Introduction

Idiopathic scoliosis (IS) is a three-dimensional deformity of the spine that can be diagnosed with a Cobb angle ≥10° and unknown causes [1]. The progression of IS is a thorny problem faced by the clinic. With the rapid growth phase, this change in bone metabolism leads to greater deformability of the bone, especially the vertebrae, which exacerbates the abnormal alignment of the vertebrae in all planes [2]. The deformities of the spine may deteriorate rapidly if no intervention to slow the progression of IS, which leads to a higher frequency of musculoskeletal complications such as pelvic tilt, asymmetries of lower extremities, decreased muscular endurance, and severe back pain [3].

Osteopenia refers to bone mineral density (BMD) below the normal reference value [4]. If low BMD continues to progress, osteoporosis may be diagnosed, which indicates a high tendency for fracture and structural deformity. The prevalence of osteoporosis is around 18.3% worldwide, which is more common in females, and the prevalence of females is 4 times that of males [5, 6]. About 27–38% of adolescent IS patients suffer from osteopenia [7]. Osteopenia and osteoporosis are recognized as the key factors associated with the progression of IS [7, 8]. Moreover, low BMD may prolong the duration of brace intervention and reduce the correction effect on the spinal curve, especially for IS patients with osteoporosis [9, 10].

However, it remains unsolved whether osteoporosis or osteopenia is an individual characteristic or a general phenomenon in IS patients. Some studies showed that the low BMD in IS patients was associated with congenital genetic factors, such as defects in the RANK/RANKL, or Runx2 signal pathway, which are associated with osteopenia and osteoporosis [11, 12]. Osteopenia is present in IS individuals with an abnormal RANKL/OPG ratio, but this genetic susceptibility is not common in the IS population [11]. Some studies have noted a reduction in BMD, but this reduction is limited and does not meet the criteria for osteopenia or osteoporosis. The results of these studies suggest that there is only a weak correlation between osteopenia and IS [13].

In contrast, some studies showed that through screening for BMD, osteopenia or osteoporosis was a systematic issue in IS patients [14], and IS patients generally had low bone density and bone mass throughout their bodies [15]. A high level of bone turnover markers was also found in IS patients [16], suggesting the impairment in the bone microstructure and a decrease in BMD. A link between scoliosis and osteopenia was found, which suggested that IS patients had abnormal bone mass profiles, such as altered cortical thickness and disordered trabecular bone structures [17,18,19].

The purpose of this systematic review is to clarify whether IS patients have less BMD and a higher prevalence of osteoporosis, compared to age and gender-matched asymptomatic controls. We hypothesized that the BMD of IS patients may be significantly lower than that in healthy controls and a higher prevalence of osteopenia and osteoporosis may be figured out in IS patients than in healthy controls.

Methods

The protocol of this systematic review was developed and registered in PROSPERO, with the registration number CRD42022309629. Q. D. and X. Z. contributed to the study's concept and design.

Search strategy

This review was conducted following the PRISMA guidelines [20]. We searched five databases on health science, including PubMed, the Cochrane Library, Embase, Web of Science (WOS), and the Cumulative Index of Nursing and Allied Health Literature (CINAHL). Terms, such as “Scoliosis”, “Children”, “Osteoporosis”, and “Bone Density”, were used in studies retrieval (detailed in Table 1). We also wrote to corresponding authors for unpublished results related to this topic. The search was restricted to human studies that were published in Chinese and English. Two reviewers (Y. Y. and X. H.) worked separately on study retrieval and title/abstract screening.

Table 1 Search strategy
Full size table

Eligibility criteria

After screening, the retained studies were further reviewed whether they fulfilled the eligibility criteria. Participants in the case group should be children and young adults diagnosed with IS. IS is defined as an abnormal spine curve with a Cobb angle greater than 10° and without specific causes [1, 21]. The control group should include age and gender-matched participants without IS. Participants should be excluded from both the IS group and control group if they (1) had any medical issues that may affect bone metabolisms, such as renal disease, rickets, thyroid disease, or osteosarcoma, or (2) previously received any interventions that may affect bone metabolisms, such as additional calcium intake, calcitriol, or therapeutic exercise (Table S1).

