Genetics, while a crucial facet of AIS development, cannot be the sole consideration in the development of AIS. In the study by Simony et al. [23], Cobb angles greater than 10˚ were observed in twins using the Danish Twin Registry. A concordance rate of 0.40 (0.10–0.70) was observed in monozygotic twins and a rate of 0.05 (−0.05 to 0.15) in dizygotic twins [23]. Thus, genetics, while imperative for the determination of AIS, does not entirely contribute toward the pathological development of the disease.

Estrogen and melatonin have long been controversial in the development of AIS and the severity of spinal curvature. In the study by Kulis et al. [24], concentrations of follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone were significantly lower in postmenarcheal female adolescents than in their control counterparts. However, in the study by Zhou et al. [25], higher serum estrogen levels and abnormal post-binding cellular responses were observed in patients with AIS. According to more recent studies, estrogen receptor-2 polymorphism and asymmetrical expression that were previously believed to be associated with abnormal spine curvature are not associated with AIS development or severity.

While serum melatonin levels are not significantly different with initial diagnosis in the AIS population, melatonin levels decrease significantly with increased curvature progression [26]. Furthermore, melatonin receptor 1A/1B polymorphisms do not seem to be associated with AIS prevalence or severity, but certain polymorphisms in these receptors have been associated with the development of AIS. The role of receptors continues to remain controversial [27-30]. Thus, it is believed that serum melatonin levels, and possibly receptors, play a crucial role in the development of AIS. In an animal model, it was further confirmed that pinealectomy-induced melatonindeficient rats had issues with mechanical spinal loading and rotational instability like patients with AIS, further supporting the role of melatonin in AIS development [31]. Pinealectomies in chicken models manifested increased spinal deformities during development after hatching. Pinealectomies earlier in development rather than later resulted in much higher levels of spinal abnormalities, thus playing a role in early physiological development [32]. This procedure, however, did not result in spinal abnormalities in rodent and primate models, which was believed to be a result of inadequate stress on the spine due to lack of movement by these animals [32].

Estrogen and melatonin, two crucial hormones in growth regulation and adaptation, are controversial targets for therapy in adolescent populations. Further research is needed to fully understand the pathophysiological progression of the signal disruption in patients with AIS, and targeted patient-specific genetic and hormonal therapies can be used to address this subset of patients.

Environmental triggers of genetic predispositions must then be considered in the etiological processes of adolescent development of pathology. Gene−diet interactions have been observed in multiple facets of growth development; most profoundly, in adolescent populations during puberty. In Jamaica, these profound dietary influences were observed post-1965 with the addition of endocrine additives to livestock. After a 10-year delay, the incidence of scoliosis was dramatically increased. Until 1983, these rates increased until finally decreasing [33]. The Dutch Hunger Winter of 1944 had similar effects on the malleable developing population, and the epidemiological mechanisms are hypothesized to be similar. DNA methylation and epigenetic factors are considered the primary mechanism behind these changes, because these epigenetic factors can trigger genetic predispositions. Specifically, dietary components that are suspected to play a role include methyl donors, bioactive polyphenols, zinc, selenium, and vitamin A [34].

Alteration of the body composition can be seen in patients with AIS. In the study by Ramirez et al. [35], patients with AIS displayed lower body mass index (BMI) values, lower levels of fat composition, and lower fat-free mass indices. Hormonal dysregulation is believed to play a role in this, but there is a possible link between AIS and anorexia nervosa. Treatment to improve patient nutrition may delay exacerbation of spinal curvature in concordance with bracing and other common treatments.

In a preliminary longitudinal case-controlled study, AIS was negatively associated with participation in dance, skating, gymnastics, karate, football, and hockey, suggesting preventative properties [33]. However, this study did not specify whether these activities were preventative measures or whether debilitation of the pathophysiology deterred involvement in these activities. Swimming, specifically exposure to heated swimming pools within the first year of life, significantly increased the rate of AIS development. It is believed that early chlorine neurotoxin exposure in the vaporization of chlorine in a swimming pool can exacerbate AIS development in younger children [36]. In 2014, Sperandio et al. [37] found that patients with AIS exhibited increased walking limitations and worse breathing patterns during exercise. However, researchers believe that increased walking-based aerobic activity will alleviate these symptoms, and these exercises should be encouraged.

Adolescent girls have higher rates of AIS development than their male counterparts. A four-part pathogenic speculative theory has been formulated: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone development; (3) white adipose tissue strengthening triglycerides and the role of leptin in energy homeostasis; and (4) leptin resistance in healthy females [38]. Thus, it is postulated that disharmony between somatic and autonomic nervous systems in the spine and trunk are exaggerated by hormonal dysregulation, resulting in skeletal overgrowth. Ultimately, it can result in physiological trunk width deviation or biomechanical disturbances in the skeletal framework.

