Potential association of metabolic and musculoskeletal disorders with lumbar intervertebral disc degeneration: Cross-sectional study using medical checkup data

Journal of Orthopaedic Science xxx (xxxx) xxx

Contents lists available at ScienceDirect

Journal of Orthopaedic Science journal homepage: http://www.elsevier.com/locate/jos

Original Article

Potential association of metabolic and musculoskeletal disorders with lumbar intervertebral disc degeneration: Cross-sectional study using medical checkup data Nobuyuki Fujita a, Shinichi Ishihara a, b, Takehiro Michikawa c, Koichiro Azuma d, Satoshi Suzuki a, Osahiko Tsuji a, Narihito Nagoshi a, Eijiro Okada a, Mitsuru Yagi a, Takashi Tsuji e, Michiyo Takayama f, Hideo Matsumoto d, Masaya Nakamura a, Morio Matsumoto a, Kota Watanabe a, * a

Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan Department of Orthopaedic Surgery, Ota Memorial Hospital, Gunma, Japan c Department of Environmental and Occupational Health, School of Medicine, Toho University, Tokyo, Japan d Institute for Integrated Sports Medicine, Keio University School of Medicine, Tokyo, Japan e Department of Orthopaedic Surgery, Fujita Health University, Aichi, Japan f Center for Preventive Medicine, Keio University Hospital, Tokyo, Japan b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 26 February 2019 Received in revised form 2 April 2019 Accepted 13 May 2019 Available online xxx

Background: The pathogenesis of intervertebral disc (IVD) degeneration is complex and involves the interaction of multiple factors. However, few systemic studies have explored the associations of metabolic disorders and age-related musculoskeletal disorders with the development of IVD degeneration. Methods: We analyzed clinical data obtained from healthy individuals who had undergone a musculoskeletal checkup. In total, 276 subjects comprising 142 males and 134 females were enrolled. The subjects were divided into two groups based on the degree of IVD degeneration according to Pfirrmann grading: those with grades 1e3, the group with non-degenerative discs; and grades 4 and 5, the group with degenerative discs. The subjects underwent examinations including abdominal circumference, blood pressure, bilateral hand grip strength, abdominal computed tomography, magnetic resonance imaging of the lumbar spine, and dual X-ray absorptiometry. To examine the independent association with IVD degeneration at L3/4, L4/5, and L5/S levels, we constructed a Poisson regression model and estimated relative risks (RRs) and 95% confidence intervals (CIs) of IVD degeneration. Results: Multivariable analysis showed that advanced age was markedly associated with IVD degeneration at all levels and that men had an inverse association with the IVD degeneration, particularly at the L4/5 level (RR ¼ 0.7, 95% CI ¼ 0.6e0.9). In addition, metabolic syndrome was significantly associated with IVD degeneration at the L5/S level (RR ¼ 1.4, 95% CI ¼ 1.1e1.8). Meanwhile, sarcopenia showed no significant association with IVD degeneration at any level. Osteoporosis was inversely associated with IVD degeneration, particularly at the L4/5 level (RR ¼ 0.7, 95% CI ¼ 0.6e0.9). Conclusions: Our data suggest that advanced age, female sex, and metabolic syndrome are associated with IVD degeneration. In addition, osteoporosis showed an inverse association with IVD degeneration. Our data should promote understanding of the etiology of lumbar IVD degeneration. © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

1. Introduction

* Corresponding author. Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. Fax: þ81 3 3353-6597. E-mail address: [email protected] (K. Watanabe).

Intervertebral disc (IVD) degeneration is one of the major causes of low back pain and various degenerative spinal disorders, including lumbar disc herniation, lumbar spinal canal stenosis, and degenerative scoliosis [1]. Considering the sharp increase in the number of patients with degenerative spinal disorders and the

https://doi.org/10.1016/j.jos.2019.05.011 0949-2658/© 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Fujita N et al., Potential association of metabolic and musculoskeletal disorders with lumbar intervertebral disc degeneration: Cross-sectional study using medical checkup data, Journal of Orthopaedic Science, https://doi.org/10.1016/j.jos.2019.05.011