The primary outcome measures were (1) BMD z score; (2) osteoporotic prevalence; (3) osteopenia prevalence; (4) areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DEXA); (5) volume bone mineral density (vBMD) measured by peripheral quantitative computed tomography (pQCT); and (6) speed of sound (SOS), broadband ultrasonic attenuation (BUA), and stiffness index (SI) measured by quantitative ultrasound. Bone morphometry and trabecular bone microarchitecture measures from pQCT were collected as the secondary outcome measures.

Data extraction and management

Two reviewers (Z. C and X. L.) independently extracted the data using a self-designed form that followed the Cochrane Collaboration’s data extraction criteria [22]. The basic information, the severity of scoliosis, interventions, outcome measurements related to bone density and bone metabolism, and the main results were among the data that were extracted. Articles from the same author or institution were re-evaluated and compared, carefully scrutinized for duplication of participants. For articles that do not provide participant enrollment time, we sent emails to inquire about the specific situation. Any missing data were inquired through the contact information of the corresponding author provided in the included articles. In order to include as many relevant studies as possible, we contacted the authors of the published conference abstracts to confirm the completeness of the data presented in the abstracts. All conference abstracts with complete data were then included. Disagreements would be discussed and settled by a third reviewer (Q. D.).

Quality assessment and certainty of evidence

The Newcastle–Ottawa scale (NOS) for case–control studies was utilized [23] for quality assessment. Y. Y. and H. Y. independently assessed the potential of bias in the collected articles, and any disagreements were settled by Q. D.

We applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to categorize the certainty of the results into high, moderate, low, or very low quality [24].

Data synthesis

STATA 16.0 (StataCorp, College Station, TX, USA) was used. The odds ratio (OR) with a 95% confidence interval (CI) was used to assess discontinuous outcomes, while the weighted mean difference (WMD) with 95% CI was used to synthesize quantitative data. The chi-squared test with I2 was used to examine statistical heterogeneity between study results. The random-effects model was applied to calculate the effect size. Subgroup analysis was performed between different gender (males + females vs. females only). The magnitude of publication bias was estimated by Begg’s test.

Results

Study characteristics

The analysis was comprised of 32 case–control studies [2, 11,12,13, 15,16,17,18,19, 25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47], and 27 studies were entered into the meta-analysis [11,12,13, 15,16,17,18,19, 26,27,28,29,30,31, 33, 34, 36,37,38,39,40,41,42,43, 45,46,47] (Fig. 1). The regions of the articles included Asia (28 articles), Europe (3 articles), and North America (1 article).

Fig. 1
figure 1

PRISMA flow diagram of studies in this review

Full size image

The demographic variables, outcome measures, and main results of the included studies are shown in Table 2. Eleven case–control studies [11, 12, 17, 28, 30, 36, 41, 42, 44, 46, 47] recruited 469 males. The body mass index (BMI) in the IS group was generally lower than that in the control group. Most studies included patients with mild to moderate scoliosis (Cobb’s angle 10–40°), while two studies focused on patients with severe scoliosis who needed surgical intervention [16, 17].

Table 2 Characteristics of included studies
Full size table

The NOS for case–control studies was used in the methodological quality assessment and 7 studies scored 9 points. The results of the risk of bias assessment are shown in Table S2. Table S3 shows the results of evidence quality assessment using the GRADE methodology.

Primary outcomes

BMD z score

The BMD z score is the standardized value calculated by comparison with BMD of the same age, gender, and ethnic group [29]. The BMD z score was reported in 12 case–control studies 11, 12, 15, 16, 18, 19, 27, 29, 38, 42, 45, 47, and the pooled analysis revealed significant differences (WMD −1.191; 95% CI −1.651 to −0.732, p < 0.001; I2  =  96.9%, p < 0.001). Evidence of publication bias was observed with Begg’s test in the BMD z score (z  =  −2.06, Pr>|z|  =   0.040).

The inclusion of the subgroup analysis was based on the gender of the participants. Eight case–control studies [15, 16, 18, 19, 27, 29, 38, 45] that exclusively included female participants showed significant differences between the IS group and control group (WMD −1.031; 95% CI −1.496 to −0.566, p  <  0.001; I2  =  96.4%, p < 0.001). Significant differences were also observed in the other four case–control studies that recruited both males and females [11, 12, 42, 47] (WMD −1.516; 95% CI −2.401 to −0.632, p  =  0.001; I2  =  93.9%, p < 0.001) (Fig. 2).

