Introduction
Evaluation of skeletal maturity is a common procedure frequently performed in clinical practice. Hand and wrist X-rays are considered as an important indicator of children's biological age. Nowadays, many methods are available to evaluate bone age. The images obtained by hand and wrist X-ray reflect the maturity of different bones. This information, associated with the characterization of the shape and changes of bones, represents an important factor of the biological maturation process. During growth, biological maturity is defined by several parameters, including the characterization of skeletal maturity, sexual maturity, dental elements eruption, menarche, spermarche, deepening of the voice, growth spurt, and the achievement of 95% of the adult height [1–3]. Many of these parameters, and particularly growth spurt and menarche, correlate better with bone age compared to chronological age [4]. Therefore, chronological age differs from bone age, so the two indexes need to be distinguished: chronological age is defined as the age in years between birth and the evaluation of a subject; bone age is defined by the age expressed in years that corresponds to the level of maturation of bones. This determination is based on the presence of particular centers of bone formation as well as the dimension and structure of the bones [3, 5–8]. Bone age may be affected by several factors, including gender, nutrition, as well as metabolic, genetic, and social factors and either acute or chronic diseases, including endocrine dysfunction [3–9].
Methods
A systematic search has been performed in PubMed to identify randomized controlled trials [RCTs], meta-analyses, and retrospective and prospective studies of different methods to evaluate bone age, focusing on strengths and weaknesses of each procedure. The keywords for the research have been “bone age” and “skeletal maturation.”
Fields of Application of Bone Age
Bone age is an interpretation of skeletal maturity. The determination of bone age is important to properly assess and guide the evaluation of short or tall stature, impaired or accelerated growth, and delayed or early puberty [10]. However, data obtained from the assessment of bone age can be widely used both in medical or nonmedical settings.
Applications in Medical Field: Role of Delayed and Advanced Bone Age
By evaluating the data obtained from bone age in the clinical setting, it is possible to distinguish three main groups of subjects: patients with delayed bone age, patients with bone age appropriate to chronological age, and patients with advanced bone age [3, 8–10].
Constitutional delay of growth and puberty is one of the most common causes of delayed bone age [10]. Conventionally, this clinical condition is defined by the presence of delayed bone age [at least 2 SD] compared to chronological age associated with short stature, a delay in both pubertal maturation, as well as in the achievement of adult height, compared to peers. These data distinguish these patients from patients with familial short stature, in whom bone age corresponds approximately to chronological age [11–14].
It is also possible to evaluate a physiological variant of familial early puberty [14], especially in some ethnic groups [15, 16].
Bone age may be used either in normal variants of delayed growth patterns with delayed puberty and accelerated growth patterns with early puberty, where it may be more consistent with height age and adult height prediction may be more consistent with genetics. Assessment of bone age is also important for the correct diagnosis, particularly with the aim of detecting the causes of bone age alteration including mainly endocrine and nutritional causes and chronic nonendocrine disorders and syndromes.
Endocrine and Nonendocrine Causes
Several endocrine diseases might induce changes in bone age [10]. In particular, subjects with severe hypothyroidism may have a delayed bone age. Congenital hypothyroidism leads to growth arrest, delayed bone age, and short stature at birth. Ossification centers are defective, appearing in an irregular and mottled pattern, with multiple foci that coalesce to give a porous or fragmented appearance. These characteristics are mainly documented in large cartilaginous centers, such as the head of the femur, head of humerus, and the tarsal navicular bone and are known as stippled epiphyseal dysgenesis. When hypothyroidism is acquired during growth, secondary centers of ossification are predominantly affected, with delayed fusion of epiphysis and with an irregular and heterogeneous ossification. The metaphyseal end of long bones usually has a sclerotic band [17–19]. In addition, subjects with long-lasting and untreated growth hormone [GH] deficiency have a delay in bone maturation. As well, hypophyseal alterations secondary to malformation, tumor, or infiltrative pathologies may also be associated with bone age delay consequently to a secondary GH deficiency or hypothyroidism. The presence of hypogonadism with the consequent lack of circulating estrogens, androgens, and other pubertal hormones may cause an important delay in bone maturation during pubertal period [20–25].
A delayed bone age is common in malnourished conditions associated with chronic diseases such as intestinal inflammatory chronic diseases, celiac disease, and cystic fibrosis [26–29].
It is also common in chronic inflammatory states or infectious diseases, such as juvenile idiopathic arthritis and states of immunodeficiency [30–37]. Children with cardiac diseases, or those with chronic kidney or liver disease, may experience a delay in skeletal maturation [38–42].
In some psychiatric conditions, such as anorexia and in subjects with states of psychosocial stress or abuse, the presence of delayed skeletal maturation is documented [43–45]. Bone age delay is also associated with genetic syndromes such as trisomy 21, Turner syndrome, and Russell–Silver syndrome [10, 46–48].
In premature babies, there is often a delayed skeletal maturation [49].
