Comparison of Bone Loss and Associated Risk Factors in Men with Spinal Cord Injury and Community-dwelling Adults

doi:10.21203/rs.3.rs-2565328/v1

Study Design: retrospective chart audit

Objectives: In individuals with spinal cord injury (SCI), bone loss proceeds rapidly to the area below the level of injury, leading to increased risk of fracture. However, there are limited data on the degree of bone loss in individuals with SCI and associated factors in comparison with community-dwelling adults.

Settings: rehabilitation center in Seoul, Republic of Korea; community in Republic of Korea

Methods: Data from men with SCI who underwent Dual-energy X-ray Absorptiometry at the National Rehabilitation Center (2008 to 2020) between 12 and 36 months after injury were analyzed. Data from community-dwelling men in the Korea National Health and Nutrition Examination Survey (KNHANES, 2008–2011) were 1:1 matched for age, height, and weight as the control group.

Results: Among 226 men (SCI, n = 113; control, n = 113), femoral neck (-1.9 versus [vs.] -0.6) and total hip T-scores (-1.6 vs. -0.1; all, p <0.001) were significantly lower in the SCI group than in the KNHANES group, whereas the lumbar spine T-score did not differ between groups (-1.1 vs. -0.8, p = 0.105). The group difference in the femoral neck T-score remained significant after adjustment for covariates (adjusted β: -1.27, vs. KNHANES, p<0.001). Among men with SCI, low body mass index and cervical level of injury (vs. thoracolumbar level) were negatively correlated with femoral neck bone mineral density.

Conclusions: Men with SCI had lower femoral neck and total hip T-score than community-dwelling men, independent of age, BMI, and other covariates.

Health sciences/Endocrinology/Endocrine system and metabolic diseases/Metabolic bone disease/Osteoporosis

Health sciences/Risk factors

Health sciences/Diseases/Neurological disorders/Spinal cord diseases

Spinal cord injury (SCI) may cause motor or sensory somatic dysfunction, leading to immobilization of the involved body part and decreased physical activity ¹. SCI alters bone metabolism homeostasis and increases bone resorption, leading to sublesional bone loss ². Bone loss in individuals with SCI is important because it increases the fracture risk of the lower limb, and lower limb fractures in SCI have a significant catastrophic correlation with lengthy hospitalization, various skin complications, nonunion, and increased premature mortality ^3-5. Hence, there is a need to identify the extent of bone loss after SCI and the associated risk factors to determine appropriate intervention timing for the prevention of osteoporotic fracture.

Bone resorption in SCI is promoted in the very early stages after SCI, with possibly up to 40% of bone loss within 6 months post-injury, the rate of which is significantly faster than bone loss in non-SCI immobilized conditions ^5,6. Twelve months after the onset of SCI, a certain level of plateau of bone loss tends to be reached, and decreased bone mineral density (BMD) on Dual-energy X-ray Absorptiometry (DXA) becomes prominent during this period ⁷. Since DXA remains the gold standard evaluation tool for SCI-related bone loss, the extent of stabilized bone loss can presumably be evaluated through DXA performed over 1 year after injury.

To date, previous studies have examined serial changes in the BMD of individuals with SCI, but they were confined to only a small number of study participants ^8,9 or were limited to individuals with motor complete SCI ^10,11. There is also a lack of studies that have analyzed clinical risk factors for bone loss in individuals with SCI compared with that in the general population ^12,13, and some of the factors that have already been studied still show mixed results in different reports ¹⁴. Therefore, this study aimed to compare DXA-measured BMD between middle-aged men with SCI and community-dwelling men and to explore the SCI-relevant risk factors for low bone mass.

Ethics statements

Ethical approval was obtained from the National Rehabilitation Center Institutional Review Board (IRB no. NRC-2021-01-011). Informed consent was obtained from all participants involved in the study.

