CLIMACTERIC 2014;17:700–704
Menopause is associated with lumbar disc degeneration: a review of 4230 intervertebral discs C. Lou, H-L. Chen, X-Z. Feng*, G-H. Xiang, S-P. Zhu, N-F. Tian, Y-L. Jin, M-Q. Fang, C. Wang and H-Z. Xu Department of Orthopedic Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang; *Department of Acupuncture and Massage & Physical Therapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
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Key words: MENOPAUSE, DEGENERATION, INTERVERTEBRAL DISC, LUMBAR SPINE, MAGNETIC RESONANCE IMAGING
ABSTRACT Objective The main objective of this study was to investigate, in a population of normal postmenopausal women, the association between menopause and severity of lumbar disc degeneration from the first lumbar to the first sacral vertebra on magnetic resonance imaging. Methods Between January 2010 and May 2013, 846 normal women and 4230 intervertebral discs were retrospectively analyzed. Age, height, weight and years since menopause (YSM) were recorded. Disc degeneration was evaluated using the modified Pfirrmann grading system. Results Compared to premenopausal and perimenopausal women, postmenopausal women had more severe disc degeneration after removal of age, height and weight effects (p ⬍ 0.0001). Postmenopausal women were divided into six subgroups for every 5 YSM. When YSM was below 15 years, there was a significant difference between every two groups, i.e. groups 1–5 YSM, 6–10 YSM and 11–15 YSM (p ⬍ 0.01). A positive trend was observed between YSM and severity of disc degeneration, respectively, i.e. L1/L2 (r ⫽ 0.235), L2/ L3 (r ⫽ 0.161), L3/L4 (r ⫽ 0.173), L4/L5 (r ⫽ 0.146), L5/S1 (r ⫽ 0.137) and all lumbar discs (r ⫽ 0.259) (p ⬍ 0.05 or 0.01). However, when YSM was above 15, there was no difference, i.e. groups 16–20 YSM, 21–25 YSM and 26–30 YSM (p ⬎ 0.05), and the significance correlation also disappeared (p ⬎ 0.05). Conclusion Menopause is associated with disc degeneration in the lumbar spine. The association almost entirely occurred in the first 15 years since menopause, suggesting estrogen decrease may be a risk factor for lumbar disc degeneration.
INTRODUCTION Postmenopausal women often suffer low back pain due to lumbar disc degeneration. Baron and colleagues1 reported a positive relationship between radiographic lumbar intervertebral disc height and hormone replacement treatment (HRT) in postmenopausal women. Postmenopausal women treated with HRT have enhanced total lumbar disc height compared to untreated postmenopausal women. Female rats had an increased tendency to develop disc degeneration after undergoing ovariectomy2. These results suggest that estrogen
deficiency might have a causal role in the pathogenesis of disc degeneration. In the earlier papers studying the effect of menopause on lumbar disc degeneration3, the authors evaluated disc degeneration by measuring the intervertebral disk space. In contrast to radiographic assessment3–5, magnetic resonance imaging (MRI) is more accurate6–8. The modified Pfirrmann grading system9, a non-invasive, simple, and convenient MR imaging method, can provide a morphologic and semiquantitative evaluation of intervertebral disc degeneration in vivo. The MRI-based, eight-level grading system is based on MR
Chao Lou and Hong-Liang Chen contributed equally to this study. Correspondence: Dr H-Z. Xu, Department of Orthopedic Surgery, The Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuanxi Road, Wenzhou, Zhejiang, People’s Republic of China. Email:[email protected]
ORIGINAL ARTICLE © 2014 International Menopause Society DOI: 10.3109/13697137.2014.933409
Received 29-04-2014 Revised 07-06-2014 Accepted 07-06-2014
Menopause and lumbar disc degeneration signal intensity and disc structure and distinguishes between the nucleus pulposus and annulus, and disc height. This useful grading system has been accepted and applied clinically. To complement the information lacking in previous reports, we evaluated disc degeneration using a MRI-based, eight-level grading system in pre-, peri- and postmenopausal women. The purpose of this study was to investigate the association between menopause and the grade of degeneration in the lumbar spine.
Lou et al. stepwise progression from Grade 1 to 8. The degeneration classification was based on signal intensity of the nucleus pulposus and the inner annulus, signal intensity difference between the inner and outer parts of the posterior annulus, and height of intervertebral discs. It has been reported that, with this eight-level grading system, the intraobserver agreement was excellent (weighted kappa range, 0.79–0.91), and the interobserver agreement, for self-training with documents and pictures, was substantial (weighted kappa range, 0.65–0.67)9.
METHODS Statistical analysis
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Study population A total of 846 normal women admitted to our department for low back pain (Department of Orthopedics, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China) from January 2010 and May 2013 were retrospectively reviewed in this study. Age, height, weight and years since menopause (YSM) were recorded. These women were divided into three groups: normally menstruating women (premenopausal group), the women with oligomenorrhea (perimenopausal group), and the normal postmenopausal women. The postmenopausal group was divided into six subgroups for every 5 YSM. Patients met the following criteria: (1) no diseases that influence the spinal structure; (2) no lumbar trauma and fracture history; (3) no diseases that influence estrogen metabolism (such as tumor of the ovary, ovariectomy); (4) no treatment with endocrine active preparations; (5) no subjection to extreme spinal loading for work-related or recreational activities; (6) no imaging evidence of lumbar vertebra fracture or abnormality other than degeneration. Back pain was not a specific inclusion or exclusion criterion.
Lumbar spine MRI Lumbar spine MR imaging was performed using a 1.5-T MRI superconducting imaging system (Siemens, Avanto, Germany). The operational modes employed were T1-weighted spin-echo sequences (TR 617 ms, TE 11 ms) and T2-weighted spin-echo sequences (TR 2500 ms, TE 107 ms). The following parameters were used: matrix ⫽ 256 ⫻ 256; field of view ⫽ 320 ⫻ 320 mm; slice thickness ⫽ 4 mm; interslice gap ⫽ 1.0 mm; number of signal acquisitions ⫽ 2. Lumbar disc grading was performed independently in the standard T2-weighted turbo spin echosagittal images by a orthopedic surgeon who was experienced in MR imaging of the spine using the modified Pfirrmann grading system.
