Clinical characteristics of geriatric patients with non-specific chronic low back pain

A comprehensive analysis of clinical information in patients with chronic low back pain (CLBP) was performed to clarify the clinical characteristics of geriatric LBP from the perspective of body composition, spinal alignment, and blood findings related to senescence. We enrolled 203 patients with an average age of 79.0 years (77 men and 126 women), with non-specific CLBP as a single-center prospective cohort study, the patients were compared with age- and sex-matched controls without CLBP using a propensity score-matching. We performed laboratory analysis, radiographic evaluations for global spinal parameter and lumbar degeneration, and body composition analysis using whole-body dual-energy X-ray absorptiometry. We observed a higher red blood cell distribution width (RDW) (p < 0.001), which is an index of aging, as well as a lower vitamin D level (p = 0.002), skeletal muscle mass index (p = 0.045) and a higher fat mass (p = 0.007) in patients with CLBP. Moreover, patients with geriatric CLBP had significantly lower lumbar lordosis (p = 0.024), and higher sagittal vertical axis (p = 0.006) was correlated with lower extremity and trunk muscle mass (p < 0.001), independent of lumbar degeneration. Geriatric patients with CLBP have sarcopenic fat accumulation and spinal sagittal malalignment with senescent status, such as elevated RDW and hypovitaminosis D.

Patients enrollment and eligibility. This observational survey was carried out from January 2018 to April 2020 in our institute from a prospectively collected database in the J-BINC, which is a single-center prospective cohort study recruiting patients from the National Center for Geriatrics and Gerontology to assess whether non-specific chronic pain in geriatric patients shows genetic overlap with clinical findings by the discovery analysis from genome-wide association study. Individuals from both the discovery and replication samples were of Japanese background to limit biases resulting from ethnic disparities, and the clinical database of individuals from the discovery samples was drawn for this study. This cohort was a patient-based study that openly recruited individuals aged ≥ 65 years with non-specific chronic pain lasting for more than 6 months, including LBP, neck pain and knee pain. Non-specific CLBP in this study was defined as follows: (1) LBP with visual analogue scale (VAS) score for LBP ≥ 3; (2) persistent pain localized below the costal margin and above the inferior gluteal folds for more than 6 months; (3) the absence of specific spinal pathology such as infection, tumors, and vertebral fractures on both plain radiographs and lumbar magnetic resonance imaging (MRI); (4) the absence of dominant leg pain caused by radicular and cauda equina disorders; (5) the absence of prominent instability such as spondylolysis, isthmic spondylolisthesis, and degenerative spondylolisthesis more than grade II; (6) no previous lumbar and/or thoracolumbar spine surgery. Degenerated lumbar structures such as the vertebral disc, facet joint, and sacroiliac joint were omitted from the inclusion criteria because available diagnostic procedures for these conditions are inaccurate 22 . In addition to patients who did not meet the above inclusion criteria, we excluded patients who were unable to stand unsupported, could not evaluate VAS due to dementia and did not agree with participation in the present study.
Age/sex-matched control. The retrospective collection was conducted with data from a prospectively maintained database of Sarcopenia Study for Elderly Patient for patients who underwent whole-body dualenergy X-ray absorptiometry (DXA) and evaluated skeletal muscle mass. Registration in this database requires that whole spine radiograph, lumbar MRI, and blood data be performed within 1 year of DXA. Of 2390 patients (65-100 year, averaged 78.7 years, male 1014 patients, female 1376 patients), 1195 patients excluding lumbar degenerative disease, 683 without complaint of LBP were recruited as control participants.
Laboratory measurements. Upon enrollment, we collected fasting venous blood samples from patients in the non-specific CLBP and control groups. We recorded complete blood count parameters such as hemoglobin, mean corpuscular volume, white blood cell (WBC) count, lymphocyte count, and red blood cell distribution width (RDW). The RDW is an automated measure of the heterogeneity of red blood cell sizes due to inflammation and senescence of erythropoietic cells in the bone marrow 23 . Additional covariates included albumin, C-reactive protein (CRP), total cholesterol, creatinine, estimated glomerular filtration rate, and 25-hydroxyvitamin D (25-OHD). Serum 25-OHD levels were determined using electrochemiluminescence immunoassay, and 25-OHD concentration was classified as sufficient, insufficient, and deficient for values ≥ 30 ng/mL, 21-29 ng/ mL, and ≤ 20 ng/mL, respectively 24 .