2

N. Fujita et al. / Journal of Orthopaedic Science xxx (xxxx) xxx

economic burden that treating these patients imposes upon aging societies, there is an urgent need to develop therapy and prophylaxis for IVD degeneration [2]. The pathogenesis of IVD degeneration is complex and involves the interaction of multiple factors, including aging, mechanical loading, hormone secretion, and inflammation [3e6]. Previous studies showed that metabolic disorders including obesity, hyperlipidemia (HL), and impaired glucose tolerance are associated with the development of lumbar IVD degeneration [3,7e10]. Regarding age-related musculoskeletal disorders, several studies previously reported the relationship between osteoporosis and IVD degeneration [11e15]. However, few reports have been published about sarcopenia, in which skeletal muscle mass, quality, and strength decrease with aging, so the association between sarcopenia and IVD degeneration has remained unclear. Moreover, to date, there have been few systemic studies exploring the potential associations of metabolic disorders and age-related musculoskeletal disorders with the development of IVD degeneration. At our facility, a musculoskeletal checkup, which includes assessment of osteoporosis, sarcopenia, and IVD degeneration, is provided as a supplement to a regular medical checkup. This allowed us to thoroughly review the clinical data of both metabolic and musculoskeletal disorders in a relatively large pool of healthy subjects. Using these datasets, we aimed to clarify the potential associations of IVD degeneration with metabolic and musculoskeletal disorders.

2.3. CT scan examination The cross-sectional areas of visceral adipose tissue (VAT) were measured at the level of the navel using CT scan images (Aquilion CXL; Toshiba Medical Systems Corporation, Tochigi, Japan). 2.4. DXA examination Bone mineral density (BMD) of the lumbar and bilateral femoral neck and appendicular skeletal muscle mass were measured by DXA (Lunar Prodigy Advance Encore 10X; GE Healthcare, Madison, WI, USA). 2.5. Demographic data Data on the following demographic variables were collected: age, body mass index (BMI), abdominal circumference, blood pressure, bilateral hand grip strength, history of common noncommunicable diseases [including hypertension (HTN), type 2 diabetes mellitus (T2DM), and HL], and blood examinations, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), and blood glucose. Blood samples were obtained under fasting conditions. Grip strength was tested twice on each hand in a standing position using a digital handgrip dynamometer (Matsumiya Seiki Factory Co., Ltd., Tokyo, Japan). The average of both hands was used for evaluation. Blood pressure was measured in the right upper arm using an automatic device, BP-900 (Tanita Co., Tokyo, Japan).

2. Materials and methods 2.6. Diagnostic criteria for metabolic and musculoskeletal disorders 2.1. Subjects Clinical data of consecutive participants who underwent a musculoskeletal checkup in addition to a regular medical checkup between July 2012 and March 2016 at our institution were retrospectively reviewed. The medical checkups included blood examinations, magnetic resonance (MR) imaging of the lumbar spine, abdominal computed tomography (CT), and dual X-ray absorptiometry (DXA). A total of 276 subjects comprising 142 males and 134 females were enrolled in this study. These participants were all presented with an opt-out option. It was explained to all participants that they could withdraw from the study at any time. All procedures in the present study were approved by the hospital's ethics committee. This study was conducted using partially data from a previous cross-sectional study [16].

2.2. Grouping of the subjects The degree of lumbar IVD degradation was evaluated based on the Pfirrmann grading system using mid-sagittal T2-weighted MR images (GE Sigma Excite HD 1.5 T; GE Healthcare, Little Chalfont, UK), as previously described [17]. As L4/5 is most frequently associated with degenerative lumbar spinal disorders [3,18], participants were divided into two groups based on the degree of degradation of the L4/5 disc. Those diagnosed with grade 4 or 5 were included in the group with degenerative discs (Group DD), with those with grades 1e3 were in the group with non-degenerative discs (Group ND). To evaluate intra-observer agreement, 100 randomly selected lumbar MR images were reevaluated by the same observer (N.F.) more than 1 month after the first evaluation. To evaluate interobserver agreement, 100 other MR images were scored by two board-certified spinal surgeons (N.F. and S.I.) using the same classification system. The intra- and interobserver agreements for IVD degeneration were high (kappa ¼ 0.93 and 0.90, respectively).