Fig. 2
figure 2

Forest plot of bone mineral density z score

Full size image

Osteoporotic prevalence

Osteoporosis prevalence was reported by five case–control studies [13, 29, 38, 41, 42]. The pooled analysis is shown in Fig. 3, which indicated that the prevalence of osteoporosis in the IS group was estimated to be 6.813 times higher than that in the control group (OR 6.813; 95% CI 2.815–16.489, p < 0.000; I2  =  18.3%, p  =  0.298).

Fig. 3
figure 3

Forest plot of osteoporotic prevalence

Full size image

In the subgroup analysis, the pooled results of three case–control studies [13, 29, 38] with only female participants showed that the prevalence of osteoporosis in the IS group was significantly higher than that in the control group (OR 10.219; 95% CI 3.024–34.536, p < 0.001; I2  =  50.9%, p = 0.131). Although there was no significant heterogeneity in the two case–control studies that recruited both males and females [41, 42], the synthesized results also showed no significant differences between the two groups (OR 3.559; 95% CI 0.935–13.547, p = 0.063; I2  =  0.0%, p = 0.575).

Osteopenia prevalence

Osteopenia is a lack of bone mass between healthy bone and osteoporotic bone. Clinically, osteopenia can be diagnosed when the BMD z score is less than –1.0 [2]. Eight case–control studies [13, 18, 19, 26, 27, 38, 42, 45] reported osteopenia prevalence, and the pooled analysis showed that the IS group had a significantly higher prevalence of osteopenia than control group (OR 1.879; 95% CI 1.548–2.281, p < 0.000; I2  =  69.4%, p = 0.002).

The gender subgroup analysis is shown in Fig. 4. When we pooled the data from studies that only included female participants [13, 18, 19, 26, 27, 38, 45], the results showed that the prevalence of osteopenia was estimated to be 1.818 times higher in the IS group than in the control group (OR 1.818; 95% CI 1.489–2.219, p < 0.000; I2  =  70.9%, p = 0.002). However, the OR increased when both males and females were enrolled in the study for the subgroup analysis (OR 3.380; 95% CI 1.469–7.777, p = 0.004) [42].

Fig. 4
figure 4

Forest plot of osteopenic prevalence

Full size image

Areal bone mineral density

The measurement of aBMD is based on two-dimensional imaging techniques, such as dual-energy X-ray absorptiometry [13] aBMD equals bone mineral content divided by the area of the region of interest (ROI). The lumbar spine and the nondominant side femoral neck are two frequently selected ROIs in clinical practice [11,12,13, 19, 28, 30, 34, 36,37,38,39,40, 42, 46, 48].

Lumbar spine BMD (LSBMD)

LSBMD was reported in 14 case–control studies [11,12,13, 19, 28, 30, 34, 36,37,38,39,40, 42, 46]. In the pooled analysis, significant differences were found between the two groups (WMD −0.096; 95% CI −0.129 to −0.062, p < 0.001; I2  =  94.6%, p < 0.001). Evidence of publication bias in LSBMD was observed with Begg’s test (z =  −2.68, Pr>|z| =  0.007).

In the gender subgroup analysis, significant differences between the IS group and control group were discovered in seven included studies [13, 19, 34, 37,38,39,40] that only enrolled female participants (WMD −0.058; 95% CI −0.090 to −0.027, p < 0.001; I2  =  91.3%, p < 0.001). The synthesized results from seven case–control studies with male and female participants [11, 12, 28, 30, 36, 42, 46] also showed significant differences between two groups (WMD −0.126; 95% CI −0.199 to −0.052, p = 0.001; I2  =  95.1%, p < 0.001) (Fig. 5a).

Fig. 5
figure 5

Forest plots of areal bone mineral density. a Lumbar spine bone mineral density (LSBMD) and b Femoral neck bone mineral density (FNBMD)

Full size image

Femoral neck BMD (FNBMD)

Nineteen studies reported FNBMD of the nondominant side in the outcome measures [11,12,13, 17,18,19, 27, 28, 30, 33, 34, 36,37,38,39,40, 42, 45, 46]. There was a significant difference between the IS and control groups in FNBMD (WMD −0.061; 95% CI −0.078 to −0.044, p < 0.001; I2  =  86.6%, p < 0.001). The Begg’s test revealed evidence of publication bias in FNBMD (z  =  −2.97, Pr>|z| =  0.003).