Radiographic evaluation (Fig. 1). All patients underwent conventional radiography in the standing position. For lateral films, the patients stood with their knees locked, with feet shoulder-width apart, and looking straight ahead. Measured parameters of interest included coronal Cobb angle between the superior edge of L1 and S1, lumbar lordosis (LL), thoracic kyphosis (TK), S1 slope (SS), sagittal vertical axis (SVA), pelvic tilt (PT), pelvic incidence (PI), the presence of spondylolisthesis (anterior slip > 3 mm), and the lumbar range of motion (ROM) defined as the difference in lumbar lordosis angle between flexion and extension. Spinopelvic mismatch was determined when PI-LL is more than 10°2 5 . Body composition analysis. Body composition was assessed using DXA (Lunar iDXA, GE-Healthcare, Tokyo, Japan). Osteoporosis was evaluated using the young adult mean on the lumbar spine (L2-4). Sarcopenia was evaluated using the appendicular lean mass derived from the sum of lean mass in the upper and lower   www.nature.com/scientificreports/ Statistical analysis. We determined that a minimum sample of 394 (197 per group) would be required for a power of 90% to detect a clinically importance between-group difference of 0.35 points (with CLBP vs without CLBP in the elderly patients) in the SMI value. Assumptions for the SMI included a two-sided alpha level of 0.05 and a mean standard deviation of 1.07 points 18 . Proportions and means with standard deviations (SD) for normally distributed data and median with minimum and maximum values for not normally distributed data were calculated for covariates and demographic information, moreover, categorical variables were expressed as frequencies or percentages. The chi-square or Fisher exact test was used to assess differences in categorical variables, and means were compared using independent t-test and Mann-Whitney U test for normally and non-normally distributed data, respectively. Normality was checked using the Kolmogorov-Smirnov test. To minimize the effects of potential confounding influences of measured covariates in the 2 study groups (CLBP vs. control), a propensity score-matched analysis for age and sex was applied. Finally, patients were matched 1:1 without replacement using a nearest-neighbor approach with caliper restrictions set at 0.2. A propensity score was calculated for each patient using the results of this model, regardless of the statistical significance of the independent variables in the model. The correlation between skeletal muscle mass and spinal sagittal alignment parameters were analyzed using simple linear regression analysis (Pearson correlation coefficient). Statistical analyses were performed using the EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan). A p value less than 0.05 was considered statistically significant.
Ethical approval. The device(s)/drug(s) is/are FDA approved or approved by the corresponding national agency for this indication. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. Ethical approval was given by National Center for Geriatrics and Gerontology Ethics Committee.
Laboratory measurements. Demographic and laboratory data of propensity score matching analysis are shown in Tables 1 and 2. There were no significant differences in anthropometry, cytometry, renal function, and nutritional condition. The RDW and the prevalence of elevated RDW were significantly higher in patients in the CLBP group than in those in the control group; however, there were no significant differences in CRP level. Serum 25-OHD levels were significantly lower in patients in the CLBP group than in those in the control group. Table 3. Extremity muscle mass, SMI, and trunk muscle CSAs were significantly lower in patients with CLBP than in those with the control. Lower extremity fat mass and body fat ratio were significantly higher in patients with the CLBP than in those with the control. www.nature.com/scientificreports/ MRI evaluation. In reference to lumbar degeneration in patients with CLBP, the frequency of lumbar spondylolisthesis was equal to that in the control and the prevalence of end plate and disc degeneration was lower in patients with CLBP than in the control group. (Table 4).

Radiographic evaluation.
A comparison of spinal sagittal alignment is shown in Table 5. LL was significantly lower in patients with the CLBP than in those with the control, whereas SVA, PT, and PI-LL were significantly higher in patients with the CLBP than in those with the control group. Spinopelvic mismatch was significantly higher in patients with the CLBP group than in those in the control group. Muscle mass in both legs  www.nature.com/scientificreports/ and trunk was negatively correlated with PT, whereas only trunk muscle mass was negatively correlated with SVA. Muscle mass in both legs and trunk was negatively correlated with PI-LL; however, trunk muscle mass was more correlated with PI-LL compared with lower extremity muscle mass. (Fig. 3).