Obesity was defined as a BMI of 25 kg/m2. HTN, HL, and T2DM were assessed by medical history and the results of physical examination and laboratory tests at the time of examination. If the subject was being treated for one of the disorders and had normal findings at the time of the study, they were still classified as having that diagnosis. HTN was defined as systolic blood pressure (BP)  140 mmHg and/or diastolic BP  90 mmHg [19]. HL was defined as LDL-C  140 mg/dL and/or TG  150 mg/dL and/or HDLC < 40 mg/dL [20]. T2DM was defined as HbA1c  6.5% [21]. Those with obesity (VAT  100 cm2) accompanied by any two of the following were diagnosed with metabolic syndrome: TG  150 mg/ dl and/or HDL < 40 mg/dl, systolic BP  130 mmHg and/or diastolic BP  85 mmHg, and fasting plasma glucose  110 mg/dl [22]. Sarcopenia was defined as low skeletal muscle index (<7.0 kg/m2 in males, <5.4 kg/m2 in females) with low handgrip strength (<26 kg in males, <18 kg in females), in accordance with the recommended diagnostic algorithm of the Asian Working Group for Sarcopenia guidelines [23]. Based on the guidelines proposed by the Japanese Society for Bone and Mineral Research, the subjects that fulfilled the following criteria were diagnosed with osteoporosis: no history of fragility fracture and BMD <70% of young adult mean (YAM) or a history of fragility fracture and BMD < 80% [24]. The lower BMD value of those for the femoral neck and vertebrae was used for diagnosis. 2.7. Statistical analysis Pearson's chi-squared test or Student's t-test was used to compare each parameter between the two groups. To examine the independent associations of age, sex, metabolic syndrome, and musculoskeletal disorders (sarcopenia and osteoporosis) with IVD degeneration, we constructed a Poisson regression model including all above items, and estimated relative risks (RRs) and 95% confidence intervals (CIs) of IVD degeneration. Poisson regression was

Please cite this article as: Fujita N et al., Potential association of metabolic and musculoskeletal disorders with lumbar intervertebral disc degeneration: Cross-sectional study using medical checkup data, Journal of Orthopaedic Science, https://doi.org/10.1016/j.jos.2019.05.011

N. Fujita et al. / Journal of Orthopaedic Science xxx (xxxx) xxx

performed using the STATA14 software (Stata Corporation, College Station, TX). In this study, a p value of <0.05 was considered to be statistically significant. 3. Results Table 1 shows the frequency of degenerative discs at each intervertebral level. The frequency of IVD degeneration was in the following order: L4/5 > L5/S > L3/4 > L2/3 > L1/2. The numbers of subjects in Groups ND and DD were 103 and 173, respectively (Table 2). The distribution of age of the subjects included in Group DD was significantly different from that in Group ND (Table 2). In addition, the proportion of women in Group DD was significantly higher than that in Group ND (p ¼ 0.025) (Table 2). Table 3 shows the gender-specific comparison of components for metabolic syndrome, sarcopenia, and osteoporosis between Group ND and Group DD. In males, the mean values of BMI, abdominal circumference, and visceral fat area were similar between the two groups, whereas in females, those of Group DD were higher than those of Group ND, albeit not significantly (Table 3). The prevalence rates of obesity,

L1/2

L2/3

L3/4

L4/5

L5/S

27.2

35.1

43.5

62.7

55.4

*IVDD: Intervertebral Disc Dgeneration. IVDD was defined as grade 4 and 5 according to Pfirrmann grading.

Table 2 Distribution of age and sex in ND and DD Groups.

Age (yr) 20e29 30e39 40e49 50e59 60e69 70e79 80e89 Sex Men Women

HTN, HL, and T2DM did not differ between the groups in both male and female subjects (Table 3). Regarding sarcopenia, the mean values of hand grip strength (p ¼ 0.0063) and the appendicular skeletal muscle mass (p ¼ 0.011) were significantly lower in Group DD than in Group ND in male subjects (Table 3). Meanwhile, female data for sarcopenia showed no significant difference between the two groups. In osteoporosis, BMD showed no significant difference between the two groups in either males or females (Table 3). In males, mean YAM of Group DD was higher than that of Group ND, albeit not significantly (Table 3). Table 4 shows the data of multivariable Poisson regression analysis for IVD degeneration of L3/4, L4/5, and L5/S. This analysis revealed that advanced age was markedly associated with IVD degeneration at all levels and that men had an inverse association with the IVD degeneration, particularly at the L4/5 level (RR ¼ 0.7, 95% CI ¼ 0.6e0.9) (Table 4). The analysis showed that metabolic syndrome was significantly associated with IVD degeneration at the L5/S level (RR ¼ 1.4, 95% CI ¼ 1.1e1.8). Sarcopenia did not show a significant association with IVD degeneration at any level. Finally, osteoporosis was inversely associated with IVD degeneration, particularly at the L4/5 level (RR ¼ 0.7, 95% CI ¼ 0.6e0.9) (Table 4). 4. Discussion

Table 1 Proportion of disc degeneration at each level.