Measurement of lumbar disc degeneration Disc degenerations from L1–2 to L5–S1 were assessed using an eight-level grading system where each grade represents a
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Analysis of covariance (ANCOVA) was specially adopted to assess the difference in lumbar disc degeneration among the different menopausal groups with removal of the confounding effect factors. Also, it was used to assess the difference in disc degeneration among the different YSM groups. Partial correlation analysis was used to test the association between disc degeneration grade and YSM by removing the confounding effect factors. A p value ⬍ 0.05 was considered statistically significant. The analysis was carried out using the statistical package SPSS 17.0 (SPSS Inc., Chicago, IL, USA).
RESULTS The characteristics of the population included in our study are shown in Table 1. The subjects had an average age of 56.3 ⫹ ⫺ 12.9 years, range 21–81 years, and age at menopause of the postmenopausal women was 49.7 ⫹ ⫺ 2.4 years, range 40–56 years. Discs were degenerated from Grade 1 to Grade 8. In the selected population, 162 subjects were normally menstruating premenopausal women, 95 women presented perimenopausal oligomenorrhea and 589 were postmenopausal women (Table 2). There was no significant difference in body weight between the three groups, but they differed in age and height. The body mass indices (BMI) in the peri-
Table 1
Baseline characteristics of the study population (n ⫽ 846) Mean ⫹ ⫺ standard deviation
Age (years) Weight (kg) Height (m) Body mass index (kg/m2) Age at menopause (years) Mean grade of disc degeneration L1/L2 L2/L3 L3/L4 L4/L5 L5/S1
Range
56.3 ⫹ ⫺ 12.9 58.1 ⫹ ⫺ 7.8 1.57 ⫹ ⫺ 0.04 23.5 ⫹ ⫺ 3.1 49.7 ⫹ ⫺ 2.4
21–81 39–103 1.45–1.76 15–41 40–56
3.40 ⫹ ⫺ 1.35 3.69 ⫹ ⫺ 1.37 4.04 ⫹ ⫺ 1.31 4.41 ⫹ ⫺ 1.34 4.27 ⫹ ⫺ 1.37
1–8 1–8 1–8 1–8 1–8
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Table 2 Demographic characteristics and disc degeneration grade in the three groups. Values in parentheses are the percentages of each grade in that group
Age (years) Weight (kg) Height (m) Body mass index (kg/m2) Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%) Grade 5 (%) Grade 6 (%) Grade 7 (%) Grade 8 (%) Years since menopause
Premenopause (n ⫽ 162)
Perimenopause (n ⫽ 95)
Postmenopause (n ⫽ 589)
37.2 ⫹ ⫺ 5.8 57.8 ⫹ ⫺ 7.2 1.59 ⫹ ⫺ 0.04 22.9 ⫹ ⫺ 2.70 50 (6.2%) 440 (54.3%) 163 (20.1%) 78 (9.6%) 42 (5.2%) 25 (3.1%) 10 (1.2%) 2 (0.2%) NA
* 46.5 ⫹ ⫺ 1.6 59.0 ⫹ 8.2 ⫺ * 1.58 ⫹ ⫺ 0.04 * 23.7 ⫹ 3.0 ⫺ 3 (0.6%) 159 (33.5%) 176 (37.1%) 63 (13.3%) 42 (8.8%) 22 (4.6%) 7 (1.5%) 3 (0.6%) NA
** 63.2 ⫹ ⫺ 8.2 58.0 ⫹ 7.8 ⫺ ** 1.57 ⫹ ⫺ 0.04 * 23.7 ⫹ 3.1 ⫺ 0 167 (5.6%) 392 (13.3%) 611 (20.7%) 1383 (47.0%) 302 (10.3%) 64 (2.2%) 26 (0.9%) 13.3 ⫹ ⫺ 8.16
NA, not applicable *, p ⬍ 0.01 vs. premenopause; **, p ⬍ 0.01 vs. premenopause and perimenopause 2 menopausal (23.7 ⫹ ⫺ 3.0 kg/m ) and postmenopausal groups 2 (23.7 ⫹ ⫺ 3.1 kg/m ) were significantly (p ⬍ 0.01) higher than 2 in the premenopausal group (22.9 ⫹ ⫺ 2.70 kg/m ). In the premenopausal women, the discs degenerated at Grade 2 at a significantly higher rate of 54.3%, while 37.1% of perimenopausal women were at Grade 3, and 47.0% of postmenopausal women were at Grade 5. Grade 6 or higher disc degeneration was observed in 4.5% (37/810), 6.7% (32/475), and 13.4% (392/2945) in pre-, peri-, and postmenopausal women, respectively. It was noted that all the observations in this study were more likely to be significant in the lower lumbar spine while less so in the upper lumbar spine. Furthermore, in our study, there was no significance correlation between weight, height, BMI and age at menopause. By removing the effects of age, height and weight, a trend of positive relationship was observed between the three different menopause periods and severity of disc degeneration (p ⬍ 0.0001), as subjects in postmenopause tended to have more severe disc degeneration (Table 3). Furthermore, to investigate the effect of menopause, the results obtained in postmenopausal women were plotted for each 5 years according to YSM. When YSM ⬍ ⫺ 15, by removing the effects of age, height and weight, a positive trend was observed between YSM and severity of disc degeneration, respectively at L1/L2 (r ⫽ 0.235), L2/L3 (r ⫽ 0.161), L3/L4 (r ⫽ 0.173), L4/L5 (r ⫽ 0.146), L5/S1 (r ⫽ 0.137) and all lumbar discs (r ⫽ 0.259) (p ⬍ 0.05 or 0.01). There were significant differences in disc degeneration between 1–5 YSM, 6–10 YSM, and 11–15 YSM (p ⬍ 0.01), as subjects with higher YSM tended to have more severe disc degeneration. When YSM ⬎ 15, the significance correlation disappeared (p ⬎ 0.05); there was no significant difference between the groups at 16–20 YSM, 21–25 YSM and 26–30 YSM (p ⬎ 0.05). The exceptions were L1/L2 and L2/L3 in the 21–25 YSM group; the degeneration was less severe compared to that of the previous groups (Table 4).
