Elucidating the inherent features of IS to better understand idiopathic scoliosis etiology and progression

Abstract

Idiopathic Scoliosis (IS) is a relatively common condition and is estimated to affect as many as 3 % of youth aged 10–17 years (in the United States an estimated approximately 1.4 million otherwise healthy individuals). A clear understanding of the etiology will better direct optimization of evaluation, treatments and therapies, especially early treatments with less invasive methods. A mechanistic explanation of factors combining to initiate and then cause progression of this common condition-- in otherwise healthy pre-teenage and teenage patients--will be discussed.

A recent well-designed structured systematic review states that ‘strong evidence is lacking for a consistent pattern of occurrence and any abnormality’, in other words there is no strong evidence for ‘other associated diagnoses’ in IS. And so, certain important inherent factors of IS merit greater discussion. Inherent, or intrinsic factors include: a natural susceptibility to develop a lateral and rotational deformity in the immature rapidly growing erect human spine, inherent torsion associated at the induction of deformity, biomechanics related to curve progression, and anthropology/bipedal gait.

We know more today about factors related to the condition and its etiology than we have previously. Across multiple disciplines, a mechanistic approach to understanding the etiopathogenesis of IS, allows a reasonable ‘theory’ for IS etiology and its progression. We will discuss these inherent intrinsic factors in order to further add to our understanding of the theoretical etiopathogenesis. A better understanding of the etiology (and progression) may better direct ways to optimize evaluation, treatments and therapies, especially early treatments with less invasive methods.

1. Introduction

Overview comments regarding IS:

• •The Burden of Disease of IS (idiopathic scoliosis)— Idiopathic Scoliosis (IS) is common and estimated to affect as many as 3 % of the youth aged 10–17 years (in the United States an estimated approximately 1.4 million otherwise healthy individuals¹).

• The Health-related quality of life (HRQOL) impact, untreated, is moderate as a chronic and lifelong condition.²

• •Universal preventative screening for IS is of benefit according to the AAOS, SRS, POSNA, AAP,³ however the USPSTF rates screening in the United States as ‘I’ (an I statement is Insufficient evidence to recommend).⁴ Parts of China have demonstrated safety and quality screening.^1,5
• •Bracing is clinically effective for the skeletally immature patient with moderate IS; effectiveness is dose dependent, the more hours a brace is worn the better the result, up to 18 hours of wear⁵; brace effectiveness also is influenced by its design.^6,7
• •IS correction surgery (posterior spinal fusion) is safe and effective and with satisfactory outcomes, barring rare complications.^8,9
• •The remaining growth of the spine behaves according to the Hueter-Volkman principle.^10,11
• •The Etiology of AIS remains not clearly known; advancements of understanding have occurred and are presented in this discussion.

2. Background

We have previously discussed in a commentary¹², a biomechanical theory of initial induction of scoliosis (initiation of deformity) that is based on inherent or intrinsic factors of the human spine—rotational instability, susceptibility (of the human spine) to deformation in the immature spine of teens and pre-teens, verticality (of the human spine) rapid growth linked with asymmetries, growth modulation due to asymmetric loads, and inherent torsion of the spine.12, 13, 14

Inherent or intrinsic factors in etiology of IS include: a susceptibility to develop a coronal and rotational deformity in the immature rapidly growing erect human spine, inherent torsion associated and present at the induction of deformity, anthropology/bipedal gait, and-- once curve induction has started, the biomechanics related to curve progression (vicious cycle).^12,13 Secondary contributing factors may include the status of bone health (osteopenia)^11,15, 16, 17 relating to progression.

Classic IS cannot be attributable to any otherwise underlying condition—for example, scoliosis that is neuromuscular; that is a congenital malformation; a syndrome related; that is an endocrine abnormality; that is a connective tissue disease (CTD); that is due to a known single gene effect—is not called idiopathic. Schlosser et al. conducted a study to systematically review and synthesize available studies to see if concomitant abnormalities were associated with IS in order to determine whether such abnormalities could assist in improving our understanding of etiology.¹⁸ An assessment of other possible abnormalities in their study fell into the following three categories: neuromuscular, anthropometric and metabolic.¹⁸ Using best evidence synthesis, they were unable to find evidence or a consistent pattern of occurrence for IS with any of the abnormalities (other diagnoses) for which there were reviewed.¹⁸ This implies that based on available literature, relevant evidence is lacking for 1) understanding the nature of IS etiology (that is, it does not relate to other diagnoses) and that 2) there is no evidence that idiopathic scoliosis patients suffer from any more generalized disorders (other diagnoses).