IVDD (%)

3

ND (n ¼ 103)

DD (n ¼ 173)

total

p value

3 13 13 29 29 14 2

0 1 9 27 43 65 28

3 14 22 56 72 79 30

<0.001

62 41

80 93

142 134

0.025

Bold indicates p value < 0.05, which is considerd as statistical significance.

The present study suggested that the factors associated with the development of IVD degeneration were advanced age, female sex, and metabolic syndrome. In addition, our analysis revealed the inverse correlation between osteoporosis and IVD degeneration. Meanwhile, sarcopenia did not show a significant association with IVD degeneration. In this work, advanced age was found to be significantly associated with lumbar IVD degeneration at all levels, indicating that advanced age is the most influential factor among all predictor variables. In addition, consistent with previous studies [9], women also tended to exhibit IVD degeneration more than men. These results are similar to the finding that osteoarthritis more commonly develops in elderly women [25]. Considering that estrogen was reported to have a protective effect against osteoarthritis or IVD degeneration [5], its absence after menopause may be involved in the degeneration of these musculoskeletal organs. However, because the present study lacks the data for period of menopause, this causal relationship is still unclear. In addition, our multivariable analysis indicated that L4/5 level of IVD degeneration was significantly associated with women. Considering that radiographic

Table 3 Parameters for metabolic syndrome, sarcopenia, and osteoporosis. Male

Age Prevalence of NCDs Obesity (BMI 25.0) HTN HL T2DM Metabolic syndrome BMI (kg/m2) Abdominal circumference (cm) Visceral fat area (cm2) Sarcopenia Hand grip strength (kg) Appendicular skeletal muscle mass Osteoporosis BMD (g/cm2) YAM (%)

Female

ND (n ¼ 62)

DD (n ¼ 80)

p value

ND (n ¼ 41)

DD (n ¼ 93)

p value

53.6 ± 15.2

68.7 ± 11.4

<0.001

59.7 ± 10.5

68.6 ± 10.7

<0.001

22 15 37 13

25 28 38 14

(31.2%) (35.0%) (47.5%) (17.5%)

0.59 0.16 0.15 0.6

7 (17.1%) 7 (17.1%) 16 (39.0%) 4 (9.8%)

24 (25.8%) 20 (21.5%) 44 (47.3%) 4 (4.3%)

0.27 0.56 0.37 0.22

24.1 ± 3.7 84.7 ± 10.3 107.1 ± 52.0

23.7 ± 3.1 84.1 ± 9.5 111.4 ± 56.8

0.44 0.75 0.65

21.5 ± 4.0 78.6 ± 10.6 67.1 ± 41.6

22.6 ± 4.0 82.5 ± 10.6 80.5 ± 42.6

0.13 0.066 0.1

35.2 ± 8.3 21.7 ± 2.9

31.0 ± 9.1 20.4 ± 3.0

0.0063 0.011

19.9 ± 5.4 14.0 ± 2.0

18.2 ± 5.8 13.9 ± 1.9

0.14 0.84

0.98 ± 0.15 97.9 ± 13.7

1.00 ± 0.17 102.5 ± 16.6

0.69 0.076

0.80 ± 0.17 83.1 ± 18.1

0.79 ± 0.13 83.3 ± 14.0

0.83 0.96

(35.4%) (24.1%) (59.7%) (21.0%)

Bold indicates p value < 0.05, which is considerd as statistical significance. NCD: Non-communicable disease; BMI: Body mass index; BMD: Bone mineral density; YAM: Young adult mean.

