Risk of Sarcopenia and Osteoporosis in Male Tuberculosis Survivors: Korea National Health and Nutrition Examination Survey

Short-term prospective studies have suggested that pulmonary tuberculosis (TB) preludes permanent loss of lean tissue and fat mass even when TB treatment is effective. The aim of this study was to estimate the risk of sarcopenia and osteoporosis among Korean male TB survivors. Data of the population-based, Korea National Health and Nutrition Examination Survey (KNHANES) (2008–2011) were analyzed, including 3,228 males aged 50 years or older who underwent chest X-ray (CXR) and dual-energy x-ray absorptiometry (DEXA). TB survivors having both medical history and TB scars on CXR had increased risk of sarcopenia (odds ratio [OR] 3.44, 95% confidence interval [CI] 1.79–6.68) and osteoporosis (OR 1.75, 95% CI 1.04–2.95) after adjusting for age, height, smoking, alcohol, physical activity, serum 25-hydroxyvitamin D, parathyroid hormone level, education, and fat mass index. Having TB scars on CXR without medical history of TB was an independent risk factor of sarcopenia (OR 2.05, 95% CI 1.05–4.00), but not a risk factor of osteoporosis. Sarcopenia and low bone mineral density are prevalent in pulmonary TB survivors with TB scars on CXR. Medical history of TB with TB scars on CXR is an independent risk factor for sarcopenia and osteoporosis.

Body composition values and BMD. Appendicular skeletal muscle mass (ASM) (P < 0.001, P for trend <0.001) and appendicular skeletal muscle mass index (ASMI) (P < 0.001, P for trend <0.001) tended to be lower in the following order: those with no evidence of TB or only a history of TB> those with only TB scars on CXR> those with both a history and TB scars on CXR. The proportion of subjects with presarcopenia and sarcopenia were higher (P < 0.001) in subjects with pulmonary TB scars on CXR compared to that of subjects without pulmonary TB scars on CXR. The proportions of sarcopenia (<2 standard deviation [SD]) for subjects without evidence of TB, with only a history of TB, with only TB scars on CXR, and with both a history and TB scars on CXR were 3.1%, 6.6%, 11.0%, and 14.5%, respectively (Table 2).
T scores of femur (P < 0.001, P for trend <0.001), femur neck (P < 0.001, P for trend <0.001), and lumbar spine (P < 0.001, P for trend <0.001) were lower in the following order: those with no evidence of TB or only a history of TB> those with only TB scars on CXR> those with both a history and TB scars on CXR. Proportions of osteoporosis for subjects without evidence of TB, with only a history of TB, with only TB scars on CXR, and with both a history and TB scars on CXR were 5.9%, 6.8%, 13.5%, and 14.6%, respectively ( Table 2). Proportions of osteopenia/osteoporosis at femur neck and lumbar spine were higher in subjects with pulmonary TB scars on CXR compared to those of subjects without pulmonary TB scars on CXR ( Fig. 2; P < 0.001 and P < 0.001, respectively).   (Table 4). ASMI values were positively correlated with T scores at femur, femur neck, and lumbar spine after adjustment for age. This positive association was more prominent in TB survivors compared to that in subjects without evidence of TB at femur, femur neck, or lumbar spine: at femur, R = 0.3732, P < 0.001 vs. R = 0.2036, P < 0.001; at femur neck, R = 0.3521, P < 0.001 vs. R = 0.1803, P < 0.001; at lumbar spine, R = 0.1110, P < 0.001 vs. R = 0.0553, P < 0.001 (Fig. 3). Proportions of subjects with overlapping low BMD and sarcopenia (<1 SD) for those without evidence of TB, those with only a history of TB, those with only TB scars on CXR, and those with both a history of TB and TB scars on CXR were 15.8%, 19.6%, 36.6%, and 45.0%, respectively (Fig. 4).

