Summary
Despite many years of dedicated research into the etiology of adolescent idiopathic scoliosis, not one single cause for this classic orthopaedic disorder has been found. Nevertheless, recent research has shed light on the role of genetics, metabolics, the central nervous system, and biomechanics of the upright human spine in this etiological enigma. This chapter aims to recapitulate the present body of knowledge.
Key words
idiopathic scoliosis – etiology – pathogenesis – bone metabolism – biomechanics – animal models – genetics – shear loads2 Etiological Theories of Idiopathic Scoliosis
2.1 Introduction
Scoliosis is a classic orthopaedic disorder, a three-dimensional (3D) rotational deformity of the spine and trunk. It consists of a coupled deviation in all three planes of the body, with rotation and intra-architectural torsion in the transverse plane, extension of the spine in the sagittal plane, and lateral deviation in the coronal plane. Genetic predisposition plays an important role. 1 , 2 , 3 , 4 , 5 , 6 , 7 It has severe consequences for the patient in terms of self-image, pain, and the serious impact of the different treatment options. 1 There are several known conditions that cause scoliosis, such as congenital spinal abnormalities, and neuromuscular and metabolic disorders. However, in most cases of scoliosis, a specific cause is not found; the patients appear otherwise normal, and therefore those cases are called “idiopathic.” The term “idiopathic” (from the Greek: ίδιοζ= one’s own and πάθοζ = suffering) is meant to imply that the disease is not linked to any physical impairment or previous medical history. The most common type, adolescent idiopathic scoliosis (AIS), develops in previously healthy children, most often girls, during early puberty, and affects 1 to 4% of the adolescent population. 1
Despite decades of extensive research into idiopathic scoliosis, the exact etiology of this disorder has still not been resolved, although recent research has shed light on the role of human upright sagittal alignment in relation to the rotational stability of the spine and genetics, as well as metabolic and neurogenic factors. 1 , 8 , 9 , 10 , 11 , 12 As a consequence, no adequate, early causal treatment is available to date. Therefore, treatment is aimed at the outcome of the disease process (i.e., an already severe deformity). A better understanding of the early evolution of the initially normal spine into the 3D pathoanatomy of AIS, and the factors that play a role in this process, is important for the identification of prognostic factors as well as for the development of earlier and potentially less invasive treatment options.
Idiopathic scoliosis is known to be a disease of the human species; it does not seem to occur naturally in other mammalians, neither quadrupedal nor bipedal. 13 Animal models lack the typical and unique human spinal loading, which is essentially different from all other species, also the bipedal ones. Furthermore, a role is attributed to the central nervous system (CNS), possibly related to proprioception and body equilibrium, and vitamin D status and bone quality have been shown to play a role in the progression of the disorder. In the subsequent paragraphs of this chapter, current knowledge on these etiopathogenetic aspects of AIS will be presented.
2.2 Biomechanics of the Upright Human Spine as Related to the Sagittal Profile, Dorsal Shear Loads
The importance of the sagittal profile of the spine in scoliosis has been recognized for a long time. Nicoladoni eloquently described the changes in scoliosis in all three planes, including the extension of the thoracic spine in the sagittal plane. 6 Dickson must be credited for reemphasizing that knowledge and elaborating on it in a number of landmark studies in the 1980s. 14 , 15 , 16 , 17 In his concept, the initial deformity in idiopathic scoliosis is a thoracic lordosis that starts to buckle under the influence of everyday flexion moments. The existence of a thoracic lordosis was confirmed in more recent studies by Schlösser et al and Newton et al. 18 , 19 , 20 , 21
Human bipedalism seems to be a prerequisite for the development of idiopathic scoliosis. 1 , 10 , 22 The fully upright human posture and ambulation differs considerably from that of other species, quadrupedal as well as bipedal. As a result, the way the upright human spine is biomechanically loaded is a unique feature of mankind and has a serious impact on rotational stability of certain spinal segments. 10 , 11 , 23
2.2.1 Evolution of the Human Pelvis, Pelvic Lordosis
The essential difference between humans and all other vertebrates is not any major difference in spinal architecture itself. Spinal architecture is relatively uniform throughout all species with broad vertebral endplates and discs to withstand axial loading, and posteriorly located synovial facet joints and protuberances for muscle and ligament attachment to withstand anteriorly directed shear loads (Fig. 2‑1a). Humans, however, have a unique combination of fully upright sagittal spinopelvic alignment, thanks to a lordosis that already starts in the pelvis, and fully upright bipedal ambulation. Due to this configuration, Homo sapiens are the only species that can simultaneously extend both hips as well as knees, putting the body’s center of gravity straight above the pelvis. In contrast, bonobos, man’s closest relatives, consistently ambulate with a flexion contracture of the hips and knees, with a center of gravity in front of the pelvis above the feet. This unique human feature poses unique, dorsally directed shear loads on certain areas of the human spine that have been shown to lead to a reduction in rotational stiffness of these exposed segments (Fig. 2‑1b, c). 8 , 10 , 11 , 23 Human sagittal spinopelvic alignment in combination with habitual bipedalism is therefore unique and introduces unique spinal biomechanics.