Discussion
In the present study, high RDW related to senescence such as chronic inflammation, oxidative stress, which present in the elderly, were observed in patients with CLBP. Moreover, low lower extremity and trunk muscle mass with high body fat were observed in geriatric patients with CLBP. Previous studies have also reported an association with skeletal muscle mass reduction and LBP in the elderly 18,19 ; thus, sarcopenia may have some impact on geriatric LBP development. However, it is unclear how lower extremity muscle mass reduction, which occurs before trunk muscle mass reduction with age 29 , causes LBP in the elderly. Although the relationship between trunk muscle atrophy and LBP has been previously highlighted [30][31][32] , it has not been concluded whether trunk muscle atrophy is the cause or result of LBP. There is a view that trunk muscle atrophy is caused by disuse, denervation, reflex suppression 33,34 , and there is conflicting evidence for a relationship between the morphological changes in the lumbar muscles and LBP. Age-related skeletal muscle mass reduction originates from type II fibers 35 ; therefore, it is known that trunk muscles containing more type I fibers develop sarcopenic changes later than those in the lower extremities 29 . Currently, international guidelines for sarcopenia evaluation, define skeletal muscle mass as the skeletal muscle mass index (SMI), which is dependent on the muscle volume of the extremities 36 . The key to investigating the cause of non-specific LBP in the elderly from the perspective of aging musculature is to proceed with the analysis of geriatric LBP focusing on lower limb skeletal muscle. Considering the pathophysiological condition of age-related skeletal muscle loss from the molecular biological mechanism of aging, senescence is associated with advanced aging in humans. Senescent cells involving irreversibly proliferative arrest can develop the SASP, consisting of proinflammatory cytokines and extracellular matrix-degrading proteins, which function as deleterious paracrine and systemic mild inflammation 37 . Thus, "inflammaing" is considered as a pervasive feature of aging tissue in age-related diseases 17 . One of the most important organs of locomotor senescence is the skeletal muscle, and sarcopenia, which is an age-related loss of muscle mass, is also considered to be a pathology associated with chronic inflammation mediated by immunosenescence 38 . RDW, which was significantly higher in elderly patients with CLBP in the present study, has been attracting attention as a prognostic factor for various acute and chronic diseases in recent years. This is because it represents the red blood cell size variation and reflects changes in circulatory half-life due to chronic inflammation [39][40][41][42] . Elevated RDW is associated with an increased risk of age-related diseases and mortality; moreover, RDW reflects overall inflammation because it is associated with overall and disease-specific mortality  Figure 3. Correlation between skeletal muscle mass and spinal sagittal alignment. Lower muscle mass in both legs and trunk was negatively correlated with PT, whereas only trunk muscle mass was negatively correlated with SVA. Muscle mass in both legs and trunk was negatively correlated with PI-LL; however, trunk muscle mass had stronger correlation with PI-LL compared with lower extremity muscle mass. The total number of plots was obtained by summing 203 cases in the CLBP group and 683 cases in the control group excluding 512 cases with LBP. PT: pelvic tilt, SVA: sagittal vertical axis, LL: lumbar lordosis, PI: pelvic incidence, PI-LL: PI minus LL.  44 performed comparative analyses of RDW and CRP for mortality prediction in patients with coronary heart disease and infectious endocarditis, respectively. They concluded that RDW, and not CRP, was associated with mortality, independent of traditional risk factors. They also suggested that RDW may be a stronger biomarker for morbidity and mortality. In our study, RDW, and not CRP, was associated with CLBP occurrence in the elderly. This suggests that CLBP may develop in the elderly based on chronic inflammation and RDW may be useful as a biomarker of chronic pain that does not reflect acute inflammation. In addition to chronic inflammation, oxidative stress is another significant mechanism that may explain the elevated RDW. Oxidative damage is an inducer of irreversible cellular senescence mediated by DNA damage, thereby leading to cell survival reduction 45 . Cellular senescence is an irreversible process. Unlike traditional biomarkers of acute inflammation, RDW is a valid indicator of senescence because it is not affected by cases of acute inflammation, such as infectious diseases; more so, it increases over time without large fluctuation, and