Please cite this article as: Fujita N et al., Potential association of metabolic and musculoskeletal disorders with lumbar intervertebral disc degeneration: Cross-sectional study using medical checkup data, Journal of Orthopaedic Science, https://doi.org/10.1016/j.jos.2019.05.011

4

N. Fujita et al. / Journal of Orthopaedic Science xxx (xxxx) xxx

Table 4 Multivariable Poisson regression analysis. total L3/4 population the number of prevalence RR (95%CI)b the patients of IVDD (%) with IVDDa Age <65 65e74

135 70

30 40

22.2 57.1

>¼75

71

50

70.4

Sex Women 134 Men 142

65 55

Metabolic syndrome No 228 Yes 47 Sarcopenia No 240 Yes 36 Osteoporosis No 205 Yes 42

L4/5

L5/S

p the number of prevalence RR (95%CI)b value the patients of IVDD (%) with IVDDa

reference 60 2.6 (1.7e3.9) < 54 0.01 3.3 (2.2e4.9) < 59 0.01

44.4 77.1

48.5 38.7

reference 93 0.8 (0.6e1.1) 0.11 80

97 22

42.5 46.8

102 18 84 20

p the number of prevalence RR (95%CI)b value the patients of IVDD (%) with IVDDa

p value

reference 59 1.6 (1.3e2.1) < 42 0.01 1.9 (1.5e2.4) < 52 0.01

43.7 60.0

reference 1.4 (1.0e1.8) 0.04

73.2

1.8 (1.3e2.3) < 0.01

69.4 56.3

reference 79 0.7 (0.6e0.9) < 74 0.01

59.0 52.1

reference 0.8 (0.7e1.1) 0.18

reference 140 1.2 (0.9e1.6) 0.28 32

61.4 68.1

reference 120 1.2 (1.0e1.5) 0.06 32

52.6 68.1

reference 1.4 (1.1e1.8) < 0.01

42.5 50.0

reference 146 0.8 (0.5e1.2) 0.35 27

60.8 75.0

reference 133 1.1 (0.9e1.3) 0.78 20

55.4 55.6

reference 0.9 (0.6e1.2) 0.41

41.0 47.6

reference 127 0.8 (0.2e1.2) 0.25 25

62.0 59.5

reference 110 0.7 (0.6e0.9) 0.02 24

53.7 57.1

reference 0.9 (0.7e1.2) 0.47

83.1

Bold indicates p value < 0.05, which is considerd as statistical significance. CI: Confidence Interval, RR: Relative Risk. a IVDD: Intervertebral Disc Degeneration, IVDD was defined as grade 4 and 5 according to Pfirrmann grading. b Adjusted for all above items.

spinopelvic parameter differs depending on gender [26], female spinopelvic alignment might increase the mechanical stress for L4/5 level of IVD. Further basic studies are warranted to elucidate the specific mechanisms involved in IVD degeneration. Consistent with the findings of previous studies showing that metabolic disorders including obesity and impaired glucose tolerance are associated with lumbar IVD degeneration [7e10], our multivariable analysis showed a significant association between metabolic syndrome and IVD degeneration at the L5/S level. These results suggest that, in patients with metabolic syndrome, the increased visceral fat might place the most burden on the lowest level of IVD in the lumbar spine. Furthermore, considering that inflammatory cytokines such as TNF-a and IL-1b are involved in IVD degeneration [6], the overproduction of inflammatory cytokines by fat tissue of patients with metabolic syndrome may induce IVD degeneration of the lumbar spine [27]. The potential association between osteoporosis and IVD degeneration has been controversial. A previous study showed no association between femoral neck BMD and lumbar IVD degeneration in 359 elderly subjects [13]. In contrast, Muraki et al. reported that disc space narrowing, which reflects IVD degeneration, is positively correlated with lumbar spine BMD in elderly women [14]. Our multivariable analysis showed an inverse correlation between the presence of osteoporosis and IVD degeneration. It is possible that the degree of mechanical stress imposed on the IVDs parallels the stiffness of the adjacent vertebral bodies; therefore, IVD degeneration may develop more rapidly when BMD remains at a higher level. This may also imply that treatment with antiosteoporotic agents could lead to the progression of IVD degeneration by increasing the stiffness of vertebral bodies. Although arguments against this hypothesis have been made in a couple of studies [28,29], our results suggest that this issue warrants further investigation. Meanwhile, unlike osteoporosis, sarcopenia was not found to be associated with IVD degeneration in the present study. However, because the sample size in this study might not be enough to draw definitive conclusions on this issue, our findings should be further validated with a larger sample.