It is generally accepted by anthropologists that human habitual bipedalism, that is, fully upright locomotion with extended hips and knees, as well as sagittal spinopelvic alignment can be attributed to morphological changes of the pelvis during human evolution. 24 , 25 In the earliest hominid specimen to date, an Australopithecus afarensis that was found in Ethiopia (also known as “Lucy”), as well as in other hominids, anthropologists observed that angulation of the ilium relative to the ischium enabled upright human locomotion. 26 Recently, Schlösser et al showed that this ischio-iliac angle or pelvic lordosis in humanlike primates ranges from –4 to 12 degrees, from 20 to 24 in hominins and from 19 to 26, respectively, in pediatric and adult Homo sapiens. 22 Even in human’s closest relatives, the bonobos and chimpanzees, there is almost no angulation between the ischium and ilium. When a primate tries to stand upright, the trunk simply swings up on the femoral heads to a point that the ischium points almost directly downward. The ischium, however, is the lever arm for the ischiofemoral muscles and plays an important role in the extension of the hips. In a primate in upright position, the ischium points straight down and the hip extensors have run out of momentum long before the spine is aligned with the vertical femoral shaft. For occasional bipedal locomotion, primates therefore need to bend their knees, which together with the flexed hips positions the center of mass of the upper body in front of the pelvis. 27 For energy-efficient bipedal locomotion as seen in humans, however, lordotic angulation of the ilium relative to the ischium was a prerequisite (Fig. 2‑2). 24 , 28 , 29
2.2.2 Dorsal Shear Loads Acting on the Human Spine
Variation in sagittal alignment of the spine is increasingly recognized in the etiopathogenesis of spinal deformities. Although all spines in nature are predominantly loaded in an axial direction, the orientation of each individual in space vertebra determines whether it is, in addition to axial loading, subject to either anteriorly directed or posteriorly directed shear loading as a result of gravity and muscle tone (Fig. 2‑1). 10 , 23 Vialle et al and Roussouly et al have shown that an excess of anterior shear, under certain circumstances, can lead to anterior displacement of the vertebral body, known as spondylolisthesis. 30 , 31 , 32 Axial compression can lead to impression fractures in its acute form and to osteochondrotic lesions (Scheuermann disease) in its more chronic form during growth. Vercauteren in 1980 and Castelein et al in 2005 have clarified that a certain area of the human spine in the upright position is posteriorly inclined and affected by dorsal shear loads (Fig. 2‑1). 10 , 23 , 33 In an experimental setup, Kouwenhoven et al have shown that an excess of posterior shear loads results in diminished rotational stiffness of the involved spinal segments. 8 Therefore, the more the spine exhibits areas with posteriorly tilted vertebrae, the more these segments are prone to develop a rotational deformity (in other words, scoliosis). 10 , 11 In this concept, rotation is the first step in the development of the overall deformity (Fig. 2‑3).
Janssen et al showed in an in vivo experiment with magnetic resonance imaging (MRI) that allowed imaging in different positions that rotation of the spine increases in healthy young adult volunteers if they move from a quadrupedal-like to an upright position. 34
The three different forces that act on the human spine can easily be seen in the deformities that occur once the most important stabilizers of the spine, the intervertebral discs (IVDs), wear out. When discs collapse as a result of an excess of axial compression, degenerative spondylolisthesis can occur as a result of anterior shear, and retrolisthesis as a result of posterior shear (Fig. 2‑4 and Fig. 2‑5). This disc degeneration leads to a reduced stiffness of the involved spinal motion segments that subsequently may start to rotate under the influence of the posteriorly directed shear loads that act predominantly on the lumbar spine in the adult (Fig. 2‑5). 35
2.2.3 Differences in Sagittal Spinal Alignment
The spinal segment that is posteriorly inclined, and thus subject to the destabilizing dorsal shear loads, is determined by the person’s highly individual sagittal spinal profile. Unfortunately, especially during the period that a child grows, this sagittal profile is very ill defined. Very little is known of the normal or pathologic development from the global kyphosis that is typical of the intrauterine and newborn spine to the more or less defined sagittal spinal shape of an adult with a pelvic, a lumbar, and a cervical lordosis (Fig. 2‑6). Janssen et al have shown that there are differences in the sagittal spinal alignment between young asymptomatic women and men. 23 The spine in women shows more backward inclination than that in men. Furthermore, Schlösser et al found that during the period of maximal growth, spines of girls are more backwardly inclined than the spines of boys. 36 Both studies suggest that the female spine, especially during peak growth velocity, is more subject to dorsally directed shear loads and thus more vulnerable to develop a rotational instability than the male spine. It was also shown that already at a very early stage of the development of scoliosis, the sagittal profile of patients with a lumbar scoliosis, as determined by defining the inclination of each individual vertebra, is significantly different from that of patients with a thoracic scoliosis. It was also shown that both scoliotic sagittal profiles differ from controls, supporting the assumption that the development of different types of scoliosis is based on differences in underlying sagittal profile (Fig. 2‑7). 19 It may be argued that these sagittal profiles have changed in the process of the development of the scoliosis, but this study looked at very mild curves with a Cobb angle of less than 20 degrees, and the sagittal changes were already much more pronounced than the coronal ones. The pelvic incidence (PI), as described by Duval Beaupère, is widely used to describe the relationship between pelvic anatomy and spinal sagittal alignment. 37 Brink et al used a very accurate 3D-reconstructed CT-based measurement of the PI (Fig. 2‑8) and showed that this determinant of sagittal spinal alignment is significantly higher in lumbar than in patients with thoracic scoliosis or controls. 38 This also points to the role of preexisting pelvic morphology and the sagittal spinal alignment in the etiopathogenesis of AIS.