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DISCUSSION This study was the first to use the modified Pfirrmann grading system to evaluate the association of menopause with disc degeneration by MR imaging. Further, to evaluate the effect of estrogen on disc degeneration, we included premenopausal and perimenopausal women as a comparison, and these methods made the results more reliable. The results Table 3 Relationship between menopause groups and severity of lumbar disc degeneration (n ⫽ 846). Data are given as estimated mean ⫹ ⫺ standard error, adjusted for age, weight and height. This was significant overall in all lumbar intervertebral discs Disc level L1/L2
L2/L3
L3/L4
L4/L5
L5/S1
All discs
Group premenopause perimenopause postmenopause premenopause perimenopause postmenopause premenopause perimenopause postmenopause premenopause perimenopause postmenopause premenopause perimenopause postmenopause premenopause perimenopause postmenopause
Grade of severity of disc degeneration 1.99 ⫹ ⫺ 0.08 2.30 ⫹ ⫺ 0.11 3.97 ⫹ ⫺ 0.04 2.09 ⫹ ⫺ 0.08 2.63 ⫹ ⫺ 0.10 4.30 ⫹ ⫺ 0.04 2.45 ⫹ ⫺ 0.07 3.05 ⫹ ⫺ 0.10 4.64 ⫹ ⫺ 0.04 2.79 ⫹ ⫺ 0.08 3.81 ⫹ ⫺ 0.10 5.00 ⫹ ⫺ 0.04 2.88 ⫹ ⫺ 0.09 3.79 ⫹ ⫺ 0.12 4.74 ⫹ ⫺ 0.05 2.74 ⫹ ⫺ 0.06 3.23 ⫹ ⫺ 0.08 4.52 ⫹ ⫺ 0.03
p Value ⬍ 0.0001
⬍ 0.0001
⬍ 0.000
⬍ 0.0001
⬍ 0.0001
⬍ 0.0001
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Menopause and lumbar disc degeneration
Lou et al.
Table 4 Relationship between years since menopause and severity of disc degeneration (n ⫽ 589). Data are given as estimated mean ⫹ ⫺ standard error, adjusted for age, weight and height. Pairwise comparisons using the latter compared to the former years since menopause Disc level L1/L2
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L2/L3
L3/L4
L4/L5
L5/S1
All discs
Years since menopause 1–5 6–10 11–15 16–20 21–25 ⬎ 26 ⫺ 1–5 6–10 11–15 16–20 21–25 ⬎ 26 ⫺ 1–5 6–10 11–15 16–20 21–25 ⬎ 26 ⫺ 1–5 6–10 11–15 16–20 21–25 ⬎ 26 ⫺ 1–5 6–10 11–15 16–20 21–25 ⬎ 26 ⫺ 1–5 6–10 11–15 16–20 21–25 ⬎ 26 ⫺
Grade of severity of disc degeneration 3.30 ⫹ ⫺ 0.17 * 3.58 ⫹ ⫺ 0.11 ** 4.19 ⫹ ⫺ 0.08 ** 4.58 ⫹ ⫺ 0.12 * 4.29 ⫹ ⫺ 0.17 4.37 ⫹ 0.25 ⫺ 3.86 ⫹ ⫺ 0.17 ** 4.23 ⫹ ⫺ 0.11 * 4.50 ⫹ 0.08 ⫺ 4.74 ⫹ 0.12 ⫺ ** 4.35 ⫹ ⫺ 0.17 4.28 ⫹ ⫺ 0.25 4.17 ⫹ ⫺ 0.16 ** 4.52 ⫹ ⫺ 0.10 * 4.81 ⫹ 0.07 ⫺ 5.00 ⫹ 0.11 ⫺ 4.84 ⫹ ⫺ 0.15 4.69 ⫹ ⫺ 0.23 4.49 ⫹ ⫺ 0.17 * 4.78 ⫹ ⫺ 0.11 ** 5.16 ⫹ ⫺ 0.08 5.23 ⫹ 0.12 ⫺ 5.20 ⫹ ⫺ 0.17 5.04 ⫹ ⫺ 0.24 4.33 ⫹ ⫺ 0.19 * 4.66 ⫹ ⫺ 0.12 * 5.00 ⫹ ⫺ 0.09 4.91 ⫹ ⫺ 0.13 4.83 ⫹ ⫺ 0.19 4.78 ⫹ ⫺ 0.28 4.03 ⫹ ⫺ 0.12 ** 4.35 ⫹ ⫺ 0.07 ** 4.74 ⫹ 0.05 ⫺ 4.89 ⫹ ⫺ 0.08 4.70 ⫹ ⫺ 0.11 4.63 ⫹ ⫺ 0.17
*, p ⬍ 0.05; **, p ⬍ 0.01
demonstrated that postmenopausal women had a mild tendency to develop more severe disc degeneration than premenopausal and perimenopausal women. Discs showed a progressive degeneration that almost entirely occurred in the first 15 years since menopause. Around the time of the menopause and postmenopause, women appear to have a serious estrogen deficiency-related bone disease as the estrogen levels decrease rapidly10,11. Clinical studies suggest that estrogen deprivation may have a pivotal role in the progress of disc
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degeneration in postmenopausal women1,12. By using the modified Pfirrmann grading system to study a cohort of 163 healthy men (mean age, 73.5 ⫹ ⫺ 4.3 years) and 196 healthy women (mean age, 73.2 ⫹ 4.1 years), the results showed that ⫺ elderly female subjects had more severe disk degeneration than male subjects at all lumbar levels13. Basic research has also confirmed that the human intervertebral disc cells contain the estrogen receptor-β gene, with estrogen-enhancing cellular proliferation in annulus cell cultures14. Reduced estrogen levels will result in the loss of the intervertebral disc extracellular matrix, thereby accelerating the degeneration of the intervertebral disc. Our conclusion was in accordance with the above-mentioned opinion. However, Gambacciani and colleagues3 reported that intervertebral disk degeneration shows a progressive decrease that almost entirely occurs in the first 5–10 years since menopause in Caucasian women. This is certainly different from the results in our paper. The reasons may be: first, lumbar intervertebral disc degeneration of Caucasian women is more serious than in Asian women, and the high-risk gene frequency (43%) was significantly higher than that of Asian women (8%)15,16. Second, to evaluate the degeneration of intervertebral discs, Gambacciani and colleagues measured the intervertebral disk space between the 12th thoracic and 4th lumbar vertebrae by dual-energy X-ray absorptiometry (DXA). In our study, we used a MRI-based, eight-level grading system on MR T2-weighted imaging. The advantages of MRI were that it reflected not only early loss of signal intensity but also later changes show concordant loss of disc height. Third, different from previous studies, we evaluated lumbar discs individually rather than grouping them together as a single unit, as the evidence showed that the former is more accurate17. Based on these three different points as reported, these different results all have their levels of confidence. On the other hand, results from this study show that the lumbar intervertebral discs were degenerating no further when YSM was above 15. Wang and colleagues13 found that lower lumbar spine BMD was associated with less severe disc degeneration. Reduced BMD leads to endplate weakening and loss of vertebral body height, a process that allows the disc to push into the endplates and expand, as described by Kwok and colleagues18. Though lower BMD may slow the disc degeneration, the pathogenesis of disc degeneration is very complex; several factors promote degeneration such as genes, age, BMI, lifestyle and biomechanical factors and will remain constant19,20, and these may explain why disc degeneration is maintained at a stable level. Unfortunately, as the sample size of our study is small, further research is needed to confirm this conclusion.