In the absence of other associated diagnoses, a mechanism of induction (initiation) of this common condition in otherwise healthy pre-teenage and teenage patients—is proposed as a clarifying theory, and approaching the condition as one due to a mechanistic explanation, due to inherent or intrinsic factors adds to our knowledge of AIS etiology theory. Interventions will be more effective when based on clearly understood causes and modifiable prognostic factors and will further advance and further optimize treatment, whether that be surgery or conservative care. Thus, approaching the condition as one due to a mechanistic explanation, we present a theoretical of IS due to these inherent or intrinsic factors.

2.1. Inherent or intrinsic factors in the etiology of IS

We note three important inherent factors that have a role in the induction, initiation and development of IS.^13,14,19, 20, 21 First, the immature developing human spine is especially susceptible to lateral and rotatory deformation during rapid growth, particularly given the greater prematurity of osteoligamentous structures in girls at onset including maturation of the vertebral ring apophysis (and based on their sagittal profile during peak growth velocity). Second, it is recognized that there is an inherent right torsion of the thoracic spine present in both IS affected and all normal individuals (to some degree). And third, asymmetric loading of the immature spine, especially in the coronal plane, takes place in accordance with the Hueter-Volkmann Principle of biomechanics: This principle states that where there is increased pressure there is growth retardation and alternatively, where there is reduced pressure the forces cause accelerated growth.¹¹ Due to the rotation of the apical vertebrae, away from the midline, loading on the anterior parts of the spine decreases, leads to a decreased pressure on the anterior discs and vertebral bodies.¹⁹ This reduced anterior loading results in the development of a relative anterior spinal overgrowth (RASO) in the apical segment of the spine.²⁰ Our research has shown that this phenomenon occurs early primarily in the discs, much less in the bone until later and that is thus more likely a secondary growth phenomenon.^13,14 Furthermore, the same RASO also occurs in neuromuscular scoliosis, it thus seems an integral part of a scoliotic deformity mechanism and is not exclusive for AIS.

It has been proposed by us and others that the asymmetric loading of the vertebral axis is the primary driving force for the development and progression of this type of spinal deformity.^11,21,22 This phenomenon of relative anterior spinal overgrowth (RASO) contributes to the further progression of the deformity. The mechanical forces enacted by asymmetrical loading create the 3D deformity ultimately observed in the spinal deformity. The fixed asymmetric loading leads to further progression.^21,22 As a curvature progresses, unequal compression on the discs and the vertebral plates result in unequal growth and a vicious cycle is created.,^21,22 The progression risk is much higher in patients with susceptibilities--osteoligamentous immaturity of the spine and significant growth remaining. The abnormal growth profiles of the anterior column of the spine hypothesis was investigated by Shi et al. using FEM (finite element models) and found significant reductions of the kyphosis in simulation results of IS, but not when using the growth profile of normal subjects.²³

2.2. Bone health

2.2.1. Osteopenia is a secondary and variable factor

AIS is commonly associated with generalized low areal bone mineral density (aBMD) measured with dual energy x-ray absorptiometry (DXA) at proximal femur and volumetric bone mineral density (vBMD) measured with peripheral quantitative computed tomography (pQCT) at distal tibiae with 30.9 % having aBMD and 27.7 % of vBMD below -1SD of the normal.²⁴ Lee et al. used multivariate analysis showing Cobb angle was inversely and independently associated with axial and peripheral BMD and BMC (p < 0.05).²⁵ Hung et al. in a longitudinal cohort study reported that the osteopenia defined as below -1SD of aBMD at the femoral neck was an independent and significant prognostic factor for curve progression with an adjusted odds ratio of 2.3.²⁶

With availability of imaging technology for evaluation of bone quality in addition to bone density, Lam et al. made use of quantitative ultrasound (QUS) at non-dominant calcaneus and found that broadband ultrasound attenuation (BUA) and velocity of sound (VOS) of AIS group were 3.8 % (P < 0.01), 0.5 % (P = 0.042), and 6.9 % (P < 0.01) lower than controls, respectively.²⁷ QUS was generally regarded as indirect measurement for both bone density and bone quality. More direct assessment with high resolution pQCT (HR-pQCT) was later employed by Yu et al. to investigate 112 AIS girls and 115 age and gender-matched non-AIS controls. As shown in Table 1, the profiles of differences in trabecular parameters, namely trabecular area, trabecular vBMD, BV/TV ratio and trabecular thickness between osteopenic and non-osteopenic subjects are different between AIS and non-AIS controls indicating osteopenia in AIS is different from that in non-AIS controls.²⁸ Similar to DXA and pQCT, differences between AIS and controls were also noted after adjusted for age for HR-pQCT parameters, namely total vBMD, cortical area, cortical vBMD, trabecular number and trabecular separation (Table 2).²⁹

Table 1.