2.2.4 Preexistent Rotation of the Nonscoliotic Spine
One of the classical enigmas in AIS has always been the relative uniformity of the curve patterns. At the adolescent age, thoracic curves rotate to the right in the vast majority of cases, with lumbar curves rotating to the left. In the very young, however, rotation is in the opposite direction. 9 , 39 , 40 It has been appreciated for a long time that the normal spine is not a symmetrical structure, and a subtle rotational pattern has been described in the nonscoliotic spine that corresponds in direction, although of a much smaller magnitude, to what is seen in the most common types of scoliosis. Interestingly, this preexistent rotation of the normal spine changes direction during growth. Based on an existing database of CT scans taken for indications not related to the spine (for instance, polytrauma where spine trauma was excluded, pulmonary disease, and follow-up of malignancy without spinal involvement), it was shown that in the age group between birth and 3 years, rotation in the thoracic area is to the left, between 3 and 9 years it is equivocal, and in the adolescent group it is to the right. 39 This corresponds to the curve patterns seen predominantly in the same age groups. Handedness does not seem to be of influence in the direction of this inherent rotational pattern; instead, organ mass asymmetry seems to play a more decisive role. 40 , 41 , 42
2.3 Animal Models
One of the major challenges regarding etiology research on AIS is that patients come to our attention after the curve starts to progress. In other words, within current clinical research, it is unknown whether the parameters examined are cause or a consequence of the scoliosis. 1 , 43 In an effort to overcome this hurdle, already more than 125 years ago, the first animal models were introduced. 44 However, there is no animal model that, without underlying disease or experimental intervention, develops a scoliosis. All spines in nature are rotationally more stable than the human spine, as was explained in the previous section. 8 , 10 , 11 Numerous animal models have been used to investigate the possible etiological pathways of AIS. 13
2.3.1 Quadrupedal Animal Models
Since scoliosis can be created only in animals by means of rather draconic interventions, it thus bears very little resemblance to the spontaneous development of the deformity in adolescent girls. Most research in quadrupedal animals has used the well-known lordotic nature of AIS. 13 , 45 Multiple interventions have been performed, either through surgery (internal tethering, sectioning of nerves, transposition of muscles) or external forces such as the use of a corset. 13 , 45 MacEwen took a different approach and aimed at disturbing proprioceptive input by intradural transection of the dorsal nerve roots of growing rabbits. They produced a scoliosis and, moreover, found that the greater the numbers of nerves cut, the greater the curve, suggesting an important role for propriocepsis. 46 Alexander et al, however, asserted that the scoliosis produced by dorsal rhizotomy was due to the fact that the surgery also damaged the anterior horn, leading to a motor paralysis that caused the scoliosis. 47 Langenskiold and Michelsson created scoliosis by unilateral rib resection which was repeated in numerous studies. 13 , 45 , 48 Another theory, extensively studied, was based on the asymmetrical neurocentral cartilage growth theory: asymmetrical growth in the neurocentral cartilage of the vertebrae leads to vertebral rotation and, subsequently, scoliosis. This was tested in pigs by Beguiristain et al and was repeated by multiple groups with mixed success rates. 49
2.3.2 Bipedal Animal Models
To approximate human spinal biomechanics more closely, naturally occurring bipedal animals have been used (chickens, penguins, and nonhuman primates) as well as animals that were made bipedal, for instance, by amputating the front legs and tails of rats. 13
The most common observed pathway in bipedal animals is the (neurohormonal) role of melatonin. This started with the study by Thillard, in 1959, on chickens in which a pinealectomy was performed and in which 65% of the chickens developed a scoliosis. This study was repeated by Machida et al in which, in induced bipedal rats, the pineal gland was either resected (100% scoliosis) or grafted in the trunk (10% scoliosis). Controls did not develop scoliosis. 50 , 51 , 52 As a result of these studies, the neurohormonal pathway of the pineal body was considered a major contributing factor in the development of experimental scoliosis and was extensively studied. Beuerlein et al investigated whether the surgery itself or the removal of the pineal gland was the mechanism leading to scoliosis. After investigating multiple surgery techniques (high cut, low cut, suction, pull, cutting the stalk leaving the gland behind), it was concluded that cutting the pineal stalk is the critical procedure and not the removal of the gland. 53 Moreover, intense light (which inhibits the melatonin production) leads to a 15% scoliosis rate in chickens. 54 However, when investigating this pathway in nonhuman primates, the results were negative. 55 Moreover, in an observational study of 48 children with pineal lesion (with 80 months’ follow-up), two patients developed a scoliosis and one of these cases of scoliosis resolved spontaneously. This suggests that within small animal models, there might be another pathway leading to an induced scoliosis and/or that the insights provided from the pinealectomized chicken studies may not be extrapolated to the human population.
