- Email: [email protected]
Leptin in adolescent idiopathic scoliosis – A meta-analysis
Journal of Clinical Neuroscience xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
Leptin in adolescent idiopathic scoliosis – A meta-analysis Seong Ho Bae a, Tae Sik Goh b, Dong Suk Kim b, Jung Sub Lee b,⇑ a b
Department of Orthopaedic Surgery, Bonbarun Hospital, 343 Cheongun-ro, Mulgeum-eup, Yangsan 50611, Republic of Korea Department of Orthopaedic Surgery, BioMedical Research Institute, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan 49241, Republic of Korea
a r t i c l e
i n f o
Article history: Received 17 July 2019 Accepted 24 August 2019 Available online xxxx Keywords: Leptin Leptin receptor Scoliosis Meta-analysis
a b s t r a c t To compare the serum levels of leptin and soluble leptin receptor (sOB-R) with adolescent idiopathic scoliosis (AIS) girls and controls through meta-analysis. The MEDLINE via PubMed, Cochrane, Scopus, and EMBASE database, from the earliest available date of indexing between January 2010 and January 2019, were searched for comparative studies evaluating serum levels of leptin and sOB-R in AIS girls. Two authors performed the data extraction independently. Any discrepancies were resolved by a consensus. Six comparative studies were identified. There was no statistically significant difference in terms of leptin between AIS girls and control [p = 0.19, WMD = 2.06 ( 5.14, 1.03) ng/mL]. However, the sOB-R level was significantly higher [p < 0.00001, WMD = 2.85 (1.81, 3.88) ng/mL] and the free leptin index was significantly lower [p = 0.0006, WMD = 0.12 ( 0.19, 0.05)] in AIS girls than those of healthy control girls. The body mass index was significantly lower in AIS girls [p = 0.03, WMD = 1.53 ( 2.95, 0.12) kg/m2]. The current meta-analysis showed that the level of sOB-R is higher in AIS patients than controls, while the concentration of leptin remains unchanged in AIS patients. Further well-designed studies would be necessary to substantiate our results. Ó 2019 Published by Elsevier Ltd.
1. Introduction Adolescent idiopathic scoliosis (AIS) is defined as three dimensional spinal deformity mostly affecting adolescent girl [1,2]. Despite plenty of research for decades, the etiology of AIS remains largely unknown [1,2]. It is generally accepted that the cause of AIS could be regarded as multifactorial [1,2], and that growth is associated with the development and progression of the scoliosis [3]. Previous studies have reported the association between AIS and lower body mass index (BMI), low body weight, tall height, longer arm span, delayed onset of menarche, and systemic low bone mass [4,5]. AIS might be a common systemic disease that could be linked to the scoliosis deformity, lower BMI, abnormal skeletal growth, and low bone mineral status. Recent studies showed that leptin is an essential peptide hormone regulating energy homeostasis [6]. Studies have shown that leptin plays a mojor role in regulating energy expenditure and bone metabolism [7,8]. Leptin is predominantly secreted by adipocytes, and soluble leptin receptor (sOB-R) can be detected in chondrocytes and osteoblasts [9]. Leptin regulates the osteogenic differentiation of bone marrow stem cells and the function of chon-
⇑ Corresponding author at: Department of Orthopaedic Surgery, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan 49241, Republic of Korea. E-mail address: [email protected] (J.S. Lee).
drocytes by directly binding to sOB-R [10]. Previous case-control studies have documented disorders in leptin levels in AIS patients, while there were some case-control studies that obtained inconsistent conclusions [11–16]. Therefore, we performed a meta-analysis and aimed to summarize the available evidences on whether abnormal leptin level is associated with the risk of AIS. 2. Materials and methods 2.1. Data search and study selection We conducted electronic English-language literature searches of MEDLINE via PubMed, Cochrane, Scopus, and Embase database from the earliest available date of indexing between January 2010 and January 2019. We also hand-searched the reference lists of identified publications for additional studies. We used a search algorithm based on a combination of terms scoliosis and leptin. 2.2. Study selection All searches were limited to human studies. The inclusion criteria were studies of scoliosis that measured leptin level. Duplicate publications were excluded, as were publications such as review articles, case reports, conference papers, and letters, which do not contain the original data. Two researchers
https://doi.org/10.1016/j.jocn.2019.08.106 0967-5868/Ó 2019 Published by Elsevier Ltd.