CONCLUSIONS In summary, our study suggests that menopause is associated with disc degeneration in the lumbar spine. The association almost entirely occurred in the first 15 years since
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Menopause and lumbar disc degeneration menopause, suggesting estrogen decrease may be a risk factor for disc degeneration. Though our study was controlled by factors such as age, weight, and height and had relatively better inclusion criteria and statistical methods, other factors such as occupation and bone mineral density were not included. At the same time, the pathogenesis of disc degeneration in different regions and ethnicities is not the same15,21; a prospective study is needed to further evaluate this issue by using more uniform assessment standards and strict inclusion criteria.
Lou et al.
ACKNOWLEDGEMENT We thank the study staff at each site and all the women who participated in our research. Conflict of interest The authors report no confl ict of interest. The authors alone are responsible for the content and writing of this paper. Source of funding
Nil.
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References 1. Baron YM, Brincat MP, Galea R, Calleja N. Intervertebral disc height in treated and untreated overweight postmenopausal women. Hum Reprod 2005;20:3566–70 2. Wang T, Zhang L, Huang C, Cheng AG, Dang GT. Relationship between osteopenia and lumbar intervertebral disc degeneration in ovariectomized rats. Calcified Tissue Int 2004;75:205–13 3. Gambacciani M, Pepe A, Cappagli B, Palmieri E, Genazzani AR. The relative contributions of menopause and aging to postmenopausal reduction in intervertebral disk height. Climacteric 2007;10:298–305 4. Miyakoshi N, Hongo M, Mizutani Y, Shimada Y. Prevalence of sarcopenia in Japanese women with osteopenia and osteoporosis. J Bone Miner Metab 2013;31:556–61 5. Wang YX, Griffith JF, Zeng XJ, et al. Prevalence and sex difference of lumbar disc space narrowing in elderly chinese men and women: osteoporotic fractures in men (Hong Kong) and osteoporotic fractures in women (Hong Kong) studies. Arthritis Rheum 2013;65:1004–10 6. Kim JY, Chae SU, Kim GD, Cha MS. Changes of paraspinal muscles in postmenopausal osteoporotic spinal compression fractures: magnetic resonance imaging study. J Bone Metab 2013;20:75–81 7. Wang YX, Zhao F, Griffith JF, et al. T1rho and T2 relaxation times for lumbar disc degeneration: an in vivo comparative study at 3.0-Tesla MRI. Eur Radiol 2013;23:228–34 8. Takatalo J, Karppinen J, Taimela S, et al. Association of abdominal obesity with lumbar disc degeneration–a magnetic resonance imaging study. PloS one. 2013; 8: e56244 9. Griffith JF, Wang YX, Antonio GE, et al. Modified Pfirrmann grading system for lumbar intervertebral disc degeneration. Spine 2007;32:E708–12 10. Richelson LS, Wahner HW, Melton LJ, Riggs BL. Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 1984;311:1273–5 11. Wallace JM, Erickson B, Les CM, Orr BG, Banaszak Holl MM. Distribution of type I collagen morphologies in bone: relation to estrogen depletion. Bone 2010;46:1349–54
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12. Imada K, Matsui H, Tsuji H. Oophorectomy predisposes to degenerative spondylolisthesis. J Bone Joint Surg Br 1995;77:126–30 13. Wang YX, Griffith JF, Ma HT, et al. Relationship between gender, bone mineral density, and disc degeneration in the lumbar spine: a study in elderly subjects using an eight-level MRI-based disc degeneration grading system. Osteoporos Int 2011;22:91–6 14. Gruber HE, Yamaguchi D, Ingram J, et al. Expression and localization of estrogen receptor-beta in annulus cells of the human intervertebral disc and the mitogenic effect of 17-beta-estradiol in vitro. BMC Musculoskelet Disord 2002;3:4 15. Siemionow K, An H, Masuda K, Andersson G, Cs-Szabo G. The effects of age, sex, ethnicity, and spinal level on the rate of intervertebral disc degeneration: a review of 1712 intervertebral discs. Spine 2011;36:1333–9 16. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene 2004;338:143–56 17. Langrana NA, Kale SP, Edwards WT, Lee CK, Kopacz KJ. Measurement and analyses of the effects of adjacent end plate curvatures on vertebral stresses. Spine J 2006;6:267–78 18. Kwok AW, Griffith JF, Ma HT, et al. Estimated volume of both vertebral body and disc decreases as BMD decreases though this effect is seen more in the vertebral body than the disc. Bone 2008;43:S66–7 19. Iatridis JC, Nicoll SB, Michalek AJ, Walter BA, Gupta MS. Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair? Spine J 2013;13:243–62 20. 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: a population-based study. Arthritis Rheum 2012;64:1488–96 21. Yoshimura N, Dennison E, Wilman C, Hashimoto T, Cooper C. Epidemiology of chronic disc degeneration and osteoarthritis of the lumbar spine in Britain and Japan: a comparative study. J Rheumatol 2000;27:429–33
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Menopause is associated with lumbar disc degeneration: a review of 4230 intervertebral discs C. Lou, H-L. Chen, X-Z. Feng*, G-H. Xiang, S-P. Zhu, N-F. Tian, Y-L. Jin, M-Q. Fang, C. Wang and H-Z. Xu Department of Orthopedic Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang; *Department of Acupuncture and Massage & Physical Therapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
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Key words: MENOPAUSE, DEGENERATION, INTERVERTEBRAL DISC, LUMBAR SPINE, MAGNETIC RESONANCE IMAGING