Pattern of differences between osteopenic and non-osteopenic subjects in AIS and non-AIS controls.¹¹

	AIS	Non-AIS
Total vBMD	S	S
Cortical Area	S	S
Cortical Thickness	S	S
Cortical Perimeter	NS	S
Cortical vBMD	S	S
Trabecular Area	NS	S
Trabecular vBMD	S	NS
Trabecular bone volume to tissue volume ratio	S	NS
Trabecular Thickness	S	NS
Trabecular Number	NS	NS
Trabecular Separation	NS	NS

S: statistically significant difference noted between osteopenic and non-osteopenic subjects NS: no statistically significant difference noted between osteopenic and non-osteopenic subjects.

Table 2.

Summary of differences in HR-pQCT parameters between AIS and controls.¹³

	Crude comparison	Adjusted for age
Total vBMD	S	S
Cortical Area	S	S
Cortical Thickness	NS	NS
Cortical Perimeter	NS	NS
Cortical vBMD	S	S
Trabecular Area	NS	NS
Trabecular vBMD	NS	NS
Trabecular bone volume to tissue volume ratio	NS	NS
Trabecular Thickness	NS	NS
Trabecular Number	S	S
Trabecular Separation	S	S

S: statistically significant difference noted between AIS and controls NS: no statistically significant difference noted between AIS and controls.

As far as prognostication for curve progression mainly of the cortical compartment, BMD was statistically different between those with and without curve progression to surgical threshold of 45°.³⁰ Vitamin D insufficiency remains highly prevalent among adolescents world-wide including subtropical cities like Hong Kong with 86.1 % having serum 25(OH)Vit-D level ≤ 50 nmol/L.³¹ Given that AIS subjects have similarly low Vit-D level and low dietary calcium intake, Lam et al. reported a clinical trial showing strong evidences of improvement of bone health and prevention of curve progression for skeletally immature female patients with adolescent idiopathic scoliosis, thus suggesting the need of evaluation of Vit-D status and bone health for scoliosis patients at primary care screening and then followed by supplementation as needed.^32,33

2.3. Genetics role in the etiology of IS: a single gene effectfor IS not implicated

While the etiology of adolescent idiopathic scoliosis is not fully known, clinical observations suggest a role of hereditary factors in the development of this condition. Over the last decades, advances in genetics with next-generation sequencing (NGS), including genome-wide association studies (GWAS) and candidate gene approaches, have attempted to shed more light onto the genetic contribution of AIS. Today, AIS is regarded as a complex disease genetically speaking.

Complex diseases are typically characterized by a major causative gene (rare variant), in addition to multiple minor susceptibility genes, epigenetics and environmental factors. These components are necessary for the disease's manifestation. The susceptibility genes can be identified by GWAS using tagSNPs. This approach is powerful for detecting common variants but is underpowered for detecting rare causative variants. The effective way to identify rare genetic variants (causal genetic component) is through direct DNA sequencing, for example, whole exome sequencing (WES) or whole genome sequencing (WGS) using next generation sequencing (NGS). As for epigenetic factors, they are crucial and involve a cascade of mechanisms that allows the control of the expression of our genes (repression or overexpression). DNA methylation, histone modification and non-coding RNA (ncRNA) associated gene silencing are currently known to be involved in the epigenetic changes, but there is no evidence concerning these changes is AIS.

Due to phenotypic complexity and heterogeneity, the genetic contribution to etiology of IS remains not clearly known at this time. Studies have supported the contribution of genetic factors34, 35, 36 and provide evidence for a heterogeneous genetic basis of IS, with diverse inheritance patterns ranging from simple Mendelian to complex polygenic patterns. The cause perhaps is associated with the effects of multiple genes (polygenic) in combination with lifestyle and environmental factors but this is not well defined.

A genetic basis of IS is supported by the observation that scoliosis often clusters in families though it does not have a clear-cut pattern of inheritance. Genetic analyses, comprising GWAS, have mapped several candidate loci predisposing and/or associated with AIS, and some rare gene variants contributing to the occurrence of AIS were found. Genetic variants in the genes that play roles in bone, cartilage, muscle, nervous system development and cilia have been reported. Using whole exome sequencing, one group recently identified rare genetic variants in a single gene, POC5 gene, as an association in adolescent idiopathic scoliosis in multiplex families of French descent (from France and French-Canadian families), thus noting a functional role of the POC5 gene in scoliosis.³⁷ The POC5 gene encodes for a centrosomal protein, interacting with centrin and inversin and is involved in cell division, polarity and motility.

As a complex multifactorial disorder with variable expressivity and penetrance, in contrast to monogenic disorders, the pathogenesis of IS might involve a complex interplay of more than one gene; perhaps these genes interact and/or may share similar biological functions. A single gene cause is no longer accepted as causative. The ultimate goal of these genetic studies should be defining the individual at risk of scoliosis and understanding the pathogenesis of AIS.

3. Conclusion

Understanding the features of IS and its underlying defects is critical in order to shed light onto disease mechanisms, disease onset, and curve progression.

Source of funding

This study was supported by a philanthropic grant from Ann & Robert H. Lurie Children's Hospital of Chicago.