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Adolescent Idiopathic Scoliosis

Top Theories for the Etiopathogenesis of Adolescent Idiopathic Scoliosis

Wang, Wei Jun PhD*; Yeung, Hiu Yan PhD*; Chu, Winne Chiu-Wing MD*; Tang, Nelson Leung-Sang MD*; Lee, Kwong Man PhD*; Qiu, Yong†,‡; Burwell, Richard Geoffrey MD, FRCS§; Cheng, Jack Chun Yiu MD, FRCS Ed(Orth)*,‡

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doi: 10.1097/BPO.0b013e3181f73c12
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Despite considerable advances made in the surgical treatment of severe scoliosis in the past few decades, many questions related to the etiopathogenesis of adolescent idiopathic scoliosis (AIS) have not been answered scientifically. This article aims to provide a general overview of hypothetical causations of AIS. An integrated theoretical model is proposed which aims to avoid controversy. Theory is essential for scientific progress and, in a multifactorial clinical disorder like AIS, needs continual appraisal so as to plan research between clinicians, biologists, and engineers of international groups and improve the acquisition of etiopathogenetic knowledge. In turn, this may help clinicians and scientists in developing new diagnostic and treatment regimes for AIS based on some knowledge of its causation.

Although there is no generally accepted “top theory or theories,” concepts of etiopathogenesis in AIS were listed and summarized in a recent review article1 that includes: genetics, biomechanical growth modulation, relative anterior spinal overgrowth (RASO), dorsal shear forces and axial rotation instability, uncoupled spinal neuro-osseous growth, postural abnormalities and hindbrain dysfunction, motor control problem, body-spatial orientation concept, neurodevelopmental concept, thoracospinal concept, systemic melatonin deficiency, systemic melatonin-signaling pathway dysfunction, systemic platelet calmodulin dysfunction, symmetry control dysfunction, developmental instability, and collective and escalator models.

Among these concepts, some are more discrete and can be tested whereas others are plausible and speculative. With the general belief that AIS is a multifactorial disorder, it is likely that the concepts involve different degrees of interaction between different factors in linear and summation causality. They are discussed here in 6 major groups:

  • Genetic factors
  • Nervous system
  • Hormones and metabolic dysfunction
  • Skeletal growth—general, spinal, extraspinal, and skull
  • Biomechanical factors
  • Environmental and life style factors


Multiple reports are available to support the role of inheritance in the development of AIS. Early studies showed that first-degree relatives of the index patients have an increased risk of developing AIS. A meta-analysis of different twin studies found the concordance rate of 73% in monozygous twins versus 36% in dizygous twins. With a large questionnaire-based study,2 the pair-wise concordance rate was 13% for monozygotic whereas none for dizygotic pairs.

Identification of Disease Gene-linkage Studies

With the advance in genetic analysis technique, family-linkage studies have revealed many different gene loci linked to AIS. Miller3 and others4 provided a comprehensive review on the genetic aspects of AIS. In 2005, Miller et al5 suggested gene loci in the primary regions in chromosome 6, 9, 16, and 17 and the secondary regions in 1, 3, 5, 7, 8, 11, 12, and 19 after scanning for 202 families with 1,198 individuals. A recent study6 also showed the genetic linkage of chromosome 18 to AIS. The genetic heterogeneity is evident by the fact that nearly half of the 23 chromosomes have being implicated.

A clear mode of inheritance of AIS has not been confirmed and reports on autosomal dominant,7 dominant major gene di-allele model,8 X-linked,9,10 or multifactorial inheritance pattern11,12 have all been reported.