Study populations

Case group: National Rehabilitation Center (NRC) cohort

This study included men diagnosed with SCI who were hospitalized in a rehabilitation program at the National Rehabilitation Center (NRC) from 2008 to 2020. The study participants were adult men aged 40–69 years who had undergone DXA between 12 and 36 months after developing SCI. Among the initial 125 participants, participants with data showing absence of femoral neck BMD or artifacts/outliers (n = 5) and absence of lumbar spine BMD (n = 7) were excluded, and a total of 113 were analyzed in the NRC cohort (Fig. 1).

Control group: Korean National Health and Nutritional Examination Survey

Community-dwelling control data were collected from the Korean National Health and Nutritional Examination Survey (KNHANES). The KNHANES is a nationwide, population-based, cross-sectional survey and health examination conducted by the Korea Centers for Disease Control and Prevention ¹⁵. KNHANES surveys are conducted annually using a rolling sampling design that involves a complex, stratified, multistage, probability cluster survey of the general population of Korea.

Overall, 6631 community-dwelling men aged 40 to 69 years participated in the fifth KNHANES 2008–2011 survey. We excluded men without DXA scan data (n = 2318) and those whose height or weight was missing (n = 9). In total, 4,304 men were included in the analysis and matched 1:1 with the NRC cohort participants using propensity score matching based on age, weight, and height. Finally, data from 226 men (NRC cohort, n = 113; KNHANES cohort, n = 113) were analyzed (Fig. 1).

Measurements of BMD

NRC cohort

All BMD measurements of the lumbar spine, femoral neck, and total hip were performed at the NRC. However, the DXA machine was changed during the study period (GE Lunar, from January 1, 2008 to January 20, 2019; Hologic Inc., from January 21, 2019 to December 31, 2020). Because there are known systemic differences in BMD values among various manufacturers, we used standardization formulas to convert BMD values from the GE Lunar to Hologic Inc. machine. The conversion equations are as follows: lumbar spine, Hologic Inc. BMD = 0.918×GE Lunar BMD–0.038; femoral neck, Hologic Inc. BMD = 0.8638×GE Lunar BMD–0.039; and total hip, Hologic Inc. BMD = 0.971×GE Lunar BMD–0.037 ¹⁶. The coefficients of variation for the lumbar spine, femoral neck, and total hip were all 1% for both the GE Lunar and Hologic Inc. machines.

KNHANES cohort

In the KNHANES cohort, the bone mineral content and BMD at the lumbar spine, femoral neck, and total hip were measured by trained technicians using DXA (DISCOVERY-W fan-beam densitometer; Hologic Inc.). The coefficients of variation for the measurements of the lumbar spine, total hip, and femur neck were 1.9%, 1.8%, and 1.5%, respectively. In both cohorts, the T-score was calculated based on the third National Health and Nutrition Examination Survey using data from young white women as a reference ¹⁷. The primary outcome of this study was the difference in the femoral neck BMD between the NRC and KNHANES cohorts.

Covariates

NRC cohort

Covariates of the NRC cohort were obtained from medical records and included age, height, weight, and medical history (history of hypertension, type 2 diabetes mellitus, and dyslipidemia). Smoking status was categorized as current smoker or nonsmoker. Heavy drinkers were defined as those drinking ³3 drinks per day. SCI-specific factors were as follows: duration since injury, cause of injury (traumatic or non-traumatic), American Spinal Injury Association Impairment Scale (AIS) (AIS-A, B classified as motor complete injury and AIS-C, D classified as motor incomplete injury) ¹⁸, and neurological level of injury (cervical, thoracic, or lumbar spine). The lower extremity motor score was calculated as the sum of manual muscle testing scores of both lower extremities from L2 to S1. To quantify the mobility of individuals with SCI, we calculated the sum of each item in the mobility indoors and outdoors’ scores of the Korean Spinal Cord Independence Measure III¹⁹. Lower extremity spasticity in both hip flexors and extensors, knee flexors and extensors, and ankle dorsiflexors and plantar flexors was measured using the Modified Ashworth Scale (MAS) ²⁰. To calculate the sum of all 6 sites measured in this study, MAS 0 was scored as 0, MAS 1 as 1, MAS 1+ as 2, MAS 2 as 3, MAS 3 as 4, and MAS 4 as 5. Skeletal muscle mass and body fat percentage were estimated in a subset of participants via a bioelectrical impedance analysis (BIA) measurement using an eight-point tactile electrode multifrequency BIA device according to the manufacturer's instructions (InBody S10 device). During the test, clip-shaped electrodes were placed on the thumb and third finger of both hands and on both ankles with the participant in the supine position. Body fat percentage was calculated by dividing the amount of body fat by total body weight.