Significant differences were observed in the subgroup of 7 studies [13, 18, 19, 27, 33, 34, 37,38,39,40, 45] with all female participants (WMD −0.043; 95% CI −0.061 to −0.025, p < 0.001; I2  =  86.5%, p < 0.001). The pooled results from the studies [11, 12, 17, 28, 30, 36, 42, 46] including both male and female participants showed significant differences between IS group and control group as well (WMD −0.090; 95% CI −0.126 to −0.055, p < 0.001; I2  =  80.6%, p < 0.001) (Fig. 5b).

Volumetric bone mineral density

Compared to DEXA, pQCT is a three-dimensional imaging tool that can reveal vBMD through the modeling of ROIs [43]. The distal radius is usually selected as the ROI during clinical practice [16].

Total vBMD

The total vBMD was presented as an outcome measure in 6 studies [13, 16, 19, 28, 43, 45]. Significant differences were found between the two groups when the results were pooled (Fig. 6a) (WMD −17.770; 95% CI −25.998 to −9.543, p  <  0.001; I2  =  47.1%, p = 0.093).

Fig. 6
figure 6

Forest plots of volumetric bone mass density (vBMD). a Total vBMD. b Cortical vBMD. c Trabecular vBMD

Full size image

The pooled data from five studies [13, 16, 19, 43, 45] with female participants disclosed significant differences between the IS group and control group (WMD −17.538; 95% CI −27.125 to −7.950, p < 0.001; I2  =  56.8%, p = 0.055). In a study with both genders [28], the BMD in the IS group was also significantly lower than that in the control group (WMD −20.500; 95% CI −39.504 to −1.496, p =  0.034).

Cortical vBMD

Four studies included cortical vBMD [16, 19, 43, 45] and significant differences were found when the data were synthesized (Fig. 6b) (WMD −28.903; 95% CI −39.992 to −17.814, p < 0.001; I2  =  35.4%, p = 0.200).

Trabecular vBMD

Trabecular vBMD was examined in 6 studies [13, 16, 19, 28, 43, 45]. Figure 6c shows that there were significant differences between the two groups (WMD −6.341; 95% CI −10.178 to −2.504, p  =  0.001; I2  =  37.9%, p  =  0.153).

After subgrouping, the IS group had significantly less trabecular vBMD than the control group, with no significant heterogeneity (WMD −5.680; 95% CI −9.340 to −2.020, p = 0.002; I2  =  34.1%, p = 0.194) according to the pooled results from [13, 16, 19, 43, 45] with all female participants.

Secondary outcomes

Bone morphometry and trabecular microarchitecture

Peripheral quantitative computed tomography can provide bone morphometry and trabecular microarchitecture measurements via high-precision imaging and software-aided analysis. The data from 4 case–control studies with 1348 participants were pooled [16, 19, 43, 45].

Regarding bone morphometry (Figure S1), the results showed that compared with the control group, the IS group had a significantly smaller cortical area (WMD −4.521; 95% CI −7.219 to −1.824, p = 0.001; I2  =  71.6%, p = 0.014) and cortical thickness (WMD −0.109; 95% CI −0.166 to −0.051, p < 0.001; I2  =  77.5%, p = 0.004). However, the cortical perimeter in the group with scoliosis was significantly larger than that in the control group (WMD 0.419; 95% CI −0.100 to 0.938, p = 0.114; I2  =  18.9%, p = 0.296).

For the measurements regarding trabecular microarchitecture (Figure S2), the IS group had a significantly smaller trabecular number (WMD −0.057; 95% CI −0.084 to −0.030, p < 0.001; I2  =  14.6%, p = 0.319) and trabecular bone volume to tissue volume ratio (BV/TV, WMD −0.005; 95% CI −0.008 to −0.002, p = 0.003; I2  =  36.8%, p = 0.191) than the control group. Meanwhile, the trabecular area in the IS group was significantly larger than that in the control group (WMD 3.861; 95% CI 0.811–6.910, p = 0.013; I2  =  0.0%, p = 0.519). No significant differences were found between the two groups in trabecular separation (WMD 0.022; 95% CI −0.012 to 0.056, p = 0.213; I2  =  91.3%, p < 0.000) or trabecular thickness (WMD −0.000; 95% CI −0.001 to 0.001, p = 0.759; I2  =  0.0%, p = 0.895).