Please cite this article as: S. H. Bae, T. S. Goh, D. S. Kim et al., Leptin in adolescent idiopathic scoliosis – A meta-analysis, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.106
2
S.H. Bae et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
independently reviewed titles and abstracts of the retrieved articles, applying the above-mentioned selection criteria. Articles were rejected if clearly ineligible. The same two researchers then independently evaluated the full-text version of the included articles to determine their eligibility for inclusion and discrepancies were resolved by consensus. 2.3. Data extraction The following information was extracted from each study: (1) information about basic study including authors, year of publication, and country of origin, study design, patients’ characteristics and technical aspects; (2) primary outcome, including serum leptin level; and (3) secondary outcomes, presented as sOB-R level, free leptin index (FLI) and BMI. 2.4. Assessment of study quality The Newcastle-Ottawa Scale (NOS) was performed to measure the methodological quality of the case-control studies [17]. The scale is composed of nine items that cover three dimension: (1) patient selection (four items); (2) comparability of the two study arms (two items); and (3) assessment of outcome (three items). Total score ranged from 0 to 9, with higher score indicating higher quality. In current study, a score 6 was defined as high quality. 2.5. Data synthesis and analysis The data from each study were analyzed using Review Manager (RevMan, Version 5.2, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). For dichotomous variables, the odds ratio (OR) and 95% confidence interval (CI) were calculated. For continuous variables, the mean difference and 95% CI were calculated when outcome measurements in all studies were conducted on the same scale. Heterogeneity among studies was assessed using v2 tests and I2 statistics, as described previously [18]. Publication bias was examined using the effective sample size funnel plot [19]. Two-sided p 0.05 was considered statistically significant. 3. Results 3.1. Literature search and selection of studies After the comprehensive computerized search was performed and references lists were extensively cross-checked, our research yielded 94 records, of which 58 records of duplicated abstracts were excluded after reviewing the title and abstract. Also, nonrelevant 13 studies, 3 animal studies, and 11 conference abstracts were excluded. Remaining 9 full text articles were assessed for eligibility. Finally, 6 studies were selected and were eligible for the systematic review and meta-analysis and no additional studies were found screening the references of these articles [11–16].
Fig. 1. Flowchart of the study selection process.
The characteristics of the included studies are presented in Table 1. The detailed procedure of study selection and quality of included studies in the current meta-analysis are shown in Figs. 1 and 2, respectively.
3.2. Meta-analysis results The leptin level of AIS and control was 7.0 and 9.0, respectively. There was no significant difference between the 2 groups [p = 0.19, WMD = 2.06 ( 5.14, 1.03) ng/mL; Fig. 3] However, the sOB-R level of AIS and control was 25.3 and 22.4, respectively. The sOBR level was significantly higher in AIS compared with in control [p < 0.00001, WMD = 2.85 (1.81, 3.88) ng/mL; Fig. 4]. Moreover, the FLI of AIS and control was 0.31 and 0.44, respectively. The FLI was significantly lower in AIS [p = 0.0006, WMD = 0.12 ( 0.19, 0.05); Fig. 5]. The BMI of AIS and control was 17.6 and 19.1, respectively. There was significant difference in the BMI between two groups [p = 0.03, WMD = 1.53 ( 2.95, 0.12) kg/m2; Fig. 6].
4. Discussion AIS girls were known to have low BMI, abnormal skeletal growth and relative anterior spinal overgrowth with uncoupled neuro-osseous growth. The observations are closely related to the bone metabolism. Previous study has suggested the possible role of leptin dysfunction in asymmetric growth that leads to spinal scoliotic deformity [20].
Table 1 Characteristics of the included studies. Authors
Ref no
Patient number AIS/Control
BMI (kg/m2) AIS/Control
Leptin (ng/ml) AIS/Control
Design
NOS score
Clark Liu Qiu Tam Tam Wang
11 12 13 14 15 16
Total:4637; 266/4371 Total:141; 95/46 Total:127; 47/80 Total:181; 94/87 Total:264; 148/116 Total:46; 31/15
17.2/17.6 17.8/19.5 17.5/20.9 17.91/18.64 17.59/18.35 17.66/19.66
4.9/5.4 7.0/8.4 8.6/14.9 6.75/7.26 7.14/9.35 7.62/8.89
Prospective Unclear Prospective Unclear Unclear Unclear
7 7 7 7 7 6
Ref no, reference number; BMI, body mass index; NOS, Newcastle-Ottawa Scale.