Association Studies and Candidate Gene Approach

Genetic association studies with candidate gene approach have been widely used in the recent years with the help of information gathered from the international HapMap project. Candidate gene selection was based on prior knowledge of the observed phenotypes expression in AIS and different single-nucleotide polymorphisms studied with case-control and case-only approaches. A number of genes have been reported to be associated with the occurrence of AIS including melatonin 1B receptor gene,13 chromodomain helicase DNA-binding protein 7,14 tryptophan hydroxylase 1,15 collagen type 1 α 2 gene,16 matrillin-1 gene,17,18 estrogen receptor α19 and β,20 interleukin-6 and matrix metalloproteinase-3,21 and γ1-syntrophin (SNTG1) gene.22 Other reports have shown an array of genes not associated with AIS; these include melatonin 1A receptor gene, growth hormone (GH) gene, dipeptidyl peptidase 9 gene, elastin, fibrillin, collagen type I,16 and aggrecan23 genes. It has also been reported that insulin-like growth factor I (IGF-I), estrogen receptor genes, and matrilin-1 were associated with curve severity of AIS but not with the initiation.17,20,24,25

It is important to note that a significant number of the reported studies have not been replicated both in the same population and other populations. Further studies are required to confirm the findings. Cheng et al26 proposed a genetic model to dissect the development of AIS into “initiation phase” and “progression phase.” This concept is based on the complex-trait disease model and the multifactorial nature of AIS to illustrate that a set of genes can play a role to initiate the development of scoliosis whereas another set could affect the curve progression/curve severity. These 2 sets of genes may act separately or overlapped in different degree. This genetic model also highlights the environmental factor involvement in the initiation and progression phase indicating the importance of the interaction between genetics and environment in the etiopathogenesis of AIS.

Even in the familial AIS cases, it is likely that multifactorial inheritance is implicated. Another aspect of the genetic study of AIS as a complex trait disease is finding the difference between familial AIS and sporadic ones. In a recent report,27 it was observed that the first-degree familial AIS girls had more severe curve and longer arm span than sporadic ones. Further subgrouping of AIS subjects for genetic analysis would be an important approach.

Genome-wide Association Studies

The development of genome-wide association studies (GWAS) of all the single-nucleotide polymorphisms in the genome provides a more comprehensive picture on the possible genes involved in the etiopathogenesis of AIS. Recently, Ward et al28 used a GWAS with 1.8 million genetic markers to compare 1200 AIS patients with 1500 controls. It showed 202 markers related to curve progression and after further refinement, 30 markers were claimed to be most useful prognostic markers for curve progression. This type of expansive large-scale GWAS would also require well-defined phenotypes sampling and multicenter collaborative efforts.

Recent evidence not only suggests that genetic factors play an important role in the etiology of AIS but also revealed the considerable heterogeneity. Although the continuation of the search for the exact genetic factors is inevitable, it is also very important to look at the functional and biological aspects to allow better understanding of the etiopathogenesis of AIS.


Abnormalities in the central nervous system (CNS) have long been thought to play a role in the etiopathogenesis of AIS. In a Symposium in 2000 on the Etiology of Adolescent Idiopathic Scoliosis, Edgar29 stated that “…the whole question of neurologic dysfunction in IS has moved to a center-stage position and now needs to be carefully considered.” In the same year, Lowe et al30 in a Scoliosis Research Society Symposium concluded that: the current thinking is that there is a defect of central control or processing by the CNS that affects the growing spine and that that the most consistent clinical studies point to the pontine and hindbrain regions as the most likely sites of primary pathology.

Relevant studies can be divided into 2 major groups: neuroanatomic/neuromorphologic studies and studies on neurophysiologic dysfunction.

Neuromorphologic Studies

Subgroups of AIS subjects have hindbrain problems with cervicothoracic syrinx,31–33 low-lying cerebellar tonsils34–36 with or without abnormal cerebrospinal fluid dynamics.34,37,38 Other workers have reported anatomic abnormalities in the mid-brain,39 pons and medulla,40 and vestibular system.41,42 With better resolution magnetic resonance imaging (MRI) and advanced intensive computer-aided image analysis of the CNS, differences were detected in regional brain volumes, white matter in corpus callosum and internal capsule (Fig. 1),43,44 and vestibular system morphology particularly semi-circular canal alignment41,42 between AIS and normal adolescents. Larger cross-sectional and longitudinal studies are needed to confirm and extend these morphologic findings and appraise their significance.44

A, With high-resolution MRI and voxel-based morphometry, different components of the brain can be segmented from the original MRI (first row). The volume of white matter (second row), gray matter (third row), and cerebrospinal fluid (fourth row) were segmented for volumetric analysis and comparison. B, The statistical Difference Map showed that the AIS with left thoracic curve have significant different white matter density when compared with control subjects. C, With the atlas-based hybrid mapping, 10 significant regional differences could be found between AIS girls and healthy-matched control subjects. One of the regions is the corpus callosum (red shaded) representing the commissural fiber between left and right brain. AIS indicates adolescent idiopathic scoliosis; MRI, magnetic resonance imaging.