KNHANES cohort

Covariates of the KNHANES, including anthropometrics factors, medical history, smoking and alcohol histories were collected using standardized health questionnaires ²¹. Smoking status was categorized as current smoker or nonsmoker. Heavy drinkers were defined as those drinking ³3 drinks per day. Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or the use of antihypertensive medications. Diabetes mellitus (DM) was considered present if the fasting glucose level was ≥126 mg/dL or if the participant was taking oral hypoglycemic agents or insulin.

Statistical analysis

Data are presented as mean ± standard deviation or median [interquartile range] for continuous variables and as numerical value (%) for categorical variables. The independent two-sample t-test, Wilcoxon rank-sum test, and χ² test were used to compare the baseline characteristics of the study populations as appropriate.

We performed propensity score matching between the NRC and KNHANES cohorts using the nearest-neighbor algorithm within a specified caliper width (0.2 of the standard deviation of the logit of the propensity score) on a 1:1 basis, without replacement. The propensity score was calculated based on age, weight, and height. Covariate balance was assessed using a standardized bias with a threshold of 20%. Differences in the BMD between the NRC and KNHANES cohorts were compared using the independent two-sample t-test and nonlinear modeling with a local polynomial curve. The independent effect of SCI on BMD changes was estimated using multivariable linear regression analysis. In the NRC cohort, linear logistic regression was used to evaluate the risk factors associated with low bone mass. In participants with BIA results, linear logistic regression analysis was performed to evaluate the effect of body composition on the bone.

Statistical analyses were performed using STATA 14.1 (Stata Corp., College Station, TX, USA). Statistical significance was set at P<0.05.

General characteristics of the NRC cohort and difference with the KNHANES cohort

The baseline characteristics of the NRC and KNHANES cohorts are presented in Table 1 and Supplementary Table 1. The mean age (SD) was 52.1 (8.3) years, and mean BMI (SD) was 22.9 (2.7) kg/m²; these variables did not differ between the two cohorts. Femoral neck and total hip T-scores showed significant differences between the two cohorts (-1.9 ± 0.9 versus [vs.] -0.6 ± 1.0, p <0.001 and -1.6 ± 1.1 vs. 0.1 ± 1.0, p <0.001, respectively), but the lumbar spine scores did not show a significant difference (-1.1 ± 1.0 vs. -0.8 ± 1.3, p = 0.105) (Table 1). The difference between the two cohorts was presented in a local polynomial smooth curve (Fig. 2).

BMD difference between men with SCI and the age-matched general population

Multivariable linear regression analysis was conducted to evaluate significant differences in BMD between the two groups. The femoral neck T-score was significantly lower in the NRC cohort than in the KNHANES cohort (adjusted β: -1.27, 95% confidence interval [CI], -1.51 - -1.02, p <0.001), even after adjusting for age, BMI, alcohol intake, smoking status, hypertension, and type 2 DM (Table 2). Older age (adjusted β: −0.02 per 1 year older, p = 0.007) and lower BMI (adjusted β: -0.06, per 1 kg/m² decrease, p = 0.016) were independent predictors of bone loss in both cohorts. The total hip T-score was also significantly low in the NRC cohort than in the KNHANES cohort (adjusted β: -1.58, 95% CI, -1.87 - -1.31, p <0.001) (Supplementary Table S2), but there was no significant difference between the two cohorts in the lumbar spine T-scores (adjusted β: -0.18 vs. KNHANES, 95% CI, -0.48 - 0.12) (data not shown).