Please cite this article as: S. H. Bae, T. S. Goh, D. S. Kim et al., Leptin in adolescent idiopathic scoliosis – A meta-analysis, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.106
S.H. Bae et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
3
Fig. 2. Risk of bias.
Fig. 3. Forest plot of the leptin level.
Fig. 4. Forest plot of the sOB-R.
Fig. 5. Forest plot of the FLI.
Leptin is one of the key regulators in pubertal bone growth and energy metabolism. The level of leptin in circulation and CSF is regulated by sOB-R in blood [21,22]. In ob/ob knockout mice, administration of leptin could significantly enhance the bone growth [23]. sOB-R may act as a protector of leptin in the blood and may
prevent the clearance of leptin by binding leptin [22,24]. The overexpression of sOB-R in ob/ob mice could promote the leptin effect on lowering body weight [22,25]. Another studies showed that high sOB-R in AIS may affect the half-life of circulatory leptin and enhance the CSF leptin bioavailability [26,27]. However, there
Please cite this article as: S. H. Bae, T. S. Goh, D. S. Kim et al., Leptin in adolescent idiopathic scoliosis – A meta-analysis, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.106
4
S.H. Bae et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
Fig. 6. Forest plot of the BMI.
currently exists no consensus whether the levels of leptin and sOBR are altered in AIS patients, although previous studies claim lower level of leptin in AIS patients than the healthy volunteers [13,15]. Therefore, we performed a meta-analysis and aimed to examine the association between leptin levels an susceptibility of AIS. This meta-analysis identified 6 comparative studies. There was no statistically significant difference in terms of leptin between AIS girls and control [p = 0.19, WMD = 2.06 ( 5.14, 1.03) ng/mL]. However, we observed that the sOB-R level was significantly higher [p < 0.00001, WMD = 2.85 (1.81, 3.88) ng/mL] and the FLI was significantly lower [p = 0.0006, WMD = 0.12 ( 0.19, 0.05)] in AIS girls than those of healthy control girls. The higher level of sOB-R and lower FLI could suggest a higher level of bound leptin in AIS girls. Although the detailed mechanism of high sOB-R is still unknown, this change of sOB-R level could be critical for the manifestation of different phenotypic expression in AIS girls including spinal scoliotic deformity. Along with other studies [4,5], AIS girls were found to have significantly lower BMI than the healthy control [p = 0.03, WMD = 1.53 ( 2.95, 0.12) kg/m2]. The current study has several limitations. In this study, 1 included study contained < 50 subjects in the smallest group. Studies with small subject number can increase heterogeneity and bias. Moreover, there may be incorporated heterogeneity because of various participants, inconsistent criteria, and different methods. Thus, the pooled data should be carefully treated [28]. In addition, we should take several important factors into consideration, such as seasons, diet and the use of drug. These factors would influence the serum leptin and sOB-R levels in the human body. This paper contains systematic review of serum leptin and sOB-R levels in AIS girls. However, included comparative studies introduced a degree of unconfirmed speculation. Therefore, more welldesigned studies are needed to further explore the association between serum leptin level and AIS.
5. Conclusion The current meta-analysis shows that the level of sOB-R is higher in AIS patients than controls, while the concentration of leptin remains unchanged in AIS patients. However further study on the in-depth mechanism of leptin bioavailability in AIS patients is warranted.
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.08.106.