Neurophysiologic Dysfunction

Apart from the neuromorphology, functional studies in AIS subjects have shown abnormalities in the following: postural balance and somatosensory function equilibrium45–48; proprioceptive function49,50; oculovestibular function51; lateral gaze palsy39; electromyography52; somatosensory evoked potentials38,46,53; with contradictory findings for both vibratory responses50,54; and transcranial magnetic stimulation55,56; and motor cortex asymmetric hyperexcitability,57 the latter attributed to dystonic dysfunction. Balance and gait studies have revealed defects mainly in dynamic balance.46,58–62

Abnormal Central Control and Neuro-osseous Maturation Timing

Various hypotheses on abnormal neuro-pathway, motor control, and coordinated control of neuro-osseous timing of maturation have been suggested.1,63–66 Herman et al67 implicated a higher level CNS disturbance producing visuospatial perceptual impairment, motor adaptation, and learning deficits which lead to faulty recalibration of proprioceptive signals from axial musculature causing IS. Veldhuizen et al63 suggested that the likely cause of IS included a neuromuscular condition and asymmetry of the transversospinalis muscles produced by spinal cord or central mechanisms.

A speculative model on the etiopathogenesis of AIS based on evidence not discussed in this article is formulated by Burwell et al.68 It states: “AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically determined upregulation) with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally through the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept=LHS concept). In some younger preoperative AIS girls, the hypothalamic upregulation to leptin also involves the somatotropic (GH/IGF) axis, with GH/IGF secretions which exaggerate the sympathetically induced asymmetric skeletal effects and contribute to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of postural mechanisms fail to control, or may induce, the spinal deformity of AIS girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any relative osteopenia, biomechanical spinal growth modulation, intervertebral disc degeneration, and platelet calmodulin dysfunction.”

More research is needed to test these main and subsidiary neuro-osseous concepts69,70


Growth Velocity and Skeletal Size for Age

The relation of skeletal growth velocity to curve progression in AIS has been widely reported,52,71–74 but its mechanism of action is unclear—causative, conditional, amplifying, or coincidental.75 The dependence of AIS progression on growth has been attributed not to growth velocity, but to rapid skeletal enlargement producing skeletal sizes for age beyond the capacity of postural mechanisms of the somatic nervous system to control the initiating deformity.68,76

General Skeletal Growth

It is generally recognized, although not universally,77 that abnormal growth is associated with the development and progression of the scoliotic curves.78,79 Numerous growth studies have reported that AIS patients are taller than the healthy controls.80–90 Accounting for the sexual maturity, Cheung et al91 found that the girls with AIS were shorter before their menarche but taller and longer in arm span during growth spurt than the control subjects. Higher growth velocity during puberty was shown in girls with moderate and severe AIS in a longitudinal study.92

Spine and Spinal Cord Growth

In line with the growth abnormality of AIS, the Roth-Porter concept of uncoupled spinal neuro-osseous growth for the pathogenesis of AIS has been extensively studied recently. The research started with Roth's speculation that IS results from a disproportion of vertebro-neural growth either because of a short spinal cord or a too rapid growth spurt of the spine.93,94 Roth93 demonstrated his speculation with a spring model. Porter64,65,95 tested the Roth concept with anatomic specimens and showed that the overall length of vertebral canal was short relative to summated vertebral bodies. Later, Guo et al96 used MRI and showed longer vertebral bodies, shorter pedicle heights, and longer interpedicular distances in patients with AIS; these observations are consistent with uncoupled endochondral-membranous ossification in the spine of patients with AIS. A histomorphometric study of the vertebral endplate of AIS patients97 also suggested a more active growth in the anterior than the posterior vertebral column (Fig. 2). Using multiplanar MRI reformatting technique, Chu et al98,99 found longer vertebral column length both in thoracic and whole spine of AIS with thoracic or thoracolumbar curves without corresponding changes in spinal cord length. The reduced ratio of cord-to-vertebral column length was also negatively correlated with the increased ratio of anteroposterior/transverse diameter of the cord, the concave and convex lateral cord space, and cerebellar tonsillar level in AIS.100 The presence of relative tethering and increased tension along the longitudinal axis of spinal cord could result in subclinical neurologic dysfunction such as abnormal somatic sensory evoked potential.100 A recent report supports the hypothesis that tonsillar ectopia may play a role in the development of the deformity but only in some patients with IS.101 These MRI studies are consistent with the hypothesis of RASO and the concept of asynchronous spinal neuro-osseous growth; the latter as an extension to the Roth-Porter concept.