This study had some limitations. First, because this was a crosssectional study, the causal association between IVD degeneration and other disorders could not be elucidated. Second, the subjects in this study were not a randomly selected population, so there was a potential for selection bias here. 5. Conclusions The present study revealed that age, sex, osteoporosis, and metabolic syndrome were potentially associated with lumbar IVD degeneration. However, given the limitations of the present study, our results must be interpreted with caution. Nevertheless, our data should promote understanding of the etiology of IVD degeneration. Funding None. Conflict of interest None. Acknowledgments None. References [1] Urban JP, Roberts S. Degeneration of the intervertebral disc. Arthritis Res Ther 2003;5(3):120e30. [2] Martin BI, Deyo RA, Mirza SK, Turner JA, Comstock BA, Hollingworth W, Sullivan SD. Expenditures and health status among adults with back and neck problems. JAMA 2008 Feb;299(6):656e64. [3] Teraguchi M, Yoshimura N, Hashizume H, Muraki S, Yamada H, Minamide A, Oka H, Ishimoto Y, Nagata K, Kagotani R, Takiguchi N, Akune T, Kawaguchi H, Nakamura K, Yoshida M. Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study. Osteoarthritis Cartilage 2014 Jan;22(1):104e10.

Please cite this article as: Fujita N et al., Potential association of metabolic and musculoskeletal disorders with lumbar intervertebral disc degeneration: Cross-sectional study using medical checkup data, Journal of Orthopaedic Science, https://doi.org/10.1016/j.jos.2019.05.011

N. Fujita et al. / Journal of Orthopaedic Science xxx (xxxx) xxx [4] Vergroesen PP, Kingma I, Emanuel KS, Hoogendoorn RJ, Welting TJ, van €n JH, Smit TH. Mechanics and biology in intervertebral disc Royen BJ, van Diee degeneration: a vicious circle. Osteoarthritis Cartilage 2015 Jul;23(7):1057e70. [5] Liu Q, Wang X, Hua Y, Kong G, Wu X, Huang Z, Huang Z, Liu J, Yang Z, Zhu Q. Estrogen deficiency exacerbates intervertebral disc degeneration induced by spinal instability in rats. Spine (Phila Pa 1976) 2019 May;44(9):E510e9. [6] Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol 2014 Jan;10(1):44e56. [7] Hangai M, Kaneoka K, Kuno S, Hinotsu S, Sakane M, Mamizuka N, Sakai S, Ochiai N. Factors associated with lumbar intervertebral disc degeneration in the elderly. Spine J 2008 Sep-Oct;8(5):732e40. [8] Samartzis D, Karppinen J, Chan D, Luk KD, Cheung KM. The association of lumbar intervertebral disc degeneration on magnetic resonance imaging with body mass index in overweight and obese adults. Arthritis Rheum 2012 May;64(5):1488e96. [9] Teraguchi M, Yoshimura N, Hashizume H, Yamada H, Oka H, Minamide A, Nagata K, Ishimoto Y, Kagotani R, Kawaguchi H, Tanaka S, Akune T, Nakamura K, Muraki S, Yoshida M. Progression, incidence, and risk factors for intervertebral disc degeneration in a longitudinal population-based cohort: the Wakayama Spine Study. Osteoarthritis Cartilage 2017 Jul;25(7):1122e31. [10] Teraguchi M, Yoshimura N, Hashizume H, Muraki S, Yamada H, Oka H, Minamide A, Ishimoto Y, Nagata K, Kagotani R, Tanaka S, Kawaguchi H, Nakamura K, Akune T, Yoshida M. Metabolic syndrome components are associated with intervertebral disc degeneration: the Wakayama Spine Study. PLoS One 2016 Feb 3;11(2):e0147565. [11] Harada A, Okuizumi H, Miyagi N, Genda E. Correlation between bone mineral density and intervertebral disc degeneration. Spine (Phila Pa 1976) 1998 Apr 15;23(8):857e61. [12] Miyakoshi N, Itoi E, Murai H, Wakabayashi I, Ito H, Minato T. Inverse relation between osteoporosis and spondylosis in postmenopausal women as evaluated by bone mineral density and semiquantitative scoring of spinal degeneration. Spine (Phila Pa 1976) 2003 Mar 1;28(5):492e5. [13] Wang YX, Kwok AW, Griffith JF, Leung JC, Ma HT, Ahuja AT, Leung PC. Relationship between hip bone mineral density and lumbar disc degeneration: a study in elderly subjects using an eight-level MRI-based disc degeneration grading system. J Magn Reson Imaging 2011 Apr;33(4):916e20. [14] Muraki S, Yamamoto S, Ishibashi H, Horiuchi T, Hosoi T, Orimo H, Nakamura K. Impact of degenerative spinal diseases on bone mineral density of the lumbar spine in elderly women. Osteoporos Int 2004 Sep;15(9):724e8.  MC, Yasui Y, Videman T. Is greater lumbar vertebral [15] Wang Y, Boyd SK, Battie BMD associated with more disk degeneration? A study using mCT and discography. J Bone Miner Res 2011 Nov;26(11):2785e91. [16] Ishihara S, Fujita N, Azuma K, Michikawa T, Yagi M, Tsuji T, Takayama M, Matsumoto H, Nakamura M, Matsumoto M, Watanabe K. Spinal epidural lipomatosis is a previously unrecognized manifestation of metabolic syndrome. Spine J 2019 Mar;19(3):493e500. [17] Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976) 2001 Sep;26(17):1873e8.