References [1] Burwell RG. Aetiology of idiopathic scoliosis: current concepts. Pediatr Rehabil 2003;6:137–70. [2] Ahn UM, Ahn NU, Nallamshetty L, et al. The etiology of adolescent idiopathic scoliosis. Am J Orthop 2002;31:387–95. [3] Lonstein JE, Carlson JM. The prediction of curve progression in untreated idiopathic scoliosis during growth. J Bone Joint Surg Am 1984;66:1061–71. [4] Cheung CS, Lee WT, Tse YK, et al. Generalized osteopenia in adolescent idiopathic scoliosis—association with abnormal pubertal growth, bone turnover, and calcium intake? Spine 2006;31:330–8. [5] Cheng JC, Qin L, Cheung CS, et al. Generalized low areal and volumetric bone mineral density in adolescent idiopathic scoliosis. J Bone Miner Res 2000;15:1587–95. [6] Sinha MK, Sturis J, Ohannesian J, et al. Ultradian oscillations of leptin secretion in humans. Biochem Biophys Res Commun 1996;228:733–8. [7] Ducy P, Amling M, Takeda S, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000;100:197–207. [8] Turner RT, Kalra SP, Wong CP, et al. Peripheral leptin regulates bone formation. J Bone Miner Res 2013;28:22–34. [9] Figenschau Y, Knutsen G, Shahazeydi S, et al. Human articular chondrocytes express functional leptin receptors. Biochem Biophys Res Commun 2001;287:190–7. [10] Han G, Jing Y, Zhang Y, Yue Z, et al. Osteogenic differentiation of bone marrow mesenchymal stem cells by adenovirus-mediated expression of leptin. Regul Pept 2010;163:107–12. [11] Clark EM, Taylor HJ, Harding I, et al. Association between components of body composition and scoliosis: a prospective cohort study reporting differences identifiable before the onset of scoliosis. J Bone Miner Res 2014;29:1729–36. [12] Liu Z, Tam EM, Sun GQ, et al. Abnormal leptin bioavailability in adolescent idiopathic scoliosis: an important new finding. Spine 2012;37:599–604. [13] Qiu Y, Sun X, Qiu X, et al. Decreased circulating leptin level and its association with body and bone mass in girls with adolescent idiopathic scoliosis. Spine 2007;15:2703–10. [14] Tam EM, Yu FW, Hung VW, et al. Are volumetric bone mineral density and bone micro-architecture associated with leptin and soluble leptin receptor levels in adolescent idiopathic scoliosis?–A case-control study. PLoS ONE 2014;9:e87939. [15] Tam EM, Liu Z, Lam TP, et al. Lower muscle mass and body fat in adolescent idiopathic scoliosis are associated with abnormal leptin bioavailability. Spine 2016;41:940–6. [16] Wang YJ, Yu HG, Zhou ZH, et al. Leptin receptor metabolism disorder in primary chondrocytes from adolescent idiopathic scoliosis girls. Int J Mol Sci 2016;17:E1160. [17] Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603–5. [18] Thompson SG. Why sources of heterogeneity in meta-analysis should be investigated. BMJ 1994;309:1351–5. [19] Deeks JJ, Macaskill P, Irwig L. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol 2005;58:882–93. [20] Burwell RG, Dangerfield PH, Moulton A, et al. Etiologic theories of idiopathic scoliosis: autonomic nervous system and the leptin-sympathetic nervous system concept for the pathogenesis of adolescent idiopathic scoliosis. Stud Health Technol Inform 2008;140:197–207.
Please cite this article as: S. H. Bae, T. S. Goh, D. S. Kim et al., Leptin in adolescent idiopathic scoliosis – A meta-analysis, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.106
S.H. Bae et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx [21] Brabant G, Horn R, von zur Mühlen A, et al. Free and protein bound leptin are distinct and independently controlled factors in energy regulation. Diabetologia 2000;43:438–42. [22] Huang L, Wang Z, Li C. Modulation of circulating leptin levels by its soluble receptor. J Biol Chem 2001;276:6343–9. [23] Iwaniec UT, Boghossian S, Lapke PD, et al. Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice. Peptides 2007;28:1012–9. [24] Zastrow O, Seidel B, Kiess W, et al. The soluble leptin receptor is crucial for leptin action: evidence from clinical and experimental data. Int J Obes Relat Metab Disord 2003;27:1472–8.
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[25] Lou PH, Yang G, Huang L, et al. Reduced body weight and increased energy expenditure in transgenic mice over-expressing soluble leptin receptor. PLoS ONE 2010;5:e11669. [26] Golden PL, Maccagnan TJ. Pardridge WM. Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J Clin Invest 1997;99:14–8. [27] Tu H, Hsuchou H, Kastin AJ, et al. Unique leptin trafficking by a tailless receptor. FASEB J 2010;24:2281–91. [28] Guyatt GH, Oxman AD, Kunz R, et al. GRADE guideline 6. Rating the quality of evidence—imprecision. J Clin Epidemiol 2011;64:1283–93.