First, the thoracospinal concept explains the asymmetrical growth in vascularity, breast size, skin temperature, and periapical rib length. It is believed that exacerbation of this asymmetry manifests as the biomechanical mechanism of pathogenesis, which is amplified during progressive growth.

Second, there has been evidence that hypothalamic leptin resistance occurs in juvenile females but not in males. It is believed to be an energy shunt to conserve energy for reproductive development. However, in some females, this process may be disrupted, resulting in increased central leptin sensitivity. In nonpathological individuals, two synchronous polarized processes called neuro-osseous timing of maturation escalators are balanced during normal growth and maturation: (1) osseous escalator and (2) neural escalator. The former relates to skeletal growth and shaping during development, whereas the latter explains the central nervous system adaptation and recalibration that occurs with growth to coordinate motor function. However, asynchrony or asymmetry during increased growth may result in pathology, due to disharmony in these two systems. The leptin sensitivity hypothesis is further supported by the negative correlation of BMI and AIS in adolescence.

Third, leptin level differences between males and females are significantly affected during puberty. With this dimorphism, females have 40% more leptin, which correlates with increased fat accumulation and adipose volume. Along with effects on adipose synthesis and metabolic effects, leptin plays a crucial role in bone formation and growth through the activation of the sympathetic system for skeletal growth. AIS has been strongly linked to increased leptin levels, which can be understood as dysregulation of symmetrical spinal growth, further explaining the increased AIS rate in females.

Thus, leptin resistance, resulting in leptin hypersensitivity, can incorrectly activate growth signals in the body resulting in disruptions of the osseous and neural escalators, which can exacerbate nonpathological asymmetries in females.

AIS primarily manifests pathophysiological detriments preceding pubescent rapid growth in the early adolescent years. However, the symptoms can be seen before the manifestations of the classical symptoms. Bone mineral density (BMD) has been proposed as a prognostic factor of curve progression in patients with AIS. Runx2, a crucial gene in the regulation of osteoblast development and differentiation, was found to be significantly decreased in patients with reduced BMD [39,40]. In the study by Sun et al. [41], the use of BMD levels was explored as an independent risk factor in the progression of the disease and the duration of bracing treatment. Premenarcheal girls with lower BMD values were seen to have greater curve magnitudes, a lower Risser grade, and a main thoracic pattern [41]. Treatment duration and prognosis of the curve progression can be predicted before the exacerbation of spinal dysregulation during adolescent growth.

Lower BMD must also be considered for other circulating factors regulating peripheral and axial growth. Receptor activator of nuclear factor-kB ligand (RANKL) and osteocalcin serum measurements were observed at higher concentrations in adolescents with AIS. RANKL-to-osteoprotegerin (OPG) serum ratios were seen at higher levels in these individuals as well. Mouse models with RANKLto-OPG disruptions treated with genetic therapy displayed a significant reduction of AIS progression [24,42]. Dipeptidyl peptidase-4, which inactivates glucagon-like peptide-1 (GLP-1) and inhibits insulin secretion and sensitivity, was observed at higher levels in girls with AIS. GLP-1 increases insulin release in the pancreas, enhancing insulin response with bone growth during adolescent development. This further explains the increased prevalence of AIS in individuals with lower BMI values [43,44].

Genetic and hormone therapy can be considered a new methodology of regulating the triggers of asymmetrical trunk bone development in the primary stages of AIS progression.

The bilateral paraxial muscles are important in the symmetrical growth and development of spinal curvature. In patients with AIS, skeletal muscle and fatty deposition imbalances have been observed in the convex and concave facets of the curvature, respectively. Larger muscle volume on the convex side observed at the apex spinal level is consequential hypertrophy, because of stretch-induced stress on satellite cells. Furthermore, the fatty deposition on the opposite, concave facet of the curve is understood as fatty infiltration of muscle atrophy [45].

Muscle physiological differences in calmodulin levels further exacerbate the manifestations of spinal deformation. Calmodulin is observed at significantly higher levels on the convex side with lower levels on the concave facets of the spinal curvature [46]. A secondary messenger of the melatonin pathway and essential to muscle contraction, calmodulin is believed to play a role in the regulation of spinal alignment. In animal models, tamoxifen inhibition of calmodulin suppresses the natural process of scoliosis, thus indicating a possible reversal of the natural development of scoliosis [4]. The bidirectional relationship of bone and muscle pathophysiology is observed through this disruption of signal-regulated development and growth.