Relative anterior spinal overgrowth as one of the possible etiopathogenetic mechanisms associated with the onset of the scoliosis. With advanced multiplanar magnetic resonance imaging (MRI) technique, the images can be reformatted to “straighten” the scoliotic spine for more accurate measurement of different segments. The anterior spinal column was shown to grow faster and longer than the posterior elements leading to hypokyphosis or lordosis of the thoracic segment.

Rib-length Asymmetry and Chest Wall Blood Supply Asymmetry

Significant asymmetry of periapical rib length102 and breast vascularity103 were reported in girls with right thoracic (RT) AIS supporting the thoraco-spinal concept of pathogenesis.104 Although the earlier studies by Korovessis et al105 evaluating chest wall blood supply did not substantiate Sevastik et al's view104 that periapical rib length asymmetry was the initiating factor in AIS pathogenesis, their recent articles106,107 report asymmetric abnormalities in the evolution of the anterior chest wall blood supply in females with progressive RT AIS, with further research needed to evaluate the pathogenetic significance for scoliosis.

Other Extraspinal Skeletal Length and Bilateral Asymmetries

In addition to periapical ribs, 2 other extraspinal sites where left-right skeletal length asymmetries have been detected in AIS subjects are upper arms108 and iliac height109,110; the latter 2 asymmetries correlate significantly with adjacent spinal curve severity—thoracic and lower spine, respectively. Skeletal length asymmetries and proximo-distal disproportion are also found in lower limbs110 where they are related not to spinal curve severity but to its presence.68 There are 3 interpretations of these extraspinal skeletal length asymmetries associated with AIS, namely: (1) secondary to the scoliosis curve; (2) nonspecific manifestations of developmental instability111; and (3) sentinels in paired bones of vertebral growth-plate asymmetries implying putative pathogenetic significance.68

Bilateral skeletal asymmetry in humans may be one of the key factors for the development of the idiopathic factor of AIS. Goldberg et al111 proposed that the onset of AIS results from developmental instability and left-right asymmetry in humans. Preliminary evidence suggests a transient asymmetry process may initiate the pathogenesis of RT AIS in girls.112

Skull Growth and Asymmetry

Recent MRI studies suggests that in girls with AIS, the skull base with a larger foramen magnum35,113 and the vault where asymmetry was found,114 are abnormal.

Intrinsic Vertebral Directional Rotational Asymmetry

Castelein et al75 added important evidence to support the abnormal skeletal asymmetry factor in AIS pathogenesis. They found that the predominant rotation of the adult human spine is to the left in high thoracic vertebrae and to the right in the mid and lower thoracic vertebrae. This pattern is reversed in subjects with situ inversus. Castelein et al115–118 proposed that the intrinsic directional rotational asymmetry in humans could predispose to, and contribute to, both the abnormal differential growth of the pedicles and spine, and to the onset and progression of AIS. This hypothesis is partially supported by the studies using artificial pedicle screw fixation to inhibit the growth of neurocentral synchondrosis creating an “idiopathic” like scoliosis in immature animals.119 However, a mathematical study120 using computational modeling to investigate the role of pedicle growth in scoliosis development, found pedicle asymmetry was not an independent cause of scoliosis. This latter observation reiterates the multifactorial nature of the initiation and progression of scoliosis. However, it is difficult to totally discard the role of asymmetry in scoliosis development. The mechanism of the development of scoliosis by the asymmetric skeletal growth during puberty is, at present, unsolved. There is recent speculation that the sympathetic nervous system contributes to the spinal and extraspinal skeletal length asymmetries of AIS girls,68,70,76,121 a view consistent with the new neuroskeletal biology.122,123