2.3.3 Genetic Animal Models
With insights gained from multiple genome-wide association studies (GWAS), candidate genes, such as GPR126, PAX1, and LBX1, have been modified in a zebrafish model to mimic the scoliosis deformity found in AIS. 56 , 57 , 58 Patten et al identified a POC5 variant in patients with idiopathic scoliosis. Hereafter, they investigated the role of POC5 in a genetically modified zebrafish. The POC5 variant led to a spine deformity within the zebrafish. 59 A similar result was seen with the PTK7 zebrafish. 60
Recently, a mouse model of idiopathic scoliosis was created following conditional deletion of Gpr126/Adgrg6 in cartilage. 61 However, while the spinal deformities induced in these animal models can help our understanding of certain deficiency in normal physiology that affect the spinal development, they are in general very restricted in truly mimicking the 3D scoliotic deformity and depicting the etiopathogenesis of AIS in humans.
2.3.4 Human Model
As an alternative to these animal models that all pose problems in translation to the human situation, the so-called experiments of nature can be of help. Examples are given in other medical disciplines: the Sjogren–Larsson syndrome is used as a model for preterm labor and the 22q11.2 deletion syndrome is used as a molecular model for human schizophrenia. 62 , 63 By identifying a group of patients that has a high risk of developing “idiopathic-like” scoliosis, certain aspects also applicable to idiopathic scoliosis may be studied. The 22q11.2 deletion syndrome population was found to develop scoliosis in around 50% of patients; age at onset and curve pattern largely resembles AIS, and this group is presently part of a prospective multicenter study. 64
2.4 The Role of the Intervertebral Disc
The avascular IVD, consisting of mostly collagen, proteoglycans, and water, plays an important role in the AIS curvature. 65 It has been observed in two-dimensional radiographs that morphological changes occur not only in the bone but also in the IVD, suggesting the latter as the causal or permissive factor for AIS. 66 , 67 In fact, when investigating the true 3D morphology and the individual contribution of the vertebral bodies and IVDs, it was demonstrated that AIS curves were characterized by a much greater deformation in the IVDs than in the vertebral bodies, as was also pointed out by Grivas et al in 2006. 68 , 69 The IVDs were at least three times more deformed in the coronal, true transverse, and true sagittal plane as compared to the vertebral bodies. These changes in the discs appeared to be more a passive phenomenon, related to altered loading, than an active growth disturbance. 70 Moreover, the increase in Cobb angle during three phases of adolescent skeletal growth and maturation occurs through disc wedging during the rapid growth spurt, with vertebral wedging occurring later and to a lesser extent. 67
Scoliotic discs removed during surgery showed distinct differences in biomechanical parameters compared to healthy discs, including an altered overall organization, proteoglycan, elastin, and collagen content. Differences between the concave and the convex sides were also noted, especially with respect to annulus fibrosus (AF) fibers. Relative to the concave side, the convex side has increased collagen I content with more cross-linking, indicating a higher collagen production, maturation, and stiffness. 71 , 72 , 73 In the normal adolescent disc, an organized network of abundant elastic fibers is found. However, in scoliotic discs, these fibers become sparse and disrupted. 74 Roberts et al observed differences in the distribution of collagen in patients with scoliosis, compared with controls. 75 In terms of fiber remodeling, matrix metalloproteinases, which are able to cleave collagen, showed differential expression across the scoliotic disc, with the highest levels in samples taken from the convexity of the curve. 76 , 77 Heidari et al used a mathematical model to demonstrate that the imbalance in collagen fiber network within the AF has the potential to contribute to the progression of scoliosis. 78 Additionally, assessment of IVD properties with shear wave elastography showed that scoliotic discs may have alterations in their AF in comparison to healthy controls. 79 Lastly, an abnormal calcification of the vertebral end plate was shown in scoliosis, which likely has an effect on nutrient supply to the IVD. 75 , 80 Obviously, many of these differences can be the result of altered loading and, therefore, it is speculative whether the discs have a causative role.