ABSTRACT Objective The main objective of this study was to investigate, in a population of normal postmenopausal women, the association between menopause and severity of lumbar disc degeneration from the first lumbar to the first sacral vertebra on magnetic resonance imaging. Methods Between January 2010 and May 2013, 846 normal women and 4230 intervertebral discs were retrospectively analyzed. Age, height, weight and years since menopause (YSM) were recorded. Disc degeneration was evaluated using the modified Pfirrmann grading system. Results Compared to premenopausal and perimenopausal women, postmenopausal women had more severe disc degeneration after removal of age, height and weight effects (p ⬍ 0.0001). Postmenopausal women were divided into six subgroups for every 5 YSM. When YSM was below 15 years, there was a significant difference between every two groups, i.e. groups 1–5 YSM, 6–10 YSM and 11–15 YSM (p ⬍ 0.01). A positive trend was observed between YSM and severity of disc degeneration, respectively, i.e. L1/L2 (r ⫽ 0.235), L2/ L3 (r ⫽ 0.161), L3/L4 (r ⫽ 0.173), L4/L5 (r ⫽ 0.146), L5/S1 (r ⫽ 0.137) and all lumbar discs (r ⫽ 0.259) (p ⬍ 0.05 or 0.01). However, when YSM was above 15, there was no difference, i.e. groups 16–20 YSM, 21–25 YSM and 26–30 YSM (p ⬎ 0.05), and the significance correlation also disappeared (p ⬎ 0.05). Conclusion Menopause is associated with disc degeneration in the lumbar spine. The association almost entirely occurred in the first 15 years since menopause, suggesting estrogen decrease may be a risk factor for lumbar disc degeneration.
INTRODUCTION Postmenopausal women often suffer low back pain due to lumbar disc degeneration. Baron and colleagues1 reported a positive relationship between radiographic lumbar intervertebral disc height and hormone replacement treatment (HRT) in postmenopausal women. Postmenopausal women treated with HRT have enhanced total lumbar disc height compared to untreated postmenopausal women. Female rats had an increased tendency to develop disc degeneration after undergoing ovariectomy2. These results suggest that estrogen
deficiency might have a causal role in the pathogenesis of disc degeneration. In the earlier papers studying the effect of menopause on lumbar disc degeneration3, the authors evaluated disc degeneration by measuring the intervertebral disk space. In contrast to radiographic assessment3–5, magnetic resonance imaging (MRI) is more accurate6–8. The modified Pfirrmann grading system9, a non-invasive, simple, and convenient MR imaging method, can provide a morphologic and semiquantitative evaluation of intervertebral disc degeneration in vivo. The MRI-based, eight-level grading system is based on MR
Chao Lou and Hong-Liang Chen contributed equally to this study. Correspondence: Dr H-Z. Xu, Department of Orthopedic Surgery, The Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuanxi Road, Wenzhou, Zhejiang, People’s Republic of China. Email:[email protected]
ORIGINAL ARTICLE © 2014 International Menopause Society DOI: 10.3109/13697137.2014.933409
Received 29-04-2014 Revised 07-06-2014 Accepted 07-06-2014
Menopause and lumbar disc degeneration signal intensity and disc structure and distinguishes between the nucleus pulposus and annulus, and disc height. This useful grading system has been accepted and applied clinically. To complement the information lacking in previous reports, we evaluated disc degeneration using a MRI-based, eight-level grading system in pre-, peri- and postmenopausal women. The purpose of this study was to investigate the association between menopause and the grade of degeneration in the lumbar spine.
Lou et al. stepwise progression from Grade 1 to 8. The degeneration classification was based on signal intensity of the nucleus pulposus and the inner annulus, signal intensity difference between the inner and outer parts of the posterior annulus, and height of intervertebral discs. It has been reported that, with this eight-level grading system, the intraobserver agreement was excellent (weighted kappa range, 0.79–0.91), and the interobserver agreement, for self-training with documents and pictures, was substantial (weighted kappa range, 0.65–0.67)9.
METHODS Statistical analysis
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Study population A total of 846 normal women admitted to our department for low back pain (Department of Orthopedics, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China) from January 2010 and May 2013 were retrospectively reviewed in this study. Age, height, weight and years since menopause (YSM) were recorded. These women were divided into three groups: normally menstruating women (premenopausal group), the women with oligomenorrhea (perimenopausal group), and the normal postmenopausal women. The postmenopausal group was divided into six subgroups for every 5 YSM. Patients met the following criteria: (1) no diseases that influence the spinal structure; (2) no lumbar trauma and fracture history; (3) no diseases that influence estrogen metabolism (such as tumor of the ovary, ovariectomy); (4) no treatment with endocrine active preparations; (5) no subjection to extreme spinal loading for work-related or recreational activities; (6) no imaging evidence of lumbar vertebra fracture or abnormality other than degeneration. Back pain was not a specific inclusion or exclusion criterion.
Lumbar spine MRI Lumbar spine MR imaging was performed using a 1.5-T MRI superconducting imaging system (Siemens, Avanto, Germany). The operational modes employed were T1-weighted spin-echo sequences (TR 617 ms, TE 11 ms) and T2-weighted spin-echo sequences (TR 2500 ms, TE 107 ms). The following parameters were used: matrix ⫽ 256 ⫻ 256; field of view ⫽ 320 ⫻ 320 mm; slice thickness ⫽ 4 mm; interslice gap ⫽ 1.0 mm; number of signal acquisitions ⫽ 2. Lumbar disc grading was performed independently in the standard T2-weighted turbo spin echosagittal images by a orthopedic surgeon who was experienced in MR imaging of the spine using the modified Pfirrmann grading system.