Discussion
In this national representative Korean population study of males who were 50 years of age or older, subjects with both a medical history and TB scars on their CXR had increased risk of sarcopenia (OR 3.44, 95% CI 1.79-6.68) and osteoporosis (OR 1.75, 95% CI 1.04-2.95) after adjusting for confounding factors. Having TB scars on CXR without medical history of TB was an independent risk factor of sarcopenia (OR 2.05, 95% CI 1.05-4.00). However, it was not a risk factor of osteoporosis. TB survivors without TB scars on CXR did not have an increased risk of sarcopenia or osteoporosis. These results differ from the impact of pulmonary TB on respiratory function. It has been reported that subjects having only a history of pulmonary TB without TB scars on CXR have lower pulmonary function and higher proportion of air flow obstruction than subjects without evidence of TB 14 .
Age-related osteoporosis in men is typically seen in those over 70 years of age. Male osteoporosis remains underdiagnosed and undertreated 15 . However, about 25% of men over 50 years of age will develop at least one osteoporosis-related fracture in their lifetime. Compared to women, men have a higher rate of mortality within one year after hip fracture 16 . BMD values are only surrogate markers for fracture risk. They do not fully predict future fractures 17 . Falls and poor neuromuscular function are risk factors of osteoporosis-related fractures in men independent of BMD 18,19 . Sarcopenia is an important risk for falling 20,21 and physical disability 22,23 . It is also considered a risk factor for low BMD [24][25][26] . Men having both low BMD and sarcopenia reportedly have a four times higher risk of fractures than men with normal BMD without sarcopenia 27 . In the present study, the proportion of those with overlapping low BMD and sarcopenia was 45.0% in subjects with both a medical history and TB scars on CXR. These subjects might have increased risk of osteoporosis-related fracture. The present findings are consistent with results of recent retrospective cohort studies in Taiwan. In these studies, frequently hospitalized patients with pulmonary TB have higher rates of new onset osteoporosis 28 and osteoporotic fracture 28,29 than matched cohorts. Past history of active TB has been found to be an independent risk factor for incident osteoporosis and osteoporotic fracture 28 . Pathogenesis of sarcopenia or osteoporosis in TB survivors is currently unknown. Mycobacterium tuberculosis infection can lead to a wide range of clinical manifestations ranging from asymptomatic infection to death. Only 10% of individuals exposed to M. tuberculosis will develop active disease, indicating that host immune response is an important factor. As a marker of under-nutrition, low BMI is the most obvious host factor for TB infection. It can increase the risk of active infection 3 , disease severity, clinical outcomes 4-7 , and death from pulmonary TB 8 . Low BMI is also a well-known risk factor for sarcopenia and low BMD. Low BMI may be an innate host trait associated with TB infection. It might increase the risk of sarcopenia and low BMD later in life. TB is a wasting disease. Most patients gain weight during treatment. However, short-term prospective studies on changes of body composition after treatment suggest that TB can lead to permanent loss of lean tissue and fat mass [11][12][13] . The destructive nature of pulmonary TB may induce chronic lung impairment even if TB treatment is effective 30,31 .   In one study, subjects with both medical history and TB lesions on CXR have a 4.5-times higher risk for chronic obstructive pulmonary disease (COPD) and 2.7-times increased risk for restriction dysfunction compared to subjects without evidence of TB 14 . Osteoporosis and sarcopenia are frequently found in patients with COPD 32 . Physical inactivity, increased levels of systemic inflammation, hypoxia, poor nutrition, and use of corticosteroids have been implicated as major contributing factors 33 . Vitamin D deficiency is a risk factor of active TB and a sustained risk factor for TB recurrence even after recovery from active TB infection 34,35 . Vitamin D deficiency and compensatory rise in PTH may influence the pathogenesis of increased osteoporosis risk in patients with TB. In this study, serum level of 25(OH)D and PTH were not significantly different between TB survivors and subjects without evidence of TB. Information concerning supplementary vitamin D intake of participants was unavailable in the Korea National Health and Nutrition Examination Survey (KNHANES). A prospective study is needed to confirm this finding. The present study does have several limitations. First, this was a cross-sectional study. It was impossible to determine a causal relationship. Second, sarcopenia was defined solely by low skeletal muscle mass. Muscle strength or physical performance was not considered in sarcopenia evaluation 36 . Third, information on the use of drugs was unavailable, making it difficult to estimate the possible influence of drugs on BMD. Fourth, TB is a deadly infectious disease with increased mortality. Therefore, the risk of sarcopenia and osteoporosis could be underestimated in TB survivors. Fifth, the prevalence of pulmonary TB survivors could lead to misclassification because it was based on participant' report of their physician's diagnosis or TB scars on CXR. However, the Korean national TB surveillance system has been ongoing since 1965. It is likely that physician's diagnosis is fairly accurate compared to that in other countries. Further prospective and longitudinal studies where the diagnosis of TB is based on objective criteria are needed to confirm our findings.
Despite adequate anti-TB treatment, TB survivors had significant loss of predicted longevity compared to a similar group without history of active TB 37 . Post-TB respiratory impairment is a well-known cause of increased morbidity and mortality. Our findings suggest that sarcopenia and osteoporosis are also causes of higher morbidity and mortality burdens following TB.
In this study, TB survivors without TB scars did not have increased risk of sarcopenia or low BMD. Early detection and complete cure of pulmonary TB could reduce the risk of musculoskeletal sequelae in TB survivors. During and after TB treatment, efforts geared toward prevention of sarcopenia and osteoporosis are needed. For TB survivors with risk factors, early detection and treatment for sarcopenia and osteoporosis are also warranted to prevent the occurrence of osteoporotic fractures and fragility.  Table 4. Odds ratios (OR) of low BMD and osteoporosis among TB survivors by evidence of prior pulmonary TB (n = 3,228). Model 1: adjusted for age and height. Model 2: as Model 1, with additional adjustment for smoking, alcohol, activity, 25(OH)D, PTH, and education. Model 3: as Model 2, with additional adjustment for FMI. BMD, bone mineral density; CXR, chest x-ray; Hx, history of physician diagnosis; TB, tuberculosis; Hx (+)/CXR (−), subjects with a history of TB without TB scars on CXR; Hx (−)/CXR (+), subjects with TB scars on CXR without a history of TB; Hx (+)/CXR (+), subjects having both a history of TB and TB scars on CXR.