Only two studies included the total area of the ROI [16, 28], and no significant difference was shown (WMD −0.514; 95% CI −5.743 to 6.772, p = 0.872; I2  =  0.0%, p = 0.514) (Figure S3).

Quantitative ultrasound

QUS is an effective and radiation-free method to measure bone mineral status in specific peripheral bones. One study [29] chose the distal radius as the measurement area of the ultrasound probe, while the calcaneus was selected as the measurement target in two studies [18, 31].

The SOS was reported in three studies [18, 29, 31], and there was no significant difference in the SOS between the IS group and the control group. (WMD −83.462; 95% CI −163.946 to 1.023, p = 0.053; I2  =  98.1%, p = 0.000). Two studies reported BUA and SI [18, 31] and significance was shown in BUA (WMD −5.610; 95% CI −9.001 to −2.219, p = 0.001; I2  =  35.4%, p = 0.213) and SI (WMD −25.401; 95% CI −30.984 to −19.818, p < 0.001; I2  =  0.0%, p = 0.828), respectively (Figure S4).

Discussion

This review aimed to explore the bone status of IS patients. Overall, the BMD z score of the IS patients was smaller than that of the control group. The prevalence of osteoporosis and osteopenia significantly increased in the IS group. The results of DEXA and pQCT measures showed a significant decrease in BMD throughout the limbs and trunk, and in both cortical and cancellous bone. The SOS measured by quantitative ultrasound did not show significant differences between the two groups. Bone morphometry and microarchitecture were also altered in the scoliosis group.

Noticeably, high heterogeneity was found in the BMD z score, and aBMD measures. Some studies have found that there was no significant difference in the prevalence of osteoporosis between IS patients and the control group [47, 49]. However, this heterogeneity was caused by the characteristics of the control group, as the participants in the control group had a history of fractures, which suggested that they may have potentially low BMD [50]. Although gender may be a source of heterogeneity [51], the results of the subgroup analysis revealed that gender disparities might not be linked to heterogeneity. Another source of heterogeneity may be the diversity of measurement methods (DEXA, CT, or QUS). For example, Hung et al. [31] found only moderate correlations (3.4 < correlation coefficient < 4.5) between QUS and DEXA indicators. when interpreting the results of this review, the above possible sources of heterogeneity should be noticed. DEXA is the gold standard technology for measuring BMD as it is recommended by some guidelines, because of the low radiation, short time required, and affordable [52]. There is also methodological heterogeneity associated with BMD measurements of different body sites in IS patients. Because DEXA uses two-dimensional imaging to measure BMD, three-dimensional spinal deformity may overlap in DEXA imaging, leading to the underestimation of BMD [53]. Studies have shown that LSBMD measured by DEXA may be underestimated by 11.5–17.5%, because of axial rotation and anteroposterior curvatures in IS patients [54]. Results of our systematic review also showed the trend that the effect size of the differences in LSBMD between IS and control groups was higher than that of FNBMD (WMDLSBMD  =  −0.096 vs. WMDFNBMD  =  −0.061). It should be noted that because of the underestimation effect of DEXA, the significant decrease of LSBMD in IS patients should be interpreted carefully.

Our results also suggested a significant increase in the prevalence of osteoporosis and osteopenia in the IS group (OR 6.813 and 1.879). However, the diagnostic criteria for osteoporosis have not yet reached a consensus because of the differences in age, gender, and race [55]. For example, the WHO recommends people with a BMD z score less than −2.5 SD would be diagnosed with osteoporosis, but this diagnostic criterion is based on Caucasian postmenopausal women [55]. Because adolescents have not yet reached the peak bone mass, the z score should be used as a reference for the diagnosis of adolescent osteoporosis, rather than the T-value that reflects the absolute bone mass [42]. Three included studies in this systematic review used BMD less than −2.0 SD as the diagnostic criterion for osteoporosis [13, 29, 41], while another 2 included studies used a threshold of less than −2.5 SD [38, 42]. However, a BMD z score of −2.0 SD standard is recommended for adolescent IS patients [56], since osteoporosis can be diagnosed and treated early, compared to the criterion of less than −2.5 SD.