Measurement of lumbar disc degeneration Disc degenerations from L1–2 to L5–S1 were assessed using an eight-level grading system where each grade represents a
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Analysis of covariance (ANCOVA) was specially adopted to assess the difference in lumbar disc degeneration among the different menopausal groups with removal of the confounding effect factors. Also, it was used to assess the difference in disc degeneration among the different YSM groups. Partial correlation analysis was used to test the association between disc degeneration grade and YSM by removing the confounding effect factors. A p value ⬍ 0.05 was considered statistically significant. The analysis was carried out using the statistical package SPSS 17.0 (SPSS Inc., Chicago, IL, USA).
RESULTS The characteristics of the population included in our study are shown in Table 1. The subjects had an average age of 56.3 ⫹ ⫺ 12.9 years, range 21–81 years, and age at menopause of the postmenopausal women was 49.7 ⫹ ⫺ 2.4 years, range 40–56 years. Discs were degenerated from Grade 1 to Grade 8. In the selected population, 162 subjects were normally menstruating premenopausal women, 95 women presented perimenopausal oligomenorrhea and 589 were postmenopausal women (Table 2). There was no significant difference in body weight between the three groups, but they differed in age and height. The body mass indices (BMI) in the peri-
Table 1
Baseline characteristics of the study population (n ⫽ 846) Mean ⫹ ⫺ standard deviation
Age (years) Weight (kg) Height (m) Body mass index (kg/m2) Age at menopause (years) Mean grade of disc degeneration L1/L2 L2/L3 L3/L4 L4/L5 L5/S1
Range
56.3 ⫹ ⫺ 12.9 58.1 ⫹ ⫺ 7.8 1.57 ⫹ ⫺ 0.04 23.5 ⫹ ⫺ 3.1 49.7 ⫹ ⫺ 2.4
21–81 39–103 1.45–1.76 15–41 40–56
3.40 ⫹ ⫺ 1.35 3.69 ⫹ ⫺ 1.37 4.04 ⫹ ⫺ 1.31 4.41 ⫹ ⫺ 1.34 4.27 ⫹ ⫺ 1.37
1–8 1–8 1–8 1–8 1–8
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Table 2 Demographic characteristics and disc degeneration grade in the three groups. Values in parentheses are the percentages of each grade in that group
Age (years) Weight (kg) Height (m) Body mass index (kg/m2) Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%) Grade 5 (%) Grade 6 (%) Grade 7 (%) Grade 8 (%) Years since menopause
Premenopause (n ⫽ 162)
Perimenopause (n ⫽ 95)
Postmenopause (n ⫽ 589)
37.2 ⫹ ⫺ 5.8 57.8 ⫹ ⫺ 7.2 1.59 ⫹ ⫺ 0.04 22.9 ⫹ ⫺ 2.70 50 (6.2%) 440 (54.3%) 163 (20.1%) 78 (9.6%) 42 (5.2%) 25 (3.1%) 10 (1.2%) 2 (0.2%) NA
* 46.5 ⫹ ⫺ 1.6 59.0 ⫹ 8.2 ⫺ * 1.58 ⫹ ⫺ 0.04 * 23.7 ⫹ 3.0 ⫺ 3 (0.6%) 159 (33.5%) 176 (37.1%) 63 (13.3%) 42 (8.8%) 22 (4.6%) 7 (1.5%) 3 (0.6%) NA
** 63.2 ⫹ ⫺ 8.2 58.0 ⫹ 7.8 ⫺ ** 1.57 ⫹ ⫺ 0.04 * 23.7 ⫹ 3.1 ⫺ 0 167 (5.6%) 392 (13.3%) 611 (20.7%) 1383 (47.0%) 302 (10.3%) 64 (2.2%) 26 (0.9%) 13.3 ⫹ ⫺ 8.16
NA, not applicable *, p ⬍ 0.01 vs. premenopause; **, p ⬍ 0.01 vs. premenopause and perimenopause 2 menopausal (23.7 ⫹ ⫺ 3.0 kg/m ) and postmenopausal groups 2 (23.7 ⫹ ⫺ 3.1 kg/m ) were significantly (p ⬍ 0.01) higher than 2 in the premenopausal group (22.9 ⫹ ⫺ 2.70 kg/m ). In the premenopausal women, the discs degenerated at Grade 2 at a significantly higher rate of 54.3%, while 37.1% of perimenopausal women were at Grade 3, and 47.0% of postmenopausal women were at Grade 5. Grade 6 or higher disc degeneration was observed in 4.5% (37/810), 6.7% (32/475), and 13.4% (392/2945) in pre-, peri-, and postmenopausal women, respectively. It was noted that all the observations in this study were more likely to be significant in the lower lumbar spine while less so in the upper lumbar spine. Furthermore, in our study, there was no significance correlation between weight, height, BMI and age at menopause. By removing the effects of age, height and weight, a trend of positive relationship was observed between the three different menopause periods and severity of disc degeneration (p ⬍ 0.0001), as subjects in postmenopause tended to have more severe disc degeneration (Table 3). Furthermore, to investigate the effect of menopause, the results obtained in postmenopausal women were plotted for each 5 years according to YSM. When YSM ⬍ ⫺ 15, by removing the effects of age, height and weight, a positive trend was observed between YSM and severity of disc degeneration, respectively at L1/L2 (r ⫽ 0.235), L2/L3 (r ⫽ 0.161), L3/L4 (r ⫽ 0.173), L4/L5 (r ⫽ 0.146), L5/S1 (r ⫽ 0.137) and all lumbar discs (r ⫽ 0.259) (p ⬍ 0.05 or 0.01). There were significant differences in disc degeneration between 1–5 YSM, 6–10 YSM, and 11–15 YSM (p ⬍ 0.01), as subjects with higher YSM tended to have more severe disc degeneration. When YSM ⬎ 15, the significance correlation disappeared (p ⬎ 0.05); there was no significant difference between the groups at 16–20 YSM, 21–25 YSM and 26–30 YSM (p ⬎ 0.05). The exceptions were L1/L2 and L2/L3 in the 21–25 YSM group; the degeneration was less severe compared to that of the previous groups (Table 4).
