD had a stronger effect on IGF1 in patients with diabetes than in those without diabetes. Many studies have found that both vitamin D and IGF1 play a vital role in the regulation of glucose metabolism. They are related to the improvement of glucose homeostasis and insulin sensitivity in diabetes [24,25,26,27]. Therefore, there may be some interaction between the two in diabetes. However, limited research is available on this; further studies are needed to explore the extraosseous interaction between vitamin D and IGF1.

The relationships between vitamin D and IGF1 have been studied in adults, children, and healthy or short stature groups, but the association between these factors remains controversial. Ameri et al. found that vitamin D level positively correlates with IGF1 level in adults with growth hormone deficiency. Furthermore, circulating IGF1 level significantly increased with increased vitamin D3 supplementation. Another interesting finding of this study was that vitamin D level was negatively correlated with the dose of recombinant human growth hormone (rhGH) [10]. A randomized controlled trial in healthy children revealed that individuals who received higher vitamin D3 supplementation doses had higher serum IGF1 levels [11]. These studies indicate that the effect of vitamin D on IGF1 is dose dependent.

Conversely, Hyppönen et al. found a saturation effect, whereby an increasing 25OHD level causes the IGF1 level to initially increase linearly. However, when the 25OHD level reaches 75–85 nmol/L, the effect stabilizes and the IGF1 level plateaued [13]. Concurrently, Kord-Varkaneh et al. suggested that there may be a negative feedback effect between vitamin D and IGF1. Their meta-analysis showed that serum vitamin D and IGF1 levels have an initial positive dose-dependent relationship. Nevertheless, vitamin D is negatively associated with IGF1 when its supplemented dose is more than 1000 IU/d and the supplementation duration is more than 12 weeks [14]. Our results are in agreement with those of Kord-Varkaneh et al. [14]. The smoothing curve generated with the generalized additive model showed that after adjusting for confounding factors, the IGF1 and 25OHD levels had an inverted U-shaped association (Fig. 2). When 25OHD level is under 75 nmol/L, it positively correlated with the IGF1 level. Contrastingly, when 25OHD level is over 75 nmol/L, a negative correlation was detected. According to the Global Consensus Recommendations on Prevention and Management of Nutritional Rickets, vitamin D status was classified according to 25OHD levels as follows: (1) Deficiency (< 30 nmol/L); (2) Insufficiency (30–50 nmol/L); (3) Sufficiency (>50 nmol/L); (4) Toxicity (>250 nmol/L) [28]. Our research results show that when the 25OHD level increased to 75 nmol/L, the relationship between 25OHD and IGF1 changed from positive to negative. That is, the 25OHD level increased by 1 nmol/L, whereas IGF1 level decreased by 0.53 ng/mL. Therefore, keeping 25OHD level at 50–75 nmol/L may be more beneficial for maintaining bone health and IGF1 level. However, the specific mechanism leading to this dose–response relationship has not been studied; hence, additional research is needed in the future to elucidate and validate the association.

Our findings suggest that within a specific range, vitamin D is positively associated with IGF1, but beyond a particular value, vitamin D may have an inhibitory effect on IGF1. Therefore, identifying an ideal range of vitamin D level may be helpful for maintaining IGF1 levels and promoting bone health. Furthermore, the effect of vitamin D must be considered when evaluating IGF1 level during rhGH therapy in growth hormone deficiency.

In addition, it is noteworthy whether vitamin D plays a role in the treatment of short stature with rhGH. The growth hormone-insulin-like growth factor 1 axis is important for linear growth in children and bone health in adulthood. Growth hormone is secreted by the pituitary gland and plays a role in promoting linear growth, mainly through IGF1. Our results are consistent with the previous studies indicating a possible relationship between vitamin D and IGF1. Several studies found that vitamin D is positively correlated with growth hormone peak [29, 30]. Ameri’s research even found that vitamin D level was negatively correlated with the dose of rhGH [10]. Therefore, future research could examine the long-term effects of vitamin D and rhGH on the growth parameters with short stature and if vitamin D supplements can reduce rhGH doses.

The following are some advantages of our study; to the best of our knowledge, this is the first in-depth research on the specific effect of 25OHD on IGF1. Second, a nationwide probability sample of the American population was selected by employing data from the NHANES; hence, strict quality control measures were applied. Third, we adjusted for potential confounding factors and performed a sensitivity analysis and hierarchical interactive analysis, whereby these methods can reduce the chances of introducing bias during data analysis; moreover, their application supports the conclusion that our research results are stable. Additionally, we used a generalized additive model to analyze and determine the association between 25OHD and IGF1. We also utilized a segmented regression model to calculate the specific inflection point of 25OHD, these implementations gave our findings higher clinical value and significance compared to similar studies performed previously.

Nevertheless, our study also had some limitations. Evidently, the observational nature is the main limitation as a cross-sectional design alone is insufficient to examine the causal association between 25OHD and IGF1. In addition, selection bias, information bias, recall bias, and others are also considered its limitations; hence, more randomized controlled trials are required. Second, the study group included only adults; hence, further research is warranted to determine the interaction between 25OHD and IGF1 in children. Finally, other confounding factors such as diet, vitamin D supplementation, and the use of rhGH might not have been included, ultimately limiting the robustness of the results shown here.

In conclusion, our findings demonstrated a nonlinear relationship between 25OHD and IGF1 and the significance of our results toward maintenance of bone health warrants further comprehensive research that includes prospective randomized controlled studies of different populations and identification of additional confounding factors.