Thus, it appears that scoliosis progresses initially with at least a reactive phenomenon in the IVDs. These gradual changes in the IVD, such as collagen network remodeling, cause the disc to maintain a wedge shape even when unloaded. Active growth in the curved spine leads to further bony vertebral wedging as part of the “vicious cycle” as described by Stokes et al. 81
2.5 Current Understanding of Genetics in AIS
Hereditary and genetic factors are widely accepted to play an important role in the etiopathogenesis of AIS. This is shown by the fact that there is a higher concordance of scoliosis in monozygotic twins (73%) and dizygotic twins (36%). 3 Moreover, first-degree relatives of patients with AIS have an increased risk (6–11%) of developing AIS as compared to the general population. 82 Genetic studies have constituted nearly 40% of all the publications in English literature related to the etiopathogenesis of AIS in the past two decades, from familial linkage studies and candidate gene and single nucleotide polymorphism association studies to GWAS and multicenter/multiethnic GWAS studies (Fig. 2‑9). The discussion in this section will focus on the more recent GWAS findings, the clinical implications, and future directions related to genetic research in AIS.
2.5.1 Genome-Wide Association Studies
Adolescent idiopathic scoliosis is most likely a multifactorial disorder with considerable genetic heterogeneity (it does not follow the classical mode of Mendelian inheritance). In other words, the inconsistent penetrance and expressivity suggests the involvement of multiple genes. 1 The advancement of GWAS made it possible to perform more comprehensive studies on possibly involved genes. In 2010, the first major GWAS on AIS was conducted. 83 However, the claim that the tool that was developed could be used as a prognostic method for predicting curve progression was not replicable in non-Caucasian ethnic groups. Yet, this was the starting point, and several large-scale GWAS using multiple ethnicities have been conducted. This led to the discovery of many new risk alleles in AIS, including LBX1, PAX1, BNC2, GPR126, and LBX1-AS1. 56 , 57 , 84 , 85 , 86 Among these variants, LBX1 was the best validated and replicated predisposing gene across different ethnic groups. 84 , 87 The next step was to link the genes to biological and functional mechanisms in the etiopathogenesis of AIS.
2.5.2 Differential Roles of Genetics and Environment Factors in Initiation/Progression of Deformity
In the past years, there has been a visible and growing acceptance of the proposed two-phase model of pathogenetic factors leading to the development of the spinal deformity called AIS: initiation phase and progression phase (Fig. 2‑10). 88 This concept is based on the multifactorial nature of AIS. The hypothesis is that a set of genes is responsible for initiating the onset of scoliosis, while another set of genes is responsible for the curve progression. These genes may act separately for each phase or may overlap in both phases. During the two phases, there is a different amount of interaction with and contribution of environmental factors (summarized conceptually in Fig. 2‑10).
Discovering Risk Factors for Susceptibility
Genetic association studies allow localization of specific genomic areas to determine their association with scoliosis in individuals or study populations. With well-planned studies constructed around clearly defined sets of stratified variables (such as gender, age at onset, curve severity, or bone mineral density) and the application of a variety of genetic statistical programs with enough power, it is possible to (1) detect true associations and (2) (partly) overcome the effect of genetic heterogeneity in AIS.
Discovering Risk Factors for Scoliosis Progression
The risk factors that influence the progression of scoliosis are clinically most important, as it would guide the clinical management strategy and timely decision making. Few gene variants were reported to be associated with AIS severity, including the SNPs in ESR1, ESR2, MATN1, TGFB1, IGF1, and SOC3 genes. More recently, decreased expression of FBN1 has been reported to be significantly correlated with the curve severity in AIS. 89
These new discoveries will help evoke new research questions and advance our understanding of the biological mechanisms and processes in AIS such as how much do genetic factors contribute toward severity; why is there a differential genetic risk in different ethnicities; what cell types are relevant in the disease process; and can genetic factors be modified to affect the curve progression and response of treatment?
2.5.3 Clinical Implications
The main benefit for clinicians and patients would be to foresee, with good reliability and reproducibility, whether patients presented with an initial curve will progress or not. By subgrouping patients into progressive versus nonprogressive groups, it may help better classify the prognostic outcomes and references for clinical decision. However, as most of these genetic findings were derived from limited underpowered studies selected for etiological and clinical correlation studies with inherent measurement errors and potential bias, at this stage the direct clinical application is still lacking.
2.5.4 Future Trends of Genetic Studies
In the past years, developmental and genetic studies of the spine, genetic linkage to vertebral anomalies, and family-based association studies have led to advances in understanding the genetic causes of scoliosis. Despite the advances in our understanding, further analysis with new advanced techniques is needed. In looking forward, some of the possible directions are suggested later.
Building Large-Scale Patient Database for Big Data Analysis
As idiopathic scoliosis is a heterogenic disease of multifactorial causes, there is a need to build a large-scale multicenter patient database to allow complex big data analysis on the interactions between genetic background, environmental, and lifestyle factors in the AIS population.
Utilization of System Biology and Bioinformatics Approaches
The potential application of modern bioinformatics can be used in sorting and analyzing the data generated by high-throughput screening, including the radiographic images, clinical genetic, orthopaedic medical records, pedigrees, longitudinal outcomes data, genotypes, and genome sequence. Application of a system biology approach through combining the effort from bioinformatics, engineering, and biological approaches might help advance the understanding of findings in basic research studies for potential clinical translation in AIS.