GH and IGF-I

The GH/IGF axis is the pivotal system124 with estrogen125 for the regulation of axial growth during puberty. As skeletal growth is thought to be one of the important factors in the etiopathogenesis of AIS, it is surprising how few studies have evaluated the GH/IGF axis in AIS subjects. In an early research, circulating GH levels in small group of AIS patients failed to show significant differences from those of control subjects.126,127 Later studies126,128,129 consistently found high levels of GH in AIS girls notably from 7 to 12 years of age, and in pubertal stage 2. Sanders et al130 reported raised levels of IGF-I. In monitoring growth therapy, IGF-I is preferred to GH as it provides a stable record in contrast to the diurnal variations with GH (Dr TL Randell, personal communication). The profile and regulation of GH secretion and IGF-I in AIS girls urgently need further studies particularly as early skeletal maturation is a feature of girls with AIS.68,77,85,131

Sex Hormones

Circulating levels of estrogen are reported to be normal or lower, and testosterone raised or lower in AIS girls.132–134 Leboeuf et al135 suggested estrogens as important pharmacologic targets to consider in AIS therapy directed to patients selected on their tissue response to melatonin. More studies are required.


Machida and colleagues136 having found lower plasma melatonin levels through 24 hours only in progressive AIS curves and concluded that melatonin disturbance has more of a role in progression than in the cause of AIS. They postulate that in the development of progressive AIS, melatonin acts through the nervous system.137 After experiments on pinealectomized bipedal rats, Dubousset and Machida138 suggested that the scoliotic deformity of the fibro-elastic and bony structures of the spine in humans was associated with the bipedal condition and an inherited disorder of neurotransmitters/neurohormones affecting melatonin synthesis and the balance of the system resulting in generation of abnormal torsional force. The hypothesis that circulating melatonin deficiency is a causative factor of AIS was controversial.139–143 Lowe et al30 concluded that it seems unlikely that IS could result from a simple absence of melatonin. Rather, scoliosis might result from alteration in the control of melatonin production, with direct or indirect consequences upon growth mechanisms. Fagan et al144 cautioned the use of the chicken models in projecting the findings to human AIS although morphologic similarities has been described in earlier studies.145,146

In addition to chicken, various pinealectomized animal models have been shown to produce idiopathic-like scoliosis with different degree of success.146–149 The C57/BL6J mouse with a naturally knockout major enzyme (NAT gene) involved in the melatonin synthesis developed scoliosis (100% with bipedal mice and 25% with quadrupedal mice).150 Contradictory reports on the effect of melatonin supplement or pineal gland transplantation150,151 on scoliosis in melatonin-deficient chickens and mice were found. Despite the positive results in chicken and mouse in some studies, there is still doubt on the exact role of melatonin in scoliosis when pinealectomized nonhuman primate failed to develop scoliosis.152 Cheung et al152 in the review of melatonin and AIS pathogenesis state: “…the possible etiologic factors producing scoliosis in lower animal…cannot necessarily be extrapolated to human beings.” Teleosts also show similar spinal curvature when made melatonin-deficient.153 Gorman and Bredenn153 hypothesize that unique morphologic, developmental, and genetic parallels between the human and guppy syndromes are because of common molecular pathways involved in the etiopathogenesis of both phenotypes.

In the last 5 years, a number of studies suggested that systemic melatonin-signaling pathway dysfunction could be more important than the actual melatonin level itself.