Please cite this article as: S. H. Bae, T. S. Goh, D. S. Kim et al., Leptin in adolescent idiopathic scoliosis – A meta-analysis, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.106
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
Leptin in adolescent idiopathic scoliosis – A meta-analysis Seong Ho Bae a, Tae Sik Goh b, Dong Suk Kim b, Jung Sub Lee b,⇑ a b
Department of Orthopaedic Surgery, Bonbarun Hospital, 343 Cheongun-ro, Mulgeum-eup, Yangsan 50611, Republic of Korea Department of Orthopaedic Surgery, BioMedical Research Institute, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan 49241, Republic of Korea
a r t i c l e
i n f o
Article history: Received 17 July 2019 Accepted 24 August 2019 Available online xxxx Keywords: Leptin Leptin receptor Scoliosis Meta-analysis
a b s t r a c t To compare the serum levels of leptin and soluble leptin receptor (sOB-R) with adolescent idiopathic scoliosis (AIS) girls and controls through meta-analysis. The MEDLINE via PubMed, Cochrane, Scopus, and EMBASE database, from the earliest available date of indexing between January 2010 and January 2019, were searched for comparative studies evaluating serum levels of leptin and sOB-R in AIS girls. Two authors performed the data extraction independently. Any discrepancies were resolved by a consensus. Six comparative studies were identified. There was no statistically significant difference in terms of leptin between AIS girls and control [p = 0.19, WMD = 2.06 ( 5.14, 1.03) ng/mL]. However, the sOB-R level was significantly higher [p < 0.00001, WMD = 2.85 (1.81, 3.88) ng/mL] and the free leptin index was significantly lower [p = 0.0006, WMD = 0.12 ( 0.19, 0.05)] in AIS girls than those of healthy control girls. The body mass index was significantly lower in AIS girls [p = 0.03, WMD = 1.53 ( 2.95, 0.12) kg/m2]. The current meta-analysis showed that the level of sOB-R is higher in AIS patients than controls, while the concentration of leptin remains unchanged in AIS patients. Further well-designed studies would be necessary to substantiate our results. Ó 2019 Published by Elsevier Ltd.
1. Introduction Adolescent idiopathic scoliosis (AIS) is defined as three dimensional spinal deformity mostly affecting adolescent girl [1,2]. Despite plenty of research for decades, the etiology of AIS remains largely unknown [1,2]. It is generally accepted that the cause of AIS could be regarded as multifactorial [1,2], and that growth is associated with the development and progression of the scoliosis [3]. Previous studies have reported the association between AIS and lower body mass index (BMI), low body weight, tall height, longer arm span, delayed onset of menarche, and systemic low bone mass [4,5]. AIS might be a common systemic disease that could be linked to the scoliosis deformity, lower BMI, abnormal skeletal growth, and low bone mineral status. Recent studies showed that leptin is an essential peptide hormone regulating energy homeostasis [6]. Studies have shown that leptin plays a mojor role in regulating energy expenditure and bone metabolism [7,8]. Leptin is predominantly secreted by adipocytes, and soluble leptin receptor (sOB-R) can be detected in chondrocytes and osteoblasts [9]. Leptin regulates the osteogenic differentiation of bone marrow stem cells and the function of chon-
⇑ Corresponding author at: Department of Orthopaedic Surgery, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan 49241, Republic of Korea. E-mail address: [email protected] (J.S. Lee).
drocytes by directly binding to sOB-R [10]. Previous case-control studies have documented disorders in leptin levels in AIS patients, while there were some case-control studies that obtained inconsistent conclusions [11–16]. Therefore, we performed a meta-analysis and aimed to summarize the available evidences on whether abnormal leptin level is associated with the risk of AIS. 2. Materials and methods 2.1. Data search and study selection We conducted electronic English-language literature searches of MEDLINE via PubMed, Cochrane, Scopus, and Embase database from the earliest available date of indexing between January 2010 and January 2019. We also hand-searched the reference lists of identified publications for additional studies. We used a search algorithm based on a combination of terms scoliosis and leptin. 2.2. Study selection All searches were limited to human studies. The inclusion criteria were studies of scoliosis that measured leptin level. Duplicate publications were excluded, as were publications such as review articles, case reports, conference papers, and letters, which do not contain the original data. Two researchers
https://doi.org/10.1016/j.jocn.2019.08.106 0967-5868/Ó 2019 Published by Elsevier Ltd.