Use of Biological Model
Further refinement and creation of appropriate new animal models would still be essential for research related to the understanding of the link of abnormal genetic or environmental factors to the development and etiopathogenesis of scoliosis at different phases that might serve as important reference for AIS in humans. Moreover, “experiments of nature” as discussed in Chapter 3.4 could be beneficial.
2.6 Bone Growth and Metabolism in Adolescent Idiopathic Scoliosis
There is rapid skeletal growth during the peripubertal period with a dramatic increase in body height and a near doubling of the total body skeletal mass. This maturation process of the bone is tightly regulated by complex hormonal changes, programmed by genetics, and is related to interaction with nutritional and environmental factors. Interestingly, the pubertal growth spurt is associated with a transient period of asynchronous bone mineralization, accretion, and growth, resulting in a transient decline in bone mineral density and cortical bone weakness. This coincides with the period of development and progression of curve deformity in AIS which then tends to stabilize at skeletal maturity in the majority of mild to moderate curves. 1
There is a clear difference between girls and boys with regard to the growth spurt; peak height velocity appears in girls 1 or more years earlier than in boys. Within girls, the age of menarche is a maturity indicator for growth potential and was reported to be associated with the incidence of AIS. 90 Various X-ray-based skeletal maturity staging methods (e.g., the Risser sign, Sanders staging, and, lately, Thumb Ossification Composite Index) have been developed to determine the peak growth velocity and the risk of curve progression in early AIS that could serve as important reference for timely treatment decisions. 91 , 92
2.6.1 Abnormal Skeletal Growth
Longitudinal growth studies have revealed a significant increase in peak height velocity in patients with AIS that occurs with a longer period of peripubertal growth. Moreover, studies reported the presence of longer arm spans and leg lengths, disproportionate growth (asymmetric left–right side of the body), iliac height, and periapical ribs that could be significantly associated with apical vertebral rotation and curve severity in AIS. RASO with disproportionate and asynchronous neuro-osseous growth of the spinal column and spinal cord has been hypothesized to be a contributing factor in the etiopathogenesis of AIS, although it has also been observed in neuromuscular scoliosis. 70 , 93 , 94 , 95 , 96
2.6.2 Body Composition and Metabolic Dysfunction
Several studies have suggested an association between a different body composition and the incidence of AIS. 97 , 98 Body compositions assessed by dual-energy X-ray absorptiometry (DEXA) showed that a decrease in lean mass and fat mass at the age of 10 was associated with a higher risk of having AIS at the age of 15 years. A decrease of one standard deviation in lean mass or fat mass at the age of 10 was associated with a 20 and 13% higher risk, respectively, of having AIS at the age of 15 years. 98 These results, along with the finding of abnormally low free leptin bioavailability in patients with AIS, suggests that leptin and soluble leptin receptor—with its physiological functions in regulating skeletal growth, bone metabolism, and energy homeostasis—might be responsible for some of the abnormal phenotypes observed in AIS. 99
2.6.3 Low Bone Mineral Density, Abnormal Bone Structure and Qualities
In recent years, a strong and consistent correlation has been reported between AIS and bone metabolism parameters. Low areal BMD (aBMD) measured with DEXA densitometry was reported in more than 30% of the AIS patients across different ethnic groups. 100 , 101 , 102 , 103 An inverse relationship between BMD and curve severity was reported in a cross-sectional study on 919 girls with AIS. 104 Importantly, bracing during the pubertal period did not significantly affect the bone mass at the spine and hip in AIS patients, suggesting that the low BMD in AIS is unlikely to be secondary to the bracing. 105
Osteopenia within AIS, defined as a Z-score of less than -1 with reference to the normal sex- and age-matched ethnic population, was found to affect both the axial and the appendicular skeletal sites, as reflected from aBMD of the hip and spine, distal tibia, radius, and calcaneus. Advancements in bone imaging technology revealed a lower volumetric bone mineral density (vBMD) in both the cortical and trabecular bone compartments. The abnormal bone qualities include (1) thinner and smaller diameter cortical bone geometry, (2) trabecular microarchitecture with decreased thickness, and (3) plate/bone volume fraction with poorer bone mineralization in AIS. The low vBMD and abnormal bone qualities collectively contribute to lower bone mechanical strength reflected by the significantly lower quantitative ultrasound value of broadband ultrasound attenuation, a lower stiffness index of the calcaneus, and apparent modulus and failure load through high-resolution peripheral quantitative computed tomography (HR-pQCT) finite element analysis. 106 , 107
Several longitudinal studies suggested that without any intervention, the lower BMD could persist throughout the pubertal period and, in one study, 86.0% of patients with AIS and osteopenia were found to remain osteopenic well beyond skeletal maturity. 108 , 109 The above observations are schematically summarized in Fig. 2‑11.