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DISCUSSION This study was the first to use the modified Pfirrmann grading system to evaluate the association of menopause with disc degeneration by MR imaging. Further, to evaluate the effect of estrogen on disc degeneration, we included premenopausal and perimenopausal women as a comparison, and these methods made the results more reliable. The results Table 3 Relationship between menopause groups and severity of lumbar disc degeneration (n ⫽ 846). Data are given as estimated mean ⫹ ⫺ standard error, adjusted for age, weight and height. This was significant overall in all lumbar intervertebral discs Disc level L1/L2
L2/L3
L3/L4
L4/L5
L5/S1
All discs
Group premenopause perimenopause postmenopause premenopause perimenopause postmenopause premenopause perimenopause postmenopause premenopause perimenopause postmenopause premenopause perimenopause postmenopause premenopause perimenopause postmenopause
Grade of severity of disc degeneration 1.99 ⫹ ⫺ 0.08 2.30 ⫹ ⫺ 0.11 3.97 ⫹ ⫺ 0.04 2.09 ⫹ ⫺ 0.08 2.63 ⫹ ⫺ 0.10 4.30 ⫹ ⫺ 0.04 2.45 ⫹ ⫺ 0.07 3.05 ⫹ ⫺ 0.10 4.64 ⫹ ⫺ 0.04 2.79 ⫹ ⫺ 0.08 3.81 ⫹ ⫺ 0.10 5.00 ⫹ ⫺ 0.04 2.88 ⫹ ⫺ 0.09 3.79 ⫹ ⫺ 0.12 4.74 ⫹ ⫺ 0.05 2.74 ⫹ ⫺ 0.06 3.23 ⫹ ⫺ 0.08 4.52 ⫹ ⫺ 0.03
p Value ⬍ 0.0001
⬍ 0.0001
⬍ 0.000
⬍ 0.0001
⬍ 0.0001
⬍ 0.0001
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Table 4 Relationship between years since menopause and severity of disc degeneration (n ⫽ 589). Data are given as estimated mean ⫹ ⫺ standard error, adjusted for age, weight and height. Pairwise comparisons using the latter compared to the former years since menopause Disc level L1/L2
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L2/L3
L3/L4
L4/L5
L5/S1
All discs
Years since menopause 1–5 6–10 11–15 16–20 21–25 ⬎ 26 ⫺ 1–5 6–10 11–15 16–20 21–25 ⬎ 26 ⫺ 1–5 6–10 11–15 16–20 21–25 ⬎ 26 ⫺ 1–5 6–10 11–15 16–20 21–25 ⬎ 26 ⫺ 1–5 6–10 11–15 16–20 21–25 ⬎ 26 ⫺ 1–5 6–10 11–15 16–20 21–25 ⬎ 26 ⫺
Grade of severity of disc degeneration 3.30 ⫹ ⫺ 0.17 * 3.58 ⫹ ⫺ 0.11 ** 4.19 ⫹ ⫺ 0.08 ** 4.58 ⫹ ⫺ 0.12 * 4.29 ⫹ ⫺ 0.17 4.37 ⫹ 0.25 ⫺ 3.86 ⫹ ⫺ 0.17 ** 4.23 ⫹ ⫺ 0.11 * 4.50 ⫹ 0.08 ⫺ 4.74 ⫹ 0.12 ⫺ ** 4.35 ⫹ ⫺ 0.17 4.28 ⫹ ⫺ 0.25 4.17 ⫹ ⫺ 0.16 ** 4.52 ⫹ ⫺ 0.10 * 4.81 ⫹ 0.07 ⫺ 5.00 ⫹ 0.11 ⫺ 4.84 ⫹ ⫺ 0.15 4.69 ⫹ ⫺ 0.23 4.49 ⫹ ⫺ 0.17 * 4.78 ⫹ ⫺ 0.11 ** 5.16 ⫹ ⫺ 0.08 5.23 ⫹ 0.12 ⫺ 5.20 ⫹ ⫺ 0.17 5.04 ⫹ ⫺ 0.24 4.33 ⫹ ⫺ 0.19 * 4.66 ⫹ ⫺ 0.12 * 5.00 ⫹ ⫺ 0.09 4.91 ⫹ ⫺ 0.13 4.83 ⫹ ⫺ 0.19 4.78 ⫹ ⫺ 0.28 4.03 ⫹ ⫺ 0.12 ** 4.35 ⫹ ⫺ 0.07 ** 4.74 ⫹ 0.05 ⫺ 4.89 ⫹ ⫺ 0.08 4.70 ⫹ ⫺ 0.11 4.63 ⫹ ⫺ 0.17
*, p ⬍ 0.05; **, p ⬍ 0.01
demonstrated that postmenopausal women had a mild tendency to develop more severe disc degeneration than premenopausal and perimenopausal women. Discs showed a progressive degeneration that almost entirely occurred in the first 15 years since menopause. Around the time of the menopause and postmenopause, women appear to have a serious estrogen deficiency-related bone disease as the estrogen levels decrease rapidly10,11. Clinical studies suggest that estrogen deprivation may have a pivotal role in the progress of disc
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degeneration in postmenopausal women1,12. By using the modified Pfirrmann grading system to study a cohort of 163 healthy men (mean age, 73.5 ⫹ ⫺ 4.3 years) and 196 healthy women (mean age, 73.2 ⫹ 4.1 years), the results showed that ⫺ elderly female subjects had more severe disk degeneration than male subjects at all lumbar levels13. Basic research has also confirmed that the human intervertebral disc cells contain the estrogen receptor-β gene, with estrogen-enhancing cellular proliferation in annulus cell cultures14. Reduced estrogen levels will result in the loss of the intervertebral disc extracellular matrix, thereby accelerating the degeneration of the intervertebral disc. Our conclusion was in accordance with the above-mentioned opinion. However, Gambacciani and colleagues3 reported that intervertebral disk degeneration shows a progressive decrease that almost entirely occurs in the first 5–10 years since menopause in Caucasian women. This is certainly different from the results in our paper. The reasons may be: first, lumbar intervertebral disc degeneration of Caucasian women is more serious than in Asian women, and the high-risk gene frequency (43%) was significantly higher than that of Asian women (8%)15,16. Second, to evaluate the degeneration of intervertebral discs, Gambacciani and colleagues measured the intervertebral disk space between the 12th thoracic and 4th lumbar vertebrae by dual-energy X-ray absorptiometry (DXA). In our study, we used a MRI-based, eight-level grading system on MR T2-weighted imaging. The advantages of MRI were that it reflected not only early loss of signal intensity but also later changes show concordant loss of disc height. Third, different from previous studies, we evaluated lumbar discs individually rather than grouping them together as a single unit, as the evidence showed that the former is more accurate17. Based on these three different points as reported, these different results all have their levels of confidence. On the other hand, results from this study show that the lumbar intervertebral discs were degenerating no further when YSM was above 15. Wang and colleagues13 found that lower lumbar spine BMD was associated with less severe disc degeneration. Reduced BMD leads to endplate weakening and loss of vertebral body height, a process that allows the disc to push into the endplates and expand, as described by Kwok and colleagues18. Though lower BMD may slow the disc degeneration, the pathogenesis of disc degeneration is very complex; several factors promote degeneration such as genes, age, BMI, lifestyle and biomechanical factors and will remain constant19,20, and these may explain why disc degeneration is maintained at a stable level. Unfortunately, as the sample size of our study is small, further research is needed to confirm this conclusion.