Association of risk factors with the femoral neck T-score among men with SCI

In the NRC cohort, lower BMI (adjusted β: -0.08, per 1 kg/m2 increase, p = 0.015) and cervical level of injury (adjusted β: -0.35 vs. SCI at the thoracolumbar level of injury, p = 0.045) were associated with higher bone loss in the femoral neck after adjustment for age, BMI, duration since injury, and complete motor injury (Table 3). In addition, a lower BMI was also significantly associated with higher bone loss in total hip and lumbar spine (adjusted β: -0.13, per 1 kg/m² decrease, p = 0.001 and adjusted β: -0.11, per 1 kg/m² decrease, p = 0.003, respectively) (data not shown).

BIA data were available for 32 men in the NRC cohort. When age, BMI, skeletal muscle mass, and body fat percentage were adjusted, the body fat percentage was associated with lower femoral neck T-score (adjusted β: -0.07, per 1% increase, p <0.001) and lower total hip T-score (adjusted β: -0.05, per 1% increase, p = 0.014) (Supplementary Table 3).

This study analyzed the degree of bone loss and the relevant risk factors for bone loss after SCI with the BMD middle-aged male SCI compared to community-dwelling healthy male adults. Overall, femoral neck and total hip T-scores in the SCI group were more than − 1.3 lower than those in the general population group. After adjustment for age, duration since injury, and motor completeness, lower BMI and cervical level of injury compared to thoracolumbar level were associated with significant bone loss.

The overall femoral neck and total hip T-scores in men with SCI were − 1.3 and − 1.7 lower, respectively, compared with those in community-dwelling adults. Since every 1.0 reduction of the T-score reflects a 1.6–1.7 times increase in fragility fracture risk of the vertebra and both upper and lower limbs ²², the male SCI population in their first to third years of injury should be regarded as a high fracture risk group, thus increasing awareness for earlier intervention and management to prevent fragility fracture. Vestergaard et al. previously demonstrated that the crude fracture rate of individuals with SCI was 2% per year, which was 2 times higher than that of controls, with an exceedingly higher rate of low-energy fractures ²³. In another study of men with paraplegic SCI, Zehnder et al. found that the overall fragility fracture incidence of the lower limb was 1% during the first year after injury, and the mean yearly incidence of fracture significantly increased with time ²⁴. However, lumbar spine T-score did not show any significant difference between two groups in our findings. This site-related bone loss discrepancy in men with SCI is consistent with the outcomes of earlier studies, in which the BMD of the lumbar spine was relatively preserved compared to that of the hip or femur ^25,26. The continuous weight-supporting function of the vertebrae is thought to partly contribute to this phenomenon, together with the effect of degenerative changes ²⁷. Understanding these regional differences in the severity of bone loss, first-line preventive pharmacologic agents for the SCI population should consider primarily targeting lower limb fracture. Based on current evidence, various bisphosphonates, including oral etidronate and intravenous zoledronate, have shown efficacy in slowing BMD decline in the hip and knee region ^28–31. Nevertheless, no definite pharmacologic guidelines for reducing the actual fracture risk in SCI have been set ^32,33, and further research should propose enhanced evidence-based preventative measures in which the fracture itself is an endpoint.