2.6.4 Abnormal Bone Turnover and Bone Cells Activity
The abnormal bone quality in AIS reflects a dysfunction in the dynamic balance of bone formation and resorption as reported from studies on serum markers; for example, bone-specific alkaline phosphatase, osteocalcin, soluble RANKL:OPG ratio, TRAP5b, and bone histomorphometry. 1 , 110 Time-lapse measurements with HR-pQCT showed new possibilities of documenting the “real-time” dynamic changes at local bone sites. 111
Current mechanistic studies focus primarily on osteoblast activity, which is under the influence of various proposed hormonal factors, such as melatonin, leptin, and estrogen. Dysfunction of the melatonin signaling pathway, attributed to the inactivation of Gi proteins, was reported in osteoblasts cultured from surgical AIS patients. 112
Osteocytes, the most abundant (>90%) and major mechanosensing bone cell, have a key role in the regulation of mineral homeostasis and bone remodeling. Lately, with advancing technology, there is an increasing interest in studying the structure and function of osteocytes. In a recent study, abnormal clusters of roundish irregular-shaped osteocytes with short and disorganized canaliculi were found (Fig. 2‑12). 113 Moreover, recent evidence indicated that serum sclerostin, primarily secreted by osteocytes, was abnormally low in AIS patients and was associated with lower BMD and abnormal bone microarchitecture. 114 Lastly, several microRNAs (a class of noncoding RNA that regulates diverse biological processes) have also been postulated to play an important role in the etiopathogenesis of AIS. 115 More studies would be needed to confirm whether changes in the serum sclerostin and microRNA could serve as a potential quantifiable prognostic factor for curve progression in AIS.
2.6.5 Lifestyle Factors Associated with Low BMD and Poor Bone Quality
The importance of physical activity and mechanical loading on bone mass accrual has been well documented, particularly in children and adolescents. A lower physical activity level was found in AIS and was independently associated with a lower cortical area and total vBMD. 116 The same study detected a lower mean calcium intake of 571.9 mg/day in the AIS group, which was well below the recommended 1000 mg/day. Balioglu et al showed a significantly lower serum 25-OH-vitamin D levelsin 229 AIS patients aged 10 to 22 years when compared with 389 age-matched athletes without scoliosis. Moreover, the vitamin D levels correlated negatively (R = –0.147) with the Cobb angle, suggesting a possible link of vitamin D to the etiopathogenesis of AIS. 117
2.6.6 Bone Mass and Bone Qualities as Prognostic Factors of Curve Progression?
In addition to widely accepted prognostic factors as chronologic age, menarchal status, Risser sign, degree of curvatures at presentation, and the curve pattern, additional evidence has suggested the prognostic value of abnormal bone qualities on curve progression in AIS. In a 6-year longitudinal follow-up study of 324 girls with AIS, it was reported that osteopenia is a significant prognostic factor for predicting curve progression in AIS with an adjusted odds ratio of 2.3. 118 Another longitudinal follow-up study of 513 AIS subjects beyond skeletal maturity indicated that the aBMD and more specifically the cortical vBMD of the distal radius at the first visit could predict the curve progression to surgical threshold with a hazard ratio of 2.25. 119 The hypothesis of the link of abnormal bone metabolism to the development and progression of AIS is summarized in Fig. 2‑13.
2.6.7 Potential Clinical Intervention and Lifestyle Modification Targeting Bone Health that Might Affect the Curve Progression in Early AIS
Though at this stage the exact underlying pathomechanism of AIS remains elusive, available evidence supports the possibility that the abnormal bone mass and bone qualities observed in AIS might serve as a novel target for clinical intervention with the aim to reduce the chance of curve progression in the early stages.
Lam et al have reported two noninvasive approaches to improve bone quality in girls with AIS. A randomized controlled trial (RCT) showed that whole body vibration (WBV) therapy as a form of mechanical loading simulating weight-bearing physical activity could improve the low femoral neck aBMD and bone qualities in osteopenic AIS during a 12-month period. 120 Another RCT on vitamin D and calcium supplementation in AIS with low baseline calcium intake and serum vitamin D levels over a 2-year period showed significant improvement in bone mass and bone qualities and a reduction in the percentage of curve progression in the treatment group when compared with the placebo control group using SRS criteria (2016 Russell A. Hibbs Clinical Research Award, SRS).
2.7 Central Nervous System
Multiple neurophysiological abnormalities in the CNS have been reported to be linked to the etiopathogenesis of AIS. These include abnormal somatosensory evoked potentials (SSEPs) with prolonged and asymmetrical latencies; body balance and postural instability; abnormal proprioceptive function, visuo-oculomotor and vestibular dysfunction, and combinations of all of the above. In addition, abnormalities associated with AIS have been demonstrated in the CNS at both the brain and spinal cord level (Fig. 2‑14).