Please cite this article as: S. H. Bae, T. S. Goh, D. S. Kim et al., Leptin in adolescent idiopathic scoliosis – A meta-analysis, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.106
2
S.H. Bae et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
independently reviewed titles and abstracts of the retrieved articles, applying the above-mentioned selection criteria. Articles were rejected if clearly ineligible. The same two researchers then independently evaluated the full-text version of the included articles to determine their eligibility for inclusion and discrepancies were resolved by consensus. 2.3. Data extraction The following information was extracted from each study: (1) information about basic study including authors, year of publication, and country of origin, study design, patients’ characteristics and technical aspects; (2) primary outcome, including serum leptin level; and (3) secondary outcomes, presented as sOB-R level, free leptin index (FLI) and BMI. 2.4. Assessment of study quality The Newcastle-Ottawa Scale (NOS) was performed to measure the methodological quality of the case-control studies [17]. The scale is composed of nine items that cover three dimension: (1) patient selection (four items); (2) comparability of the two study arms (two items); and (3) assessment of outcome (three items). Total score ranged from 0 to 9, with higher score indicating higher quality. In current study, a score 6 was defined as high quality. 2.5. Data synthesis and analysis The data from each study were analyzed using Review Manager (RevMan, Version 5.2, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). For dichotomous variables, the odds ratio (OR) and 95% confidence interval (CI) were calculated. For continuous variables, the mean difference and 95% CI were calculated when outcome measurements in all studies were conducted on the same scale. Heterogeneity among studies was assessed using v2 tests and I2 statistics, as described previously [18]. Publication bias was examined using the effective sample size funnel plot [19]. Two-sided p 0.05 was considered statistically significant. 3. Results 3.1. Literature search and selection of studies After the comprehensive computerized search was performed and references lists were extensively cross-checked, our research yielded 94 records, of which 58 records of duplicated abstracts were excluded after reviewing the title and abstract. Also, nonrelevant 13 studies, 3 animal studies, and 11 conference abstracts were excluded. Remaining 9 full text articles were assessed for eligibility. Finally, 6 studies were selected and were eligible for the systematic review and meta-analysis and no additional studies were found screening the references of these articles [11–16].
Fig. 1. Flowchart of the study selection process.
The characteristics of the included studies are presented in Table 1. The detailed procedure of study selection and quality of included studies in the current meta-analysis are shown in Figs. 1 and 2, respectively.
3.2. Meta-analysis results The leptin level of AIS and control was 7.0 and 9.0, respectively. There was no significant difference between the 2 groups [p = 0.19, WMD = 2.06 ( 5.14, 1.03) ng/mL; Fig. 3] However, the sOB-R level of AIS and control was 25.3 and 22.4, respectively. The sOBR level was significantly higher in AIS compared with in control [p < 0.00001, WMD = 2.85 (1.81, 3.88) ng/mL; Fig. 4]. Moreover, the FLI of AIS and control was 0.31 and 0.44, respectively. The FLI was significantly lower in AIS [p = 0.0006, WMD = 0.12 ( 0.19, 0.05); Fig. 5]. The BMI of AIS and control was 17.6 and 19.1, respectively. There was significant difference in the BMI between two groups [p = 0.03, WMD = 1.53 ( 2.95, 0.12) kg/m2; Fig. 6].
4. Discussion AIS girls were known to have low BMI, abnormal skeletal growth and relative anterior spinal overgrowth with uncoupled neuro-osseous growth. The observations are closely related to the bone metabolism. Previous study has suggested the possible role of leptin dysfunction in asymmetric growth that leads to spinal scoliotic deformity [20].