By contrast, subjects with hyperthyroidism may present precocious puberty associated with advanced bone age [18, 19]. Moreover, weight gain and obesity are one of the most important causes of pediatric advanced bone age; the mechanisms underlying these alterations are not fully clarified, although insulin resistance and hormonal factors produced by adipose tissue might play an important role [50, 51]. Likewise, some pathological clinical diseases such as ovarian tumors, Leydig cells or germ cells, as well as adrenal tumors or adrenal diseases [e.g., congenital adrenal hyperplasia] [52–55] are typically associated with excessive production of pubertal hormones that cause a rapid progression of bone age, thus advanced bone maturation.
Medical treatment, either oral or dermal, can affect pubertal effects on bone age. In particular, estrogens and oral contraceptives or creams containing testosterone or estrogens can cause an early closure of the growth plate. Similarly, an excessive intake of foods containing phytoestrogens such as soya, according to some studies, may have an effect on bone age progression [56–63].
Nonmedical Field
Data obtained by hand and wrist radiography during bone age assessment are also used in many nonmedical fields for example in sports [64] and for national policy in many countries [10]. In fact, bone age can provide important information for athletes in order to distribute physical, human, and monetary resources properly [65–67].
Assessment of bone age is often required during international immigration programs [68, 69]. In many European countries, the increase in illegal immigration and above all the immigration of children and adolescents unaccompanied by parents and without identity documents posed important doubts and stressed the need for new procedures aimed at ensuring a better assistance and protection for young people. In Sweden, many asylum applications in 2016 were made by lone refugee children, thus requiring novel proposed guidelines. In particular, the method of medical age assessment proposed consisted of taking X-rays of wisdom teeth and MRI scans of knee joints, which are then analyzed by dentists and radiologists. In Italy, a multidisciplinary approach is suggested to evaluate bone age using the Greulich–Pyle TW3 methods for a complete characterization of chronological age of the refugee. However, bone age itself cannot be considered the only absolute and incontrovertible datum to define the chronological age [68–79]; therefore, limits and accuracy of this examination in predicting chronological age, especially in relation to different ethnic groups and underlying diseases, need to be considered.
Maturation and Skeletal Development
Skeletal maturation is based on the activation and interaction of a complex series of physiological mechanisms. This process is characterized by a predictable sequence of development and progression of ossification centers.
Each bone segment begins its maturation first in the primary ossification center and then, through different stages of enlargement and remodeling, reaches the final shape; many bones, like long bones, have many centers of maturation [epiphysis]. Although several body areas have been studied over the years in order to define a standardized and universal method [3, 6], the wrist and knee areas represent the gold standard procedures [3, 7]. In addition, studies have shown that, in some bones, ossification typically begins at birth, while in others, it typically begins between 14 and 17 years of life. Therefore, the bone maturation process can be better characterized by the evaluation of the knee region in children under the age of 3, while in those older than 3 years, the assessment of hand and wrist bones is the most appropriate [80–82].
At birth, long bones present different centers of ossification that proliferate continuously until the terminal or epiphyseal part of the bone melt definitively with the diaphyseal one. This process is strongly affected by numerous factors, including GH and insulin-like growth factor-1 [IGF-1]. Moreover, a deficit of thyroid hormones or an excess of corticosteroids causes a cell division reduction in the proliferation zone, inducing a growth delay. Not only hormones but also gender might affect this process. In particular, bone age is more advanced in female than in male individuals with the same chronological age. In fact, the bone maturation process lasts longer in male than in female individuals [83–85], and the moment of closure of the epiphyseal region occurs is roughly 2 years earlier in girls than in boys. Therefore, carpal bones are not ossified at birth, and this process typically advances from the center of ossification [80]. Usually, the first ossification center to appear is in the context of capitate and hamate at the second month in female individuals and around the fourth month in male individuals and remain the only useful observable features for the next 6 months.
Then, the remaining centers progressively appear [Figure 1] [80]. Assessments of skeletal maturity in prepubertal children are primarily based on the epiphyseal size of the phalanges as they relate to the adjacent metaphyses. During this stage of development, the ossification centers for the epiphyses increase in width and thickness, becoming as wide as the metaphyses. During puberty, the contours of the epiphyses begin to overlap, or cap, the metaphyses. Thereafter, the pisiform and the sesamoid become recognizable. During late puberty, the fusion of the epiphyses to the metaphyses in the long bones of the hand tends to occur in a characteristic pattern:
[1] fusion of the distal phalanges,
[2] fusion of the metacarpals,
[3] fusion of the proximal phalanges, and
[4] fusion of the middle phalanges.
FIGURE 1
Figure 1. Images of hand and wrist x-rays in four female subjects compatible with physiological skeletal maturation in different ages: A [4 years], B [8 years], C [12 years], D [16 years]. To note, usually the first ossification center to appear is in the contest of Capitate and Hamate at the second month in females and around the fourth month in males. Then the remaining centers appear, including Triquetrum at 2 years in females and 3 years in males, Lunate at 3 years in females and 4 years in males, Trapezium at 3 years in females and 4 years in males, Trapezoid at 4 years in females and 6 years in males, Scaphoid at 4 years in females and 6 years in males, Pisiform at 9 years in females and 12 years in males [77].
After puberty, all carpals, metacarpals, and phalanges are completely developed, their physes are closed, and the assessment of skeletal maturity is based on the degree of epiphyseal fusion of the ulna and radius [80–82].
Standardization of Hand and Wrist Radiography
During a hand and wrist X-ray procedure, the child is exposed to