With regard to the pathogenesis of osteoporosis in IS patients, our study shows that IS patients have higher rates of osteopenia (OR = 1.879) and osteoporosis (OR = 6.813), suggesting that osteoporosis may not be an occasional symptom but comorbidity in IS patients. This condition may be associated with genetic susceptibility to osteoporosis in IS patients. Compared with normal people, IS patients have higher osteoprotegerin (OPG) and lower RANKL, disrupting the balance of RANKL/RANK and OPG. So the number of osteoclasts increases excessively, which enhances bone resorption, and leads to a decrease in BMD [11]. On the other hand, some studies have suggested the importance of lifestyle factors. Szalay et al. suggested that the main cause of osteopenia in IS patients is low body mass index, which is an outcome measure that is related to lifestyle [41]. Some studies showed that sufficient vitamin D intake may increase calcium absorption by approximately 40% during puberty maturation [57], while adolescents with vitamin D deficiency may not achieve peak bone mass [58]. Physical activity is another important factor related to BMD. Weight-bearing activities, such as running and climbing, can significantly improve lumbar spine BMD in adolescents [59].

Subgroup analyses showed that male IS patients might have lower BMD and a higher prevalence of osteopenia than female IS patients, which was inconsistent with previous findings that low BMD is more common in females than in males [6]. It might be explained that internal (such as genetic factors) or external factors (such as daily habits) may be associated with low BMD in male IS patients. Studies have shown that BMD increased significantly in males between the ages of 15–18, and the BMD of males may not catch up to that of females until eighteen [60]. This suggested that male adolescents may have less BMD than females before the age of 15. In the prevalence of osteoporosis, subgroup analysis showed that only the female IS patients showed a significantly higher prevalence of osteoporosis, suggesting that female IS patients may have a poor prognosis. In contrast, male IS patients may have osteopenia but have not reached the degree of osteoporosis. The results also indicated that BMD in both male and female patients should be carefully concerned and evaluated.

Regular BMD screening can help detect bone problems early and avoid the negative impact of osteopenia on IS progression. Our results suggested that DEXA and pQCT might be two effective instruments for BMD screening. Although nonradiative quantitative ultrasound may be more acceptable to patients and their parents, our results showed that the validity of SOS may need to be further verified, including discriminant validity between IS group and control group and the association between SOS and BMD measured by DEXA and pQCT. Early intervention can be used to counter the effect of osteopenia on the progression of IS.

Due to the generally low BMD of IS patients, bone improvement should be included in their comprehensive interventions. In terms of pathogenesis, since many factors of daily life are associated with osteoporosis, the economical and efficient intervention may include increased physical activity and calcium and vitamin intake [61, 62]. In the future, more clinical evidence can be provided by promoting research on the effect of these osteoporotic interventions in improving IS patients.

Limitations

There were several limitations to our systematic review. Although IS patients showed lower BMD z scores and aBMD and a higher prevalence of osteopenia, the heterogeneity arising from the methodology needs attention, such as the differences in the measurements of BMD and diagnostic criteria of osteoporosis. It is necessary to establish a standardized BMD measurement scheme and unified diagnostic criteria to reduce methodological heterogeneity among studies. In addition, this systematic review only included case–control studies that compared BMD between the IS group and the control group, which could not provide direct evidence for the pathogenesis of osteoporosis or clinical intervention in IS patients. In the future, well-designed RCT studies on potential intervention protocols for BMD improvement will be needed, and long-term cohort studies will also be required to clarify low BMD in the pathogenesis of IS.

Conclusion

In this systematic review and meta-analysis, the BMD of both male and female IS patients was generally decreased, with an increase in the prevalence of osteopenia and osteoporosis. It is necessary to regularly monitor BMD through DEXA or pQCT while the employ of quantitative ultrasound in BMD screening should be further validated. Targeted interventions are necessary for IS patients during clinical practice. Future research should focus on the etiology of osteoporosis in individuals with scoliosis to determine the intervention target.