Melatonin-signaling Pathway Dysfunction

In progressive AIS, Moreau et al154,155 reported impaired melatonin-signaling transduction in osteoblasts, myoblasts, and lymphocytes linked to the inactivation of Gi proteins. Moreau et al's studies revealed 3 different functional subgroups of AIS according to their cyclic adenosine monophosphate response to melatonin.154,155 The melatonin-signaling transduction was associated with high levels of a circulating protein P factor (which was recently revealed as osteopontin) that seems essential for the initiation and progression of AIS through a specific signaling action during a postnatal window.155–157 The authors are actively exploring the potential of further developing this and other biological markers for early prediction and prognostication, curve classification, and medical treatment.155,158,159 A novel mechanism on systemic abnormality of cell differentiation in the pathogenesis of AIS is proposed.160

Early reports of the abnormal effect of melatonin on the proliferation and differentiation of osteoblast and chondrocytes from AIS were presented.161,162 Further studies are necessary to allow better understanding of the signaling-pathway dysfunction that may also help to explain the clinical phenotype of low bone mineral density (BMD) and abnormal skeletal growth in AIS.

The finding that promoter polymorphisms of the gene for melatonin receptor 1B13 and not 1A, is associated with the occurrence of AIS, but not directly with curve severity, supports the hypothesis of melatonin-signaling pathway dysfunction in AIS (Fig. 3).

Abnormality of melatonin signaling pathway in osteoblasts from adolescent idiopathic scoliosis (AIS) as reported in publications (Ref.13,154,155,161,162). AMP indicates adenosine monophosphate; ATP, adenosine triphosphate; GDP, guanosine diphosphate; GTP, guanosine triphosphate.


Calmodulin regulates the contractile properties of muscle and platelets through its interaction with actin and myosin and regulation of calcium fluxes from the sarcoplasmic reticulum of muscle fibers. Melatonin functions may include modulating calcium-activated calmodulin.163 Lowe et al164 found increased calmodulin levels in platelets to be associated with progression of AIS. This study suggested altered paraspinal muscle activity in an attempt to explain the relationship between platelet calmodulin level changes and Cobb angle changes in AIS patients with calmodulin acting as a systemic mediator of tissues having a contractile system. Asymmetric distribution of calmodulin in paraspinal muscle was found in AIS patients in another study that might further support this hypothesis.165

An alternative speculative concept to explain the findings of Lowe et al164 was formulated as the platelet-skeletal concept.166 This concept describes how a small scoliosis curve transmits the axial loads directly to the vertebral body growth plates in which a micro-insult is created. The insult causes dilatation of juxta-physeal vessels that in turn activate the platelet calmodulin and subsequently growth factors release. The growth factors then abet the hormone-driven growth of the already mechanically compromised vertebral endplates to promote the RASO and the curve progression of AIS.

This platelet-skeletal concept links several fields of study in each of which research within ethical restraints is suggested to refute it. In articular processes excised at surgery,167 significantly lower calmodulin in bone cells without left-right asymmetry was found in AIS compared with congenital scoliosis subjects, suggesting possible link of calmodulin to the development and progression of AIS.

Osteopenia and Abnormal Bone Quality

Low BMD was reported in patients with IS firstly by Burner et al168 and in subsequent studies.169–171 Serial studies on low BMD in AIS were carried out by Cheng and Guo172 in which BMD measured by dual energy x-ray absorptiometry showed osteopenia in 33.3% of girls with AIS. Low BMD was also found in both cortical and cancellous bone measured by peripheral quantitative computed tomography (CT). An important observation revealed that persistent osteopenia was found in 80% of the osteopenic AIS followed up longitudinally to skeletal maturity,173,174 suggesting a life-long systematic bone metabolism disorder in girls with AIS. Osteopenia was also found to be a prognostic factor of curve progression in AIS.175 The osteopenia in girls with AIS might be caused by the late onset of menarche,175 higher bone turnover, and relative low-calcium intake when compared with normal controls.176,177 Low BMD in patients with AIS could result from abnormal bone mineralization coupling with increased bone growth during puberty. With recent advancement in biotechnology, pilot studies on the bone quality using quantitative ultrasound, high-resolution quantitative CT and micro-CT (Fig. 4) also revealed abnormal bone quality in microstructural and bone strength parameters in addition to the low BMD in AIS.178

A, The most advanced HR-pQCT was used in vivo to obtain serial cross-sectional images of the distal extremities for the objective 3D histomorphometry longitudinally (Bar=5 mm). B, The representative cross-sectional images of the distal radius of a girl with adolescent idiopathic scoliosis. The radius is contoured automatically (green lines) for the 3D evaluation. The fine trabecular bone can be observed with the cortical shell. C, The 3D image of the distal radius of an AIS subject obtained from HR-pQCT (resolution: 40 μm voxel size) with the discrimination of cortical shell and the inner trabecular bone network. The right panel showed the representative portion of trabecular bone structure from bone biopsy of AIS subject with in vitro micro-CT (resolution: 12 μm voxel size). 3D indicates 3-dimensional; AIS, adolescent idiopathic scoliosis; HR-pQCT, high-resolution peripheral quantitative computed tomography.