it has a low reversibility 43,44 . The study results indicate that age-related physical changes in body composition, such as skeletal muscle loss and fat accumulation, are mechanisms of senescence that occur based on chronic inflammation. Thus, senescence might play a role in the development of CLBP in the elderly. Additionally, recent studies have linked vitamin D, which is known to be effective in preventing falls in the elderly 46 , with chronic pain development 47 . Furthermore, the action of vitamin D is mediated by receptors within muscle cells and bone tissue. Vitamin D is one of the essential elements for the development and maintenance of the musculoskeletal metabolic system, thereby predisposing the patients to sarcopenia 48 . Conversely, vitamin D has anti-inflammatory properties, and pro-inflammatory cytokines are produced during vitamin D deficiency 49 . Vitamin D deficiency causes increased nociceptive skeletal muscle innervation, even before muscle or bone pathology occurs 50 . Moreover, patients with chronic pain and low vitamin D levels are have elevated central hypersensitivity, namely, increased mechanical pain sensitivity and somatic symptom severity 51 . In our study, skeletal muscle mass and 25-OHD levels decreased without bone density loss in patients with geriatric CLBP, which is a noteworthy mechanism of chronic pain mediated by the skeletal muscle system.
The feasibility of application to treatment for geriatric LBP in consideration of the involvement of senescence in the elderly with chronic pain is significant; however, the relationship between inflammation and pain is merely an issue of the pain threshold 52 , and the pathological conditions that trigger the occurrence of LBP are essential. Spinal sagittal alignment, which was significantly different in elderly patients with CLBP in this study, is also one of the most important factors influencing mechanical LBP in elderly patients. Progressive sagittal imbalance is strongly associated with health-related quality of life 8 . Skeletal muscle is important for maintaining sagittal spinal balance; thus, it is conceivable that sagittal imbalance occurs in elderly patients due to age-related muscle mass reduction and/or atrophy other than vertebral fracture. Since patients with vertebral fractures were excluded from this study, the increase in SVA in patients with CLBP was attributed to a decrease in skeletal muscle mass. Although a significant association between skeletal muscle mass reduction and high PT was found in both limbs and trunk, an association between SVA increase and skeletal muscle mass reduction was found only in the trunk. Considering that the decrease in skeletal muscle mass with aging occurs from the lower extremities, it is assumed that the subsequent decrease in trunk muscles accelerates the increase in SVA following pelvic posterior tilt due to skeletal muscle reduction in the extremities. The effect of skeletal muscles on pelvic tilt in our study is consistent with the findings of Hiyama, which demonstrated that pelvic tilt is the sagittal parameter most closely related to skeletal muscle mass in patients with spinal degeneration disease 14 . Studies evaluating LBP and skeletal muscle mass 19,20,53,54 have reported the effect of skeletal muscle on sagittal spinal balance 14,55,56 ; however, our study is the first to analyze the relationship between skeletal muscle reduction and spinal sagittal balance in elderly patients with CLBP. There is no other way than highly invasive surgical treatment to correct spinal deformity in the elderly, and there is no better treatment for sarcopenia. Given the fact that the underlying solution for mechanical LBP is practically challenging, thus it could make sense to seek other treatments to improve geriatric CLBP from an anti-inflammatory and/or anti-senescent perspective.
Our study has a limitation because we used data from heterogeneous patient database of Sarcopenia Study for Elderly Patient for patients who underwent DXA without CLBP as a control. It is unclear whether similar results can be obtained by comparing patients with CLBP and healthy elderly persons. In addition, the cross-sectional study design of our study prevents renders our findings inclusive regarding the role of skeletal muscle mass and spinal alignment in the development of CLBP. Longitudinal investigations on changes in skeletal muscle and spinal parameters in the elderly are needed to clarify the cause of geriatric CLBP.
In conclusion, RDW, which is an index of aging, was high in elderly patients with CLBP. Moreover, geriatric CLBP is associated with vitamin D deficiency, which affects the pain threshold, and triggers CLBP due to the age-related loss of skeletal muscle mass and spinal sagittal malalignment. www.nature.com/scientificreports/