CONCLUSIONS In summary, our study suggests that menopause is associated with disc degeneration in the lumbar spine. The association almost entirely occurred in the first 15 years since
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Menopause and lumbar disc degeneration menopause, suggesting estrogen decrease may be a risk factor for disc degeneration. Though our study was controlled by factors such as age, weight, and height and had relatively better inclusion criteria and statistical methods, other factors such as occupation and bone mineral density were not included. At the same time, the pathogenesis of disc degeneration in different regions and ethnicities is not the same15,21; a prospective study is needed to further evaluate this issue by using more uniform assessment standards and strict inclusion criteria.
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ACKNOWLEDGEMENT We thank the study staff at each site and all the women who participated in our research. Conflict of interest The authors report no confl ict of interest. The authors alone are responsible for the content and writing of this paper. Source of funding
Nil.
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References 1. Baron YM, Brincat MP, Galea R, Calleja N. Intervertebral disc height in treated and untreated overweight postmenopausal women. Hum Reprod 2005;20:3566–70 2. Wang T, Zhang L, Huang C, Cheng AG, Dang GT. Relationship between osteopenia and lumbar intervertebral disc degeneration in ovariectomized rats. Calcified Tissue Int 2004;75:205–13 3. Gambacciani M, Pepe A, Cappagli B, Palmieri E, Genazzani AR. The relative contributions of menopause and aging to postmenopausal reduction in intervertebral disk height. Climacteric 2007;10:298–305 4. Miyakoshi N, Hongo M, Mizutani Y, Shimada Y. Prevalence of sarcopenia in Japanese women with osteopenia and osteoporosis. J Bone Miner Metab 2013;31:556–61 5. Wang YX, Griffith JF, Zeng XJ, et al. Prevalence and sex difference of lumbar disc space narrowing in elderly chinese men and women: osteoporotic fractures in men (Hong Kong) and osteoporotic fractures in women (Hong Kong) studies. Arthritis Rheum 2013;65:1004–10 6. Kim JY, Chae SU, Kim GD, Cha MS. Changes of paraspinal muscles in postmenopausal osteoporotic spinal compression fractures: magnetic resonance imaging study. J Bone Metab 2013;20:75–81 7. Wang YX, Zhao F, Griffith JF, et al. T1rho and T2 relaxation times for lumbar disc degeneration: an in vivo comparative study at 3.0-Tesla MRI. Eur Radiol 2013;23:228–34 8. Takatalo J, Karppinen J, Taimela S, et al. Association of abdominal obesity with lumbar disc degeneration–a magnetic resonance imaging study. PloS one. 2013; 8: e56244 9. Griffith JF, Wang YX, Antonio GE, et al. Modified Pfirrmann grading system for lumbar intervertebral disc degeneration. Spine 2007;32:E708–12 10. Richelson LS, Wahner HW, Melton LJ, Riggs BL. Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 1984;311:1273–5 11. Wallace JM, Erickson B, Les CM, Orr BG, Banaszak Holl MM. Distribution of type I collagen morphologies in bone: relation to estrogen depletion. Bone 2010;46:1349–54
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12. Imada K, Matsui H, Tsuji H. Oophorectomy predisposes to degenerative spondylolisthesis. J Bone Joint Surg Br 1995;77:126–30 13. Wang YX, Griffith JF, Ma HT, et al. Relationship between gender, bone mineral density, and disc degeneration in the lumbar spine: a study in elderly subjects using an eight-level MRI-based disc degeneration grading system. Osteoporos Int 2011;22:91–6 14. Gruber HE, Yamaguchi D, Ingram J, et al. Expression and localization of estrogen receptor-beta in annulus cells of the human intervertebral disc and the mitogenic effect of 17-beta-estradiol in vitro. BMC Musculoskelet Disord 2002;3:4 15. Siemionow K, An H, Masuda K, Andersson G, Cs-Szabo G. The effects of age, sex, ethnicity, and spinal level on the rate of intervertebral disc degeneration: a review of 1712 intervertebral discs. Spine 2011;36:1333–9 16. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene 2004;338:143–56 17. Langrana NA, Kale SP, Edwards WT, Lee CK, Kopacz KJ. Measurement and analyses of the effects of adjacent end plate curvatures on vertebral stresses. Spine J 2006;6:267–78 18. Kwok AW, Griffith JF, Ma HT, et al. Estimated volume of both vertebral body and disc decreases as BMD decreases though this effect is seen more in the vertebral body than the disc. Bone 2008;43:S66–7 19. Iatridis JC, Nicoll SB, Michalek AJ, Walter BA, Gupta MS. Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair? Spine J 2013;13:243–62 20. 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: a population-based study. Arthritis Rheum 2012;64:1488–96 21. Yoshimura N, Dennison E, Wilman C, Hashimoto T, Cooper C. Epidemiology of chronic disc degeneration and osteoarthritis of the lumbar spine in Britain and Japan: a comparative study. J Rheumatol 2000;27:429–33
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