The adipocyte-derived cytokine, leptin, known as the satiety hormone, has been shown to mediate energy expenditure in females during their lifetime, and to regulate body growth and development particularly during childhood and adolescence.123,179–181 In girls with AIS, significantly lower circulating leptin levels were found when compared with age and sex-matched controls after adjusting for menstrual status; leptin levels also correlated significantly with body weight, body mass index, and BMD.182 Burwell et al68,76 drawing upon the new skeletal biology122,123 speculated that selective hypothalamic dysfunction with an upregulation of sensitivity to circulating leptin through the sympathetic nervous system may create skeletal length asymmetries in vertebrae, ribs, upper arms, ilia, and initiate AIS.


Vicious Cycle and Mechano-transduction in the Spine

The progression of skeletal deformity during growth is believed183 to be governed by laws including the “Hueter-Volkmann Law,” which states that growth depends on the amount of compression of the growth plate, which can be retarded by increased compression and accelerated by tension. The concept of “vicious cycle” in the progression of AIS was invoked by Stokes et al184,185 who speculated that a preexisting scoliosis curve initiates the mechanically modulated alterations of vertebral body growth.185 Scoliosis deformity produces asymmetrical loading of the skeletally immature spine, which in turn causes asymmetrical growth and hence progressive wedging deformity. The vicious cycle can lead to vertebral wedging and abnormal disc loading. In addition, the spinal curvature will invoke the biological phenomenon of mechano-transduction which affects biologic processes in skeletal tissues, muscles, tendons, and ligaments.185

Recently, Wills et al186 measured curve progression longitudinally in AIS girls separately by intervertebral disc wedging and vertebral body wedging in relation to the maturity assessed by digital skeletal age. Disc wedging contributed mainly to early curve progression with vertebral wedging occurring mainly after the curve acceleration phase. Early rapid curve progression is attributed to convex-vertebral endplates under relative tension growing more rapidly than concave-vertebral endplates by which they are functionally tethered.

Curve Initiation

Wills and colleagues186 consider the view that IS is probably initiated by unknown extraspinal factors.187 Other possible mechanisms for the initiation of RT AIS may involve RASO,96,97 asynchronous spinal neuro-osseous growth,98,99 dorsal shear forces combined with normal axial rotational vertebral asymmetry,75,115–118 and a transient asymmetry process.112 The latter concept relaters to vertebral growth plates causing the initial spinal imbalance from which spinal growth velocity combined with biomechanical, postural, and melatonin-signaling factors sustain and aggravate the curve.112

Bipedalism and Spinal Consequences

Bipedalism with upright posture predisposed humans to a series of changes in their spine and trunk in 3-dimension, affecting sagittal shape, axial pelvi-spinal rotations and counter-rotations in the transverse plane,188,189 and trunk broadening in the frontal plane.68 The sagittal spinal alignment results in intrinsic dorsally directed shear forces. According to Castelein and colleagues,75,115–118 these changes together with normally presented rotational asymmetry of vertebrae cause asymmetric loading, asymmetric growth, and axial rotational instability in the immature spine, that may contribute to the onset and progression of AIS. Moreover, the effects of the dorsal shear force can be further enhanced by the rotational instability associated with the hypokyphosis or lordosis caused by the RASO and by the unique human axial spinal movements.189

Gorman and Breden153 propose that rather than bipedalism per se, expression of idiopathic-type scoliosis is dependent on normal spinal loading applied along the cranio-caudal axis that interacts with an unknown factor causing the primary curve.