In this study, lower BMI was associated with significant bone loss in the femoral neck, total hip, and lumbar spine in men with SCI. This finding corresponds with results of previous reports proposing a low BMI as a lower extremity fragility fracture risk factor after SCI ^34–36. This finding is also in agreement with existing knowledge established in the general population without SCI ³⁷. Additionally, our study showed that the higher the body fat percentage the lower the femoral neck and total hip T-scores, indicating a possible impact of body composition on BMD. In some previous reports, the tendency of increasing body fat composition in individuals with SCI has been demonstrated, and Pelletier et al. recently showed that 57% of individuals with SCI were sarcopenic and 42% were diagnosed with sarcopenic obesity ^38–40. In the non-SCI population, a systematic review and meta-analysis proposed that elderly individuals with sarcopenic obesity had lower femoral neck BMD and were prone to falls compared with individuals with obesity, sarcopenia, or neither conditions ⁴¹. Our findings suggest that sarcopenic obesity might be one of the major causes of osteoporotic fractures, which merits further validation. Furthermore, to decrease adiposity or improve body composition in the SCI population, a few pilot studies advocated the combination of routine exercise training and dietary modification ^42,43.

In the SCI-related factor analysis, individuals with cervical injury had lower femoral neck T-scores than those with thoracolumbar injury. Most existing studies comparing the BMD of paraplegics and tetraplegics have reported no meaningful relationship between the level of injury and bone loss, but the majority failed to consider the effect of other possible related factors other than the level of injury, e.g., completeness of injury or ambulatory capacity ^14,44,45. Our study differed from previous studies in that the analysis was adjusted for motor completeness, age, BMI, duration since injury, and motor completeness which confers further evidence of the importance of our outcome. The low femoral neck BMD found in higher levels of SCI may result from relative deprivation of lower extremity mechanical loading, such as difficulty in standing up or ambulating, which requires assistive support using the upper extremities.

This study has several limitations. First, the DXA equipment for measuring bone mineral density changed from the GE Lunar machine to the Hologic Inc. machine during the study period. To minimize inter-device error, we converted all BMD values measured by the GE Lunar machine into Hologic Inc. values using a standardization equation formula. Based on the converted BMD value, the T-score was calculated based on that of the white women in the KNHANES III. Second, the study population included only male individuals with SCI. However, the incidence of SCI is several times higher in men than in women ⁴⁶, and excluding women when interpreting bone loss enabled us to isolate menopausal effects of female sex hormones. Finally, according to the International Society for Clinical Densitometry official position statement, the recommended measurement sites for BMD are the total hip, distal femur, and proximal tibia, but the BMD value in the current study was only accessible for the total hip and femoral neck. This study showed significant BMD loss at the femoral neck and total hip in the SCI group, which merits further contextual investigation regarding other recommended measurement sites.

In conclusion, middle-aged men with SCI had significantly lower femoral neck and total hip T-score than community-dwelling men, independent of age, BMI, and other covariates in our study. Additionally, since a low BMI and cervical level of injury in SCI were associated with higher bone loss in the femoral neck BMD, prompt screening tests and careful attention to prevent early fragility fractures should be emphasized in individuals with SCI with high-risk factors.

Data Availability Statement

The data analyzed during this study can be found within the published article and its supplementary files. Additional data are available from the corresponding author on reasonable request.

Acknowledgements

This study was assisted by a grant (NRCRSP-21TB03, NRCRSP-22TB04) by the Korea National Rehabilitation Center.

Author Contributions

SS was responsible for study design, data review, interpreting results, and writing report. SH was responsible for analyzing data, interpreting results, and writing report. OK and NH contributed to study design and feedback of the report.

Fundings

This study was funded by a grant (NRCRSP-21TB03, NRCRSP-22TB04) by the Korea National Rehabilitation Center.

Ethical Approval

Ethical approval was obtained from the National Rehabilitation Center Institutional Review Board (IRB no. NRC-2021-01-011).

Competing Interests

No potential conflict of interest relevant to this article was reported.