2.7.1 Neurophysiological Dysfunction
Postural Balance and Gait Analysis
Research studies have shown abnormalities in the pelvic distortion, body posture asymmetry, and standing imbalance in female AIS patients as compared to matched controls. The 3D gait analysis using kinematic and kinetic measurements also showed asymmetrical torsional offset of the upper trunk with respect to the pelvic rotation. 121 Although gait analysis did not show a direct correlation between gait asymmetry and curve direction, magnitude, or vertebral rotation, there was a significantly higher postural instability in AIS that included limb load symmetry, sway length, and velocity in anteroposterior and laterolateral directions. Moreover, dynamic studies revealed a longer duration of gait initiation and much slower balancing in AIS. 122 , 123
Somatosensory Evoked Potentials
Abnormal SSEPs were reported in AIS patients with thoracolumbar curves. 124 MRI studies showed that the incidence of tonsillar ectopia in AIS patients with and without abnormal SSEPs was 33.3 and 2.9%, respectively. Syringomyelia was found in 33.3% of AIS with tonsillar ectopia versus 0.7% in those without. 125 Tonsillar ectopia was found in 27.3% of patients with severe AIS, in 6.7% of AIS patients with moderate AIS, and in 5.8% of patients with mild AIS. 126 No similar abnormality was observed in healthy controls. Both left and right SSEPs have been reported to be positively correlated to the Cobb angle and negatively to the ratio of sensory analysis–vestibular and balance parameters. 127
2.7.2 Neuromorphological Changes (MRI-Based Studies)
Spinal Column and Spinal Cord
MRI studies have demonstrated a number of neuromorphological differences between AIS and healthy controls including low lying cerebellar tonsil level (both in static and dynamic MRI), larger foramen magnum with preserved CSF dynamics, alteration of cross-sectional shape, and altered position of the spinal cord. Using a reformatted MRI imaging technique, a longitudinal study has identified the cord to vertebral length ratio, the ratio of anteroposterior to transverse cross-sectional diameter of the cord, and the degree of deviation of the spinal cord within the spinal canal as new prognostic factors in predicting curve progression in AIS. 128 , 129 , 130 , 131 , 132
T2-weighted reformatted MRI has shown the relative shortening of spinal cord suggesting subclinical tethering in patients with AIS. In addition to traditional MRI, noninvasive diffusion tensor imaging (DTI) technique can capture the microstructure tissue status and functional orientations which have been utilized to delineate abnormal subtle changes in the CNS. A study using DTI showed a significant decrease in fractional anisotropy (FA) values and increase in mean diffusivity (MD) values in medulla oblongata and upper cervical segment (C1–C5) of the spinal cord in AIS. 133 This microstructural change in the neural pathway is in agreement with the clinical observation of abnormal somatosensory evoked potentials in AIS. 126
Brain
The mean brain volume, after normalization, has been found to be significantly different in 22 of 99 anatomical regions in AIS subjects, which include the corpus callosum and brainstem. 134 Altered cerebral cortical thickness maturation pattern, focal cortical thickness, regional cerebellar volume, and cortical structural network patterns have also been reported. Brain regions in AIS found to be abnormal are closely related to motor control, vestibular, or somatosensory functions. Lastly, the splenium of the corpus callosum was consistently different from normal controls. 135 These observations, coupled with the additional finding of significant decreased FA values in the genu and splenium of the corpus callosum, suggest that a primary deficit in interhemispheric coordination might play a role in the etiopathogenesis of AIS. 136 As the interhemispheric fiber tract serves as the interconnection of the somatosensory and visual cortices via the splenium, the change in corpus callosum might partially explain the increased association of somatosensory function impairment and visuo-oculomotor dysfunction with curve severity. 126
Vestibular System
The vestibular system is known to be one of the major organs responsible for postural balance in human and other animal species. Unbalanced vestibulospinal control has been reported to be associated with the development and/or curve progression in AIS. A study using a frog model was conducted to observe the development of the spine from larval stage to metamorphosis by unilaterally removing the labyrinthine end organs, which resulted in deformities of the spine similar to those of AIS. 137 An MRI study of the vestibular system using an advanced computational segmentation technique reported greater orientation asymmetry along the z-axis between the right- and left-sided semicircular canals associated with significant difference in shape and alignment in the left-sided semicircular canals in typical right thoracic AIS. 138
Neurotransmitters
As part of the onset of AIS, many neurohormonal pathways have been investigated. 139 A key example is the role of melatonin and melatonin signaling pathway as discussed in the animal model section. In normal growth and development, there is a dynamic physiological balance between increasing skeletal size, changing skeletal shape, relative mass of the different body segments, and the growing brain and CNS. In AIS, it was hypothesized that an abnormal neurohormonal pathway could lead to a disbalance between the osseous structures and the neural structures that might contribute to the onset or progression of the spinal deformity. 139
The role of neurotransmitters has been extensively studied in the field of psychiatry, in which abnormalities are shown in patients with depression, bipolar disorders, and schizophrenia. 140 , 141 , 142 Several neurotransmitters, such as serotonin, norepinephrine, and histamine, play an important role in maintaining postural balance. 143 A preliminary study by Morningstar et al showed abnormal baseline neurotransmitter levels in AIS patients which can be corrected by a nutrition program. 144 A statistical difference in neurotransmitter abnormalities was found between nonprogressive and progressive scoliosis cases. 145 Further research needs to be done to better understand the possible link to the etiopathogenesis.
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