Other Factors

The presence of normal left-right asymmetries particularly in the trunk, and the abnormal segmental skeletal length asymmetries, might also predispose the spine to abnormal biomechanical forces that could initiate and affect the progression of the scoliosis curve. Whatever may initiate AIS, its development may be compounded by mechanical and postural factors particular to humans, relative osteopenia of vertebrae, accelerated disc degeneration,190,191 and biomechanical spinal growth modulation.184,185


There are sporadic reports of the possible link between environmental and life-style factors177,192 with the prevalence of AIS, such as nutrition, diet, calcium, vitamin D intake, and exercise level. The lower body mass index of AIS girls found in several reports suggests implications for body development, abnormal spinal development, or nutrition of patients with AIS.68,193 More structured cross-sectional and longitudinal studies of environmental and life-style factors on a larger scale are needed.

Integrative Model on the Etiopathogenesis of AIS

On the basis of the reported findings in the past few decades, considerable heterogeneity evidently exists in the clinical condition of AIS. AIS is a multifactorial disease which contains different subgroups of patients who have different subtle expression between each other.

A descriptive “integrative model” on the etiopathogenesis of AIS to incorporate all the different concepts currently described is proposed as follows:

  • AIS is a multifactorial disorder caused by mutations in many different genes, interaction of several biological, biomechanical mechanisms modified by environmental factors, occurring in linear causality or in summation causality resulting in abnormal control and modulation of growth, and manifested phenotypically as scoliosis associated with abnormal general skeletal and/or spinal growth.


Considerable progress has been made in the past 2 decades in understanding the etiopathogenesis of AIS. However, current knowledge is still fragmented and we are still far from understanding fully the different etiopathogenetic pathways and mechanisms. For example, the general skeletal and RASOs of AIS girls have not been related securely to endocrinology; and the abnormal extraspinal skeletal length asymmetries of AIS girls are of unknown pathogenetic significance. The current treatment at best is treating the morphologic and functional sequelae of AIS and not the cause of the disease. For whatever hypothesis or theory, several fundamental questions and facts of AIS need to be properly addressed and explained.68,194

  1. Why AIS is exclusive to the bipedal humans?
  2. Are AIS different from other types of scoliosis?
  3. Why girls more than boys?
  4. Why occurring at the peri-pubertal period and closely related to growth and growth rate?
  5. Why some curves progress and majority do not?
  6. Why the vertebral bodies grow faster than the posterior parts of the vertebrae?
  7. How to explain the 3-dimensional rotatory deformity in AIS?
  8. Familial versus nonfamilial AIS—are they the same?
  9. Are there factors common to all types of AIS in girls, familial and nonfamilial?
  10. Are we seeing the primary or the secondary effects?
    • (a) Factors contributing to initiation of curve—are they same as those contributing to progression of curve?
    • (b)AIS with abnormal neuromorphology and neurophysiologic function versus normal—are they the same?
    • (c) Is the primary tissue defect in the CNS, muscle, disc, bone, cartilage, soft tissue, connective tissue, or a combination of all/part of the above in cascades?
    • (d) Laterality and patterns of the curves. Thoracic versus double curve, lumbar curves—are they the same?
  11. Is AIS one disease or heterogeneous grouping?

In moving forward in the perusal of further advancement of our understanding of the etiopathogenetic mechanisms and future evidence-based prevention and management of AIS, multidisciplinary and multicenter innovative research collaboration is imminently important and necessary in helping:

  • To pool enough clinical cases for studies particularly for boys.
  • To study jointly the molecular genetics, metabolic pathway, morphologic, functional, translational to clinical and epidemiologic research.
  • To define better the phenotype and endophenotypes with standardized clinical database.
  • To cross-validate and replicate studies in different centers and across different ethnic groups.
  • To address the fundamental questions and key points.
  • To derive evidence-based regimes in the prevention, prognosis, and treatment of occurrence and progression of the scoliotic deformity and other associated abnormalities in AIS.
  • To evaluate continually new evidence from the standpoint of theoretical understanding of AIS etiopathogenesis to define questions, basic and applied, for solution by collaboration between worldwide centers.


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adolescent idiopathic scoliosis; etiopathogenesis; genetics; growth; metabolism; bone mineral density

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