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Table 1. General characteristics of men with SCI and their community-dwelling matched control
	NRC cohort (n=113)	KNHANES cohort (n=113)	P-value
Age (years)	52.4 ± 7.3	51.9 ± 9.1	0.619
Body mass index (kg/m²)	22.7 ± 2.6	23.0 ± 2.7	0.440
Heavy drinker, n (%)	23 (20.3%)	12 (10.1%)	0.043
Current smoker, n (%)	23 (20.3%)	21 (18.6%)	0.737
Hypertension, n (%)	26 (23%)	19 (16.8%)	0.244
Type 2 diabetes mellitus, n (%)	17 (15%)	6 (5.3%)	0.016
Lumbar T-score	-1.1 ± 1.0	-0.8 ± 1.3	0.105
Femoral neck T-score	-1.9 ± 0.9	-0.6 ± 1.0	<0.001
Hip T-score	-1.6 ± 1.1	0.1 ± 1.0	<0.001
Osteoporosis,* n (%)	38 (34%)	13 (12%)	<0.001

The results are expressed as the number of participants (column percentage) for categorical variables and as average±standard deviation.

* Osteoporosis was defined as £-2.5 SDs (T-score ≤-2.5 SD) of any lumbar spine, femoral neck, and total hip BMD.

SD, standard deviation; SCI, spinal cord injury; NRC, National Rehabilitation Center; KNHANES, Korean National Health and Nutritional Examination Survey; BMD, bone mineral density.

Table 2. Effects of spinal cord injury on femoral neck bone mineral density
	Univariate model		Multivariable model
Variable	Unadjusted β (95% CI)	P-value	Adjusted β (95% CI)	P-value
Men with SCI (vs. community-dwelling controls)	-1.31 (-1.55 to -1.07)	< 0.001	-1.27 (-1.50 to -1.02)	<0.001
Age (per 1 year older)	-0.03 (-0.05 to -0.01)	0.002	-0.02 (-0.37 to -0.01)	0.007
Body mass index (per 1 kg/m² decrease)	-0.07 (-0.12 to -0.01)	0.015	-0.06 (-0.11 to -0.01)	0.016
Heavy drinker (vs. social, non-drinker)	-0.25 (-0.66 to 0.16)	0.234	-0.05 (-0.38 to 0.29)	0.790
Current smoker (vs. nonsmoker)	-0.03 (-0.41 to 0.34)	0.863	0.02 (-0.28 to 0.32)	0.886
Hypertension (vs. non-hypertension)	-0.37 ( -0.74 to 0.00)	0.051	-0.22 (-0.55 to 0.11)	0.199
Type 2 diabetes mellitus (vs. non-type 2 diabetes mellitus)	-0.40 ( -0.89 to 0.09)	0.109	0.02 (-0.38 to 0.43)	0.899

vs., versus; CI, confidence interval; SCI, spinal cord injury; BMI, bone mass index.

Table 3. Association of risk factors with the femoral neck T-score among men with spinal cord injury
	Univariate model		Multivariable model
Variable	Unadjusted β (95% CI)	P-value	Adjusted β (95% CI)	P-value
Age (per 1 year older)	-0.03 (-0.05 to -0.01)	0.002	-0.01 (-0.04 to 0.00)	0.081
Body mass index (per 1 kg/m² decrease)	-0.07 (-0.12 to -0.01)	0.015	-0.08 (-0.13 to -0.01)		0.031
Duration since injury (per 1 months longer)	0.01 (-0.02 to 0.04)	0.499	0.01 (-0.02 to 0.04)		0.440
Neurological level of injury (Cervical vs. thoracolumbar level)	-0.34 (-0.69 to 0.01)	0.054	-0.35 (-0.69 to -0.01)		0.045
Motor completeness (AIS A, B vs. AIS C, D)	0.06 (-0.27 to 0.38)	0.728	-0.09 (-0.41 to 0.23)		0.569

vs., versus; CI, confidence interval; AIS, American Spinal Injury Association Impairment Scale

There is no duality of interest

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Comparison of Bone Loss and Associated Risk Factors in Men with Spinal Cord Injury and Community-dwelling Adults

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Discussion

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