Table 1 Characteristics of the included studies. Authors
Ref no
Patient number AIS/Control
BMI (kg/m2) AIS/Control
Leptin (ng/ml) AIS/Control
Design
NOS score
Clark Liu Qiu Tam Tam Wang
11 12 13 14 15 16
Total:4637; 266/4371 Total:141; 95/46 Total:127; 47/80 Total:181; 94/87 Total:264; 148/116 Total:46; 31/15
17.2/17.6 17.8/19.5 17.5/20.9 17.91/18.64 17.59/18.35 17.66/19.66
4.9/5.4 7.0/8.4 8.6/14.9 6.75/7.26 7.14/9.35 7.62/8.89
Prospective Unclear Prospective Unclear Unclear Unclear
7 7 7 7 7 6
Ref no, reference number; BMI, body mass index; NOS, Newcastle-Ottawa Scale.
Please cite this article as: S. H. Bae, T. S. Goh, D. S. Kim et al., Leptin in adolescent idiopathic scoliosis – A meta-analysis, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.106
S.H. Bae et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
3
Fig. 2. Risk of bias.
Fig. 3. Forest plot of the leptin level.
Fig. 4. Forest plot of the sOB-R.
Fig. 5. Forest plot of the FLI.
Leptin is one of the key regulators in pubertal bone growth and energy metabolism. The level of leptin in circulation and CSF is regulated by sOB-R in blood [21,22]. In ob/ob knockout mice, administration of leptin could significantly enhance the bone growth [23]. sOB-R may act as a protector of leptin in the blood and may
prevent the clearance of leptin by binding leptin [22,24]. The overexpression of sOB-R in ob/ob mice could promote the leptin effect on lowering body weight [22,25]. Another studies showed that high sOB-R in AIS may affect the half-life of circulatory leptin and enhance the CSF leptin bioavailability [26,27]. However, there
Please cite this article as: S. H. Bae, T. S. Goh, D. S. Kim et al., Leptin in adolescent idiopathic scoliosis – A meta-analysis, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.106
4
S.H. Bae et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
Fig. 6. Forest plot of the BMI.
currently exists no consensus whether the levels of leptin and sOBR are altered in AIS patients, although previous studies claim lower level of leptin in AIS patients than the healthy volunteers [13,15]. Therefore, we performed a meta-analysis and aimed to examine the association between leptin levels an susceptibility of AIS. This meta-analysis identified 6 comparative studies. There was no statistically significant difference in terms of leptin between AIS girls and control [p = 0.19, WMD = 2.06 ( 5.14, 1.03) ng/mL]. However, we observed that the sOB-R level was significantly higher [p < 0.00001, WMD = 2.85 (1.81, 3.88) ng/mL] and the FLI was significantly lower [p = 0.0006, WMD = 0.12 ( 0.19, 0.05)] in AIS girls than those of healthy control girls. The higher level of sOB-R and lower FLI could suggest a higher level of bound leptin in AIS girls. Although the detailed mechanism of high sOB-R is still unknown, this change of sOB-R level could be critical for the manifestation of different phenotypic expression in AIS girls including spinal scoliotic deformity. Along with other studies [4,5], AIS girls were found to have significantly lower BMI than the healthy control [p = 0.03, WMD = 1.53 ( 2.95, 0.12) kg/m2]. The current study has several limitations. In this study, 1 included study contained < 50 subjects in the smallest group. Studies with small subject number can increase heterogeneity and bias. Moreover, there may be incorporated heterogeneity because of various participants, inconsistent criteria, and different methods. Thus, the pooled data should be carefully treated [28]. In addition, we should take several important factors into consideration, such as seasons, diet and the use of drug. These factors would influence the serum leptin and sOB-R levels in the human body. This paper contains systematic review of serum leptin and sOB-R levels in AIS girls. However, included comparative studies introduced a degree of unconfirmed speculation. Therefore, more welldesigned studies are needed to further explore the association between serum leptin level and AIS.
5. Conclusion The current meta-analysis shows that the level of sOB-R is higher in AIS patients than controls, while the concentration of leptin remains unchanged in AIS patients. However further study on the in-depth mechanism of leptin bioavailability in AIS patients is warranted.
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.08.106.
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Please cite this article as: S. H. Bae, T. S. Goh, D. S. Kim et al., Leptin in adolescent idiopathic scoliosis – A meta-analysis, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.106