5

[18] Aono K, Kobayashi T, Jimbo S, Atsuta Y, Matsuno T. Radiographic analysis of newly developed degenerative spondylolisthesis in a mean twelve-year prospective study. Spine (Phila Pa 1976) 2010 Apr;35(8):887e91. [19] 1999 World health Organization-International society of hypertension guidelines for the management of hypertension. Guidelines subcommittee. J Hypertens 1999 Feb;17(2):151e83. [20] Tada H, Kawashiri MA, Nohara A, Inazu A, Kobayashi J, Yasuda K, Mabuchi H, Yamagishi M, Hayashi K. Lipid management in a Japanese community: attainment rate of target set by the Japan Atherosclerosis Society Guidelines for the prevention of atherosclerotic cardiovascular diseases 2012. J Atheroscler Thromb 2017 Mar;24(3):338e45. [21] International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009 Jul;32(7):1327e34. [22] Definition and the diagnostic standard for metabolic syndrome–Committee to evaluate diagnostic standards for metabolic syndrome. Nihon Naika Gakkai Zasshi 2005 Apr 10;94(4):794e809. [23] Chen LK, Liu LK, Woo J, Assantachai P, Auyeung TW, Bahyah KS, Chou MY, Chen LY, Hsu PS, Krairit O, Lee JS, Lee WJ, Lee Y, Liang CK, Limpawattana P, Lin CS, Peng LN, Satake S, Suzuki T, Won CW, Wu CH, Wu SN, Zhang T, Zeng P, Akishita M, Arai H. Sarcopenia in asia: consensus report of the asian working group for sarcopenia. J Am Med Dir Assoc 2014 Feb;15(2):95e101. [24] Orimo H, Hayashi Y, Fukunaga M, Sone T, Fujiwara S, Shiraki M, Kushida K, Miyamoto S, Soen S, Nishimura J, Oh-Hashi Y, Hosoi T, Gorai I, Tanaka H, Igai T, Kishimoto H. Osteoporosis diagnostic criteria review committee: Japanese society for bone and mineral Research. Diagnostic criteria of primary osteoporosis : year 2000 revision. J Bone Miner Metab 2001;19(6):331e7. [25] Muraki S, Akune T, Oka H, Ishimoto Y, Nagata K, Yoshida M, Tokimura F, Nakamura K, Kawaguchi H, Yoshimura N. Incidence and risk factors for radiographic knee osteoarthritis and knee pain in Japanese men and women: a longitudinal population-based cohort study. Arthritis Rheum 2012 May;64(5):1447e56. [26] Yukawa Y, Matsumoto T, Kollor H, Minamide A, Hashizume H, Yamada H, Kato F. Local sagittal alignment of the lumbar spine and range of motion in 627 asymptomatic subjects: age-related changes and sex-based differences. Asian Spine J 2019. In press. [27] Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Investig 2003 Dec;112(12):1821e30. [28] Luo Y, Zhang L, Wang WY, Hu QF, Song HP, Su YL, Zhang YZ. Alendronate retards the progression of lumbar intervertebral disc degeneration in ovariectomized rat. Bone 2013 Aug;55(2):439e48. [29] Luo Y, Zhang L, Wang WY, Hu QF, Song HP, Zhang YZ. The inhibitory effect of salmon calcitonin on intervertebral disc degeneration in an ovariectomized rat model. Eur Spine J 2015 Aug;24(8):1691e701.

Please cite this article as: Fujita N et al., Potential association of metabolic and musculoskeletal disorders with lumbar intervertebral disc degeneration: Cross-sectional study using medical checkup data, Journal of Orthopaedic Science, https://doi.org/10.1016/j.jos.2019.05.011