Low BMD Osteoporosis
In conclusion, sarcopenia and low BMD are prevalent in pulmonary TB survivors with TB scars on CXR. Medical history of TB with TB scars on CXR is an independent risk factor for sarcopenia and osteoporosis.

Materials and Methods
Study population and data collection. This study was based on data obtained from the KNHANES between 2008 and 2011. KNHANES is a population-based, cross-sectional, and nationally representative survey designed to examine the health and nutritional status of civilian non-institutionalized population of the Republic of Korea. KNHANES followed a multi-stage cluster probability sampling design to ensure independent and homogenous sampling for each year as well as nationally representative sampling. Among 5,872 male subjects aged 50 years or older, a total of 3,228 participants who underwent CXR and DEXA were identified. Subjects who had active TB (n = 29), who did not receive DEXA (n = 1,196), who had no CXR data (n = 1,186), non-responders to health questionnaires (n = 76), and those who had no data for BMI or PTH level (n = 157) were excluded (Fig. 1)   an examination vehicle. Two radiologists independently interpreted CXR results for the presence of lung disease. Individual readings were compared weekly and CXR results demonstrating TB related lesions were re-interpreted by six radiology specialists to confirm the results.
TB survivors were defined as those with a self-reported history of physician-diagnosed TB or TB lesions on CXR. They were categorized into the following TB subgroups: 1) those with history of TB but had no TB scars on CXR, 2) those had TB scars on CXR without a history of TB, and 3) those had both a history of TB and TB scars on CXR.
DEXA and definitions of sarcopenia and low BMD. Body composition was analyzed with DEXA using a Discovery fan beam densitometer (Hologic Inc., Bedford, MA, USA). ASM was calculated as the sum of skeletal muscle in arms and legs. ASMI was defined as ASM divided by the square of height. Sarcopenia and presarcopenia were defined according to the presence of ASMI values that were <2 SD and between 1 and 2 SD, respectively, below the mean value of a young male reference group aged 20-39 years. Calculated ASMI cut-off values for sarcopenia were 6.96 kg/m 2 for 1 SD and 6.06 kg/m 2 for 2 SD, respectively. Subjects with presarcopenia or sarcopenia were collectively termed 'sarcopenia <1 SD' . FMI was calculated as the sum of whole body fat divided by the square of height.
Osteoporosis, osteopenia, and normal BMD were identified according to the lowest T-score of femur, femur neck, and lumbar spine. They were defined according to the World Health Organization criteria: osteoporosis, T-score ≤−2.5; osteopenia, T-score between −2.5 and −1; and normal BMD. T-score >−1 38 . Subjects with either osteoporosis or osteopenia were collectively termed 'low BMD' .
Lifestyle and biochemical variables. Demographics, personal medical history, and lifestyle behaviors such as cigarette smoking, alcohol consumption, and physical activity of participants were collected from standardized health questionnaires. Smoking was defined as lifetime smoking of more than 100 cigarettes, including both current and past smoking. Regular exercise was defined as engaging in moderate or vigorous exercise on a regular basis (at least three times per week, 20 min each time). Regular alcohol dinking was defined as more than once every month in the last year. Household income was categorized according to quartile of total income of each member in the household.
Collected blood samples were analyzed within 24 hours after transportation in a central laboratory. Level of 25(OH)D was measured by radioimmunoassay (DiaSorin, Stillwater, MN) using a Wizard model 1470 gamma counter (PerkinElmer, Finland). Plasma PTH was measured by N-tact PTH assay using LIAISON chemiluminescence immunoassay system (DiaSorin, Stillwater, MN, USA).

Statistical analyses.
To produce an unbiased national estimate, a sample weight was assigned for participating individuals in order to represent the Korean population. Sampling weights were constructed to account for the complex survey design, survey non-response, and post-stratification. Continuous variables were expressed as means with standard errors while categorical variables were presented as cases per category and frequency of responses. Baseline characteristics, body composition values, and BMD of participants based on historical or radiographic evidence of pulmonary TB were analyzed by analysis of variance (ANOVA) or Chi-square test. The association of different groups for sarcopenia or low BMD was modeled by logistic regression after adjusting for age, height, smoking, alcohol, physical activity, 25(OH) D level, PTH level, education, and FMI. P for trend was calculated by assigning the mean of body composition values and odds ratio of distinct TB evidence groups as continuous variables. Age adjusted linear regression analysis and scatter plot analysis were performed between ASMI and T scores at femur, femur neck, and lumbar spine. All statistical analyses were performed with SAS version 9.4 (SAS Institute, Cary, NC, USA) and a value of P < 0.05 was considered statistical significance. Data Availability. This study was based on data obtained from KNHANES between 2008 and 2011. The datasets are available from the official website of KNHANES: https://knhanes.cdc.go.kr/knhanes/main.do. English-language information is available via. https://knhanes.cdc.go.kr/